Oncology Research 25(9) Abstracts

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Oncology Research, Vol. 25, pp. 1421-1430, 2017
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DOI: https://doi.org/10.3727/096504016X14826089198805
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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MicroRNA-133b Inhibits Cell Proliferation and Invasion in Osteosarcoma by Targeting Sirt1

Shi Ying,* Huang Jianjun,† Yi Xue,* Yu Shuwei,* Zhang Liyuan,* Wang Jie,* and Cheng Lixian*

*Department of Pathology, Xiamen Medical College, Xiamen, Fujian, P.R. China
†Department of Orthopedics, Xiamen HaiCang Hospital, Xiamen, Fujian, P.R. China

MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs for translational repression or degradation. In this study, we showed that the miR-133b expression level was decreased while the Sirt1 mRNA expression level was increased in osteosarcoma tissue and cell lines. A low expression of miR-133b was significantly associated with tumor size, distant metastasis, and advanced clinical stage. In addition, osteosarcoma patients with a low miR-133b expression showed a worse prognosis when compared to those with a high level of miR-133b expression. Thus, we identified Sirt1 as a novel direct target of miR-133b. Overexpression of miR-133b suppressed Sirt1 expression and attenuated cell proliferation and invasion. Forced expression of Sirt1 could partly rescue the inhibitory effect of miR-133b in osteosarcoma cells. Our finding also suggested that the inhibitory effects of the miR-133b/Sirt1 axis on osteosarcoma progression were involved in the Wnt/β-catenin pathway. Taken together, these findings will shed light on the role and mechanism of miR-133b in regulating osteosarcoma cell growth via the miR-133b/Sirt1 axis, and miR-133b may serve as a potential therapeutic target in osteosarcoma in the future.

Key words: miR-133b; Sirt1; Osteosarcoma; Proliferation; Invasion

Address correspondence to Professor Shi Ying, Department of Pathology, Xiamen Medical College, No. 1999 Guankou Road, Xiamen, 361023 Fujian, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1431-1440, 2017
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DOI: https://doi.org/10.3727/096504017X14835311718295
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Cyclin-Dependent Kinase Inhibitor 3 Promotes Cancer Cell Proliferation and Tumorigenesis in Nasopharyngeal Carcinoma by Targeting p27

Huimin Wang,* Hexin Chen,† Hang Zhou,* Wenfa Yu,* and Zhenmin Lu*

*Department of Otolaryngology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, P.R. China
†Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China

Nasopharyngeal carcinoma (NPC) is a common malignancy of the head and neck that arises from the nasopharynx epithelium and is highly invasive. Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the dual-specificity protein phosphatase family, which plays a key role in regulating cell division. Abnormal expression of CDKN3 has been found in numerous types of cancer. In the current study, we explored the possible role of CDKN3 in cell proliferation, ability to invade, and radiosensitivity in NPC cells. We reported that CDKN3 was upregulated and p27 was downregulated in NPC tissues and is associated with a worse prognosis for patients. In addition, downregulation of CDKN3 and upregulation of p27 decreased cell proliferation, induced cell cycle arrest, increased apoptosis, decreased cell invasion, and enhanced radiosensitivity. Silencing of p27 significantly inhibited the effects of the knockdown of CDKN3. Moreover, downregulation of CDKN3 and upregulation of p27 inhibited the increase in tumor volume and weight in implanted tumors, decreased the phosphorylation of Akt, and increased the expression of cleaved caspase 3 in tumors. CDKN3 expression was also inversely correlated with p27 expression in NPC patients. Knockdown of CDKN3 increased p27 expression. Silencing of p27 markedly inhibited the effects of CDKN3 on cell proliferation, cell cycle progression, apoptosis, invasion, and radiosensitivity. These results demonstrate that upregulation of p27 is involved in the knockdown of CDKN3-induced decrease in cell proliferation, increase in cell cycle arrest and apoptosis, decrease in invasion, and increase in radiosensitivity. The results demonstrate that the CDKN3/p27 axis may be a novel target in the treatment of NPC.

Key words: Nasopharyngeal carcinoma (NPC); Cyclin-dependent kinase inhibitor 3 (CDKN3); p27; Cell proliferation; Radiosensitivity

Address correspondence to Zhenmin Lu, Department of Otolaryngology, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No. 88, Weihui 453100, Henan, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Hexin Chen, Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080 Guangdong, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1441-1451, 2017
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DOI: https://doi.org/10.3727/096504017X14926854178616
E-ISSN 1555-3906
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The Inhibitory Effects of HYDAMTIQ, a Novel PARP Inhibitor, on Growth in Human Tumor Cell Lines With Defective DNA Damage Response Pathways

Enrico Mini,* Ida Landini,* Laura Lucarini,† Andrea Lapucci,* Cristina Napoli,‡ Gabriele Perrone,* Renato Tassi,* Emanuela Masini,† Flavio Moroni,† and Stefania Nobili‡

*Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
†Department of NEUROFARBA, University of Florence, Florence, Italy
‡Department of Health Sciences, University of Florence, Florence, Italy

The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI.

Key words: PARP inhibitors (PARPIs); HYDAMTIQ; 5-Fluorouracil (5-FU); Human tumor cell lines; DNA damage response

Address correspondence to Enrico Mini, Department of Experimental and Clinical Medicine, University of Florence, Viale Pieraccini, 6, 50139 Firenze, Italy. Tel: +39-055-2758368; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Stefania Nobili, Department of Health Sciences, University of Florence, Viale Pieraccini, 6, 50139 Firenze, Italy. Tel: +39-055-2758386; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1453-1462, 2017
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DOI: https://doi.org/10.3727/096504017X14886494526344
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Basic Transcription Factor 3 Is Required for Proliferation and Epithelial–Mesenchymal Transition via Regulation of FOXM1 and JAK2/STAT3 Signaling in Gastric Cancer

De-Zhong Zhang,* Bing-He Chen,* Lan-Fang Zhang,† Ming-Kun Cheng,‡ Xiang-Jie Fang,* and Xin-Jun Wu*

*The Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, P.R. China
†The Department of Gastrointestinal, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, P.R. China
‡ICU, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, P.R. China

Gastric cancer (GC) is the most common epithelial malignancy worldwide. Basic transcription factor 3 (BTF3) plays a crucial role in the regulation of various biological processes. We designed experiments to investigate the molecular mechanism underlying the role of BTF3 in GC cell proliferation and metastasis. We confirmed that BTF3 expression was decreased in GC tissues and several GC cell lines. Lentivirus-mediated downregulation of BTF3 reduced cell proliferation, induced S and G2/M cell cycle arrest, and increased apoptosis. Knockdown of BTF3 significantly reduced the expression of Forkhead box M1 (FOXM1). Upregulation of FOXM1 significantly inhibited the decrease in cell proliferation due to BTF3 silencing, S and G2/M cell cycle arrest, and increase in apoptosis. Knockdown of BTF3 decreased Ki-67 and PCNA expression, whereas it increased p27 expression, which was inhibited by upregulation of FOXM1. Knockdown of BTF3 significantly decreased the ability to invade and migrate. Moreover, knockdown of BTF3 increased E-cadherin expression, whereas it decreased N-cadherin and ZEB2 expression, indicating a decrease in epithelial–mesenchymal transition (EMT). Phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) was significantly inhibited by knockdown of BTF3. IL-6-stimulated phosphorylation of STAT3 and JAK2 markedly suppressed inhibition of EMT due to BTF3 silencing. Silencing of BTF3 decreased tumor volume and weight and reduced peritoneal nodules in implanted tumors. Our findings provide a novel understanding of the mechanism of GC and highlight the important role of BTF3/FOXM1 in tumor growth and BTF3/JAK2/STAT3 in EMT and metastasis.

Key words: Basic transcription factor 3 (BTF3); Gastric cancer (GC); Epithelial–mesenchymal transition (EMT); Forkhead box M1 (FOXM1); Janus kinase 2/signal transducers and activators of transcription

Address correspondence to Xin-Jun Wu, The Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui 453100, Henan, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1463-1470, 2017
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DOI: https://doi.org/10.3727/096504017X14878518291077
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Procaine Inhibits Proliferation and Migration and Promotes Cell Apoptosis in Osteosarcoma Cells by Upregulation of MicroRNA-133b

Boda Ying,* Hong Huang,† Hongfei Li,* Meng Song,* Sizhan Wu,* and Hongliang Ying†

*Norman Bethune Health Science Center of Jilin University, Changchun, P.R. China
†Department of Orthopedics, China–Japan Union Hospital of Jilin University, Changchun, P.R. China

Procaine (PCA) is a conventional chemotherapeutic agent for osteosarcoma. Recent studies have proposed that the growth-inhibitory effect of PCA is through regulation of microRNAs (miRNAs). miR-133b has been proven to be a tumor suppressor in osteosarcoma, but whether it is involved in the antitumor effects of PCA on osteosarcoma has not been investigated. In this study, we aimed to explore the effects of PCA on osteosarcoma MG63 cells by regulation of miR-133b, as well as its underlying mechanisms. MG63 cells were treated with different concentrations of PCA, and cell viability, apoptosis, and miR-133b expression were then detected by MTT, flow cytometry, and qRT-PCR, respectively. Cells were then transfected with the miR-133b inhibitor and treated with 2 μM PCA. Thereafter, cell viability, migration, and apoptosis were detected. Analysis of signaling pathways was detected by Western blot. Our results showed that PCA significantly inhibited cell viability and promoted apoptosis and the expression level of miR-133b in a dose-dependent manner (p < 0.05 or p < 0.01). Moreover, we observed that PCA + miR-133b inhibitor dramatically reversed the effects of PCA on cell viability, apoptosis, and migration (p < 0.05 or p < 0.01). In addition, PCA significantly decreased the levels of p/t-AKT (p308 or p473), p/t-ERK, and p/t-S6, whereas PCA + miR-133b inhibitor rescued these effects. Our results suggest that PCA inhibits proliferation and migration but promotes apoptosis in osteosarcoma cells by upregulation of miR-133b. These effects may be achieved by inactivation of the AKT/ERK pathways.

Key words: Procaine (PCA); Osteosarcoma; Proliferation; Migration; Apoptosis; MicroRNA-133b

Address correspondence to Hongliang Ying, Department of Orthopedics, China–Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun 130033, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1471-1478, 2017
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DOI: https://doi.org/10.3727/096504017X14886689179993
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Long Noncoding RNA MEG3 Suppresses Glioma Cell Proliferation, Migration, and Invasion by Acting as a Competing Endogenous RNA of miR-19a

Nan Qin,*1 Gui-Feng Tong,†1 Li-Wei Sun,‡ and Xiao-Lin Xu†

*Department of Electrophysiology, Tianjin Huan-Hu Hospital, Jin-Nan District, Tianjin, P.R. China
†Department of Neurology, Tianjin Huan-Hu Hospital, Jin-Nan District, Tianjin, P.R. China
‡Department of Oncology, Tianjin Huan-Hu Hospital, Jin-Nan District, Tianjin, P.R. China

Glioma, with varying malignancy grades and histological subtypes, is the most common primary brain tumor in adults. Long noncoding RNAs (lncRNAs) are non-protein-coding transcripts and have been proven to play an important role in tumorigenesis. Our study aims to elucidate the combined effect of lncRNA maternally expressed gene 3 (MEG3) and microRNA-19a (miR-19a) in human glioma U87 and U251 cell lines. Real-time PCR revealed that MEG3 was downregulated and miR-19a was upregulated in malignant glioma tissues and cell lines. Bioinformatics analyses (TargetScan, miRanda, and starBase V2.0) showed that phosphatase and tensin homolog (PTEN) is a target of miR-19a with complementary binding sites in the 3′-UTR. As expected, luciferase results verified the putative target site and also revealed the complementary binding between miR-19a and MEG3. miR-19a represses the expression of PTEN and promotes glioma cell proliferation, migration, and invasion. However, MEG3 could directly bind to miR-19a and effectively act as a competing endogenous RNA (ceRNA) for miR-19a to suppress tumorigenesis. Our study is the first to demonstrate that lncRNAMEG3 suppresses glioma cell proliferation, migration, and invasion by acting as a ceRNA of miR-19a, which provides a novel insight about the pathogenesis of glioma.

Key words: Maternally expressed gene 3 (MEG3); miR-19a; Glioma; Long noncoding RNAs (lncRNAs); Phosphatase and tensin homolog (PTEN); Competing endogenous RNA (ceRNA)

1Nan Qin and Gui-Feng Tong are co-first authors and provided equal contribution to this work.
Address correspondence to Xiao-Lin Xu, M.D., Department of Neurology, Tianjin Huan-Hu Hospital, No. 6 Ji’zhao Road, Jin-Nan District, Tianjin 300350, P.R. China. Tel: +86-022-60367500; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1479-1488, 2017
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DOI: https://doi.org/10.3727/096504017X14886420642823
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Downregulation of Calcium-Binding Protein S100A9 Inhibits Hypopharyngeal Cancer Cell Proliferation and Invasion Ability Through Inactivation of NF-κB Signaling

Ping Wu, Huatao Quan, Jing Kang, Jian He, Shi Luo, Chubo Xie, Jing Xu, Yaoyun Tang, and Suping Zhao

Department of Otorhinolaryngology Head and Neck Surgery, Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha, P.R. China

Hypopharyngeal cancer (HPC) frequently presents at an advanced stage and displays early submucosal spread, resulting in a poor prognosis. It is among the worst of all cancers in the head and neck subsites. Therefore, detection of HPC at an earlier stage would be beneficial to patients. In this study, we used differential in-gel electrophoresis (DIGE) and two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics analysis to identify the potential biomarkers for HPC. Among the differential proteins identified, calcium-binding protein S100A9 was overexpressed in HPC tissues compared with normal adjacent tissues, and S100A9 expression in metastatic tissues and advanced tumor tissues was higher than in nonmetastatic tissues and early tumor tissues. S100A9 expression was further confirmed in a large additional cohort. Our data showed that a higher S100A9 level was associated with a poor prognosis for HPC patients, and this may be an independent factor for predicting their prognosis. In addition, S100A9 protein expression was upregulated in human HPC cell lines compared with normal oral cavity epithelia. Knockdown of S100A9 induced significant inhibition of cell growth and their invasive ability. Mechanically, we found that downregulation of S100A9 significantly reduced the expression of NF-κB, phosphorylation of NF-κB and Bcl-2, as well as the expression of MMP7 and MMP2. Restoration of NF-κBexpression sufficiently reversed the inhibitory effects on cell proliferation and invasion induced by S100A9 downregulation in vitro and in vivo. In conclusion, for the first time, we have identified S100A9 as an independent prognostic factor for HPC. Inhibiting S100A9 expression would be a potential novel diagnostic biomarker and therapeutic target for HPC treatment.

Key words: Hypopharyngeal cancer (HPC); Proteomics analysis; S100A9; Biomarker; NF-κB

Address correspondence to Professor Suping Zhao, Department of Otorhinolaryngology Head and Neck Surgery, Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha 410008, Hunan, P.R. China. Tel: +86-0731-89753045; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Professor Yaoyun Tang, Department of Otorhinolaryngology Head and Neck Surgery, Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha 410008, Hunan, P.R. China. Tel: +86 0731-89753045; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1489-1494, 2017
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DOI: https://doi.org/10.3727/096504017X14897145996933
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Examining the In Vitro Efficacy of the IAP Antagonist Birinapant as a Single Agent or in Combination With Dacarbazine to Induce Melanoma Cell Death

Vesna Vetma,*†‡ Jan Rožanc,§ Emilie M. Charles,*† Christian T. Hellwig,*†‡¶ Leonidas G. Alexopoulos,§# and Markus Rehm*†‡#

*Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
†Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland
‡Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
§ProtATonce Ltd., Athens, Greece
¶Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
#Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece

Antagonists of inhibitors of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumors. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the antitumor efficacy of dacarbazine in vitro, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5,400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression. Surprisingly, functionally relevant synergies or response potentiation in combination treatments was not observed, and only one cell line modestly responded to birinapant single treatment (approximately 16% cell death). Although we did not study the underlying resistance mechanisms or more complex in vivo scenarios in which dacarbazine/birinapant response synergies may still possibly manifest, our findings are nevertheless noteworthy because IAP antagonists were demonstrated to strongly enhance responses to DNA-damaging agents in cell lines of other cancer types under comparable experimental conditions in vitro.

Key words: Melanoma; Birinapant; Dacarbazine; Synergy; Cell death

Address correspondence to Professor Dr. Markus Rehm, Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany. Tel: +49-711-68566988; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1495-1504, 2017
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DOI: https://doi.org/10.3727/096504017X14883287513729
E-ISSN 1555-3906
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Overexpression of T-box Transcription Factor 5 (TBX5) Inhibits Proliferation and Invasion in Non-Small Cell Lung Carcinoma Cells

Ruoting Ma,*† Yu Yang,* Qiuyun Tu,† and Ke Hu‡

*Department of Senile Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
†Department of Senile Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
‡Department of Clinical Medicine, Hunan University of Medicine, Changsha, Hunan, P.R. China

T-box transcription factor 5 (TBX5), a member of the conserved T-box transcription factor family that functions in organogenesis and embryogenesis, has recently been identified as a critical player in cancer development. The aim of this study was to determine the role of TBX5 in non-small cell lung carcinoma (NSCLC). Immunohistochemistry was used to detect the correlation between levels of TBX5 and clinicopathological features of NSCLC patients in tissue microarray. Expression of TBX5 in NSCLC tissues and cell lines was evaluated by quantitative PCR and Western blot. The role of TBX5 in regulating proliferation, colony formation, invasion, and apoptosis of NSCLC cells was evaluated in vitro. Finally, a tumorigenicity assay was performed to determine the effect of TBX5 on tumor growth in vivo. The levels of TBX5 in NSCLC tissues were significantly correlated with the TNM stage (p = 0.016), histopathologic type (p = 0.029), and lymph node status (p = 0.035) of NSCLC. TBX5 overexpression markedly suppressed in vitro NSCLC cell proliferation, colony formation, and invasion and induced apoptosis. In vivo tumor growth was significantly suppressed by TBX5. TBX5 has a tumor-suppressing effect in NSCLC and may serve as a therapeutic target for diagnoses and treatment of NSCLC.

Key words: T-box transcription factor 5 (TBX5); Non-small cell lung carcinoma (NSCLC); Tumor growth; Proliferation; Invasion

Address correspondence to Yu Yang, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, P.R. China. Tel: +86-0731-85294318; Fax: +86-0731-85294318; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1505-1515, 2017
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DOI: https://doi.org/10.3727/096504017X14886485417426
E-ISSN 1555-3906
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MicroRNA-342-3p Inhibits the Proliferation, Migration, and Invasion of Osteosarcoma Cells by Targeting Astrocyte-Elevated Gene-1 (AEG-1)

Shaokun Zhang,* Lidi Liu,* Zhenshan Lv,* Qiao Li,* Weiquan Gong,* and Hong Wu†

*Department of Spine Surgery, The First Hospital of Jilin University, Changchun, P.R. China
†Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, P.R. China

Recent studies suggest that microRNAs (miRNAs) are critical regulators in many types of cancer, including osteosarcoma. miR-342-3p has emerged as an important cancer-related miRNA in several types of cancers. However, the functional significance of miR-342-3p in osteosarcoma is unknown. The aims of this study were to investigate whether miR-342-3p is dysregulated in osteosarcoma and to explore the biological function of miR-342-3p in regulating cellular processes of osteosarcoma cells. We found that miR-342-3p expression was significantly decreased in osteosarcoma tissues and cell lines. Overexpression of miR-342-3p inhibits the proliferation, migration, and invasion of osteosarcoma cells. In contrast, the inhibition of miR-342-3p exhibited the opposite effect. Astrocyte-elevated gene-1 (AEG-1) was identified as one of the target genes of miR-342-3p in osteosarcoma cells by bioinformatics analysis, dual-luciferase reporter assay, real-time quantitative polymerase chain reaction, and Western blot analysis. Overexpression of miR-342-3p also inhibited the Wnt and nuclear factor κB signaling pathways. Moreover, overexpression of AEG-1 partially rescued the inhibitory effects of miR-342-3p mediated on the proliferation, migration, and invasion of osteosarcoma cells. Overall, our results show that miR-342-3p inhibits the proliferation, migration, and invasion of osteosarcoma cells through targeting AEG-1, suggesting a potential target for the development of miRNA-based therapy for osteosarcoma.

Key words: Astrocyte-elevated gene-1 (AEG-1); miR-342-3p; Osteosarcoma; Wnt; Nuclear factor κB (NF-κB)

Address correspondence to Hong Wu, Department of Ophthalmology, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun 130041, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1517-1527, 2017
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DOI: https://doi.org/10.3727/096504017X14859934460780
E-ISSN 1555-3906
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FOXO1–MALAT1–miR-26a-5p Feedback Loop Mediates Proliferation and Migration in Osteosarcoma Cells

Juntao Wang and Guodong Sun

Department of Traditional Chinese Orthopedics and Traumatology, the Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong Province, P.R. China

miR-26a has been found to be downregulated in osteosarcoma (OS) when compared with normal control tissues and has been shown to suppress the malignant behaviors of OS cells. The underlying mechanism, nevertheless, remains unknown. In our study, the long noncoding RNA MALAT1, confirmed to be significantly upregulated in OS, is first shown to be capable of promoting proliferation and migration by directly suppressing miR-26a-5p in OS cells. In addition, we have identified forkhead box O1 (FOXO1) as a transcriptional factor of MALAT1 that can negatively regulate MALAT1. We have shown that MALAT1 promoted growth and migration through inhibiting miR-26a-5p in OS cells. Suppression of FOXO1, identified as a regulatory transcriptional factor of MALAT1, was shown to be able to slow down both proliferation and metastases in OS cells, suggesting that targeting FOXO1 can be useful in the therapy of patients with OS.

Key words: Osteosarcoma (OS); miR-26a-5p; MALAT1; Forkhead box O1 (FOXO1); Metastasis

Address correspondence to Guodong Sun, Department of Traditional Chinese Orthopedics and Traumatology, the Affiliated Hospital of Shandong Academy of Medical Sciences, No. 38 Wuyingshan Road, Jinan, Shandong Province 250031, P.R. China. Tel: 0086-0531-58628811; Fax: 0086-0531-85953187; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1529-1541, 2017
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DOI: https://doi.org/10.3727/096504017X14888987683152
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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UCA1 Regulates the Growth and Metastasis of Pancreatic Cancer by Sponging miR-135a

Xiaobo Zhang,* Feng Gao,* Lei Zhou,* Huaitao Wang,* Gang Shi† and Xiaodong Tan*

*Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Liaoning, P.R. China
†Department of Colorectal Surgery, Liaoning Cancer Hospital, Liaoning, P.R. China

Pancreatic cancer (PC) is a devastating malignant disease with a poor prognosis. This study aimed to investigate the role of urothelial carcinoma associated 1 (UCA1) in the progression of PC. Our results revealed that long noncoding RNA (lncRNA) UCA1 was overexpressed in PC tissues compared with adjacent histologically normal tissues. A downregulated level of UCA1 was also detected in five human PC cell lines (SW1990, BxPC-3, MiaPaCa-2, PANC-1, and CAPAN-1) compared with normal pancreatic duct epithelial HPDE cells. The proliferation of PC cells was inhibited after UCA1 was suppressed by a lentiviral vector. The cell apoptosis rate was largely promoted by downregulating UCA1. Further research revealed that microRNA (miRNA)-135a is a direct target of UCA1. The expression of miR-135a was decreased in PC tissues and cell lines compared with control groups. In addition, the decreased level of miR-135a was elevated by adding miR-135a mimic in SW1990 cells transfected with lncRNA UCA1. Similarly, an upregulated level of miR-135a was downregulated by adding miR-135a inhibitor in SW1990 cells transfected with UCA1 siRNA. Luciferase activity assay further confirmed the targeting relationship between UCA1 and miR-135a. Moreover, miR-135a reversed the effect of UCA1 on cell apoptosis rate and cell viability in SW1990 cells. The migration and invasion capacities of PC cells were suppressed by UCA1. siRNA was then enhanced by the miR-135a inhibitor. In vivo, UCA1 siRNA effectively suppressed tumor growth and the expression of migration markers. Taken together, our research revealed that UCA1 works as an oncogene by targeting miR-135a. The UCA1–miR-135a pathway regulated the growth and metastasis of PC, providing new insight in the treatment of PC.

Key words: Urothelial carcinoma associated 1 (UCA1); miR-135a; Pancreatic cancer (PC); Growth; Metastasis

Address correspondence to Xiaodong Tan, Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning 110004, P.R. China. Tel: 86-18940255168; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1543-1553, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14886444100783
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Inhibition of MMP-2 Expression Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinoma by Suppressing the PI3K/AKT/mTOR Pathway

Wenliang Tan,*†1 Sicong Zhu,*†1 Jun Cao,*† Lei Zhang,*† Wenda Li,*† Kairui Liu,*† Jinyi Zhong,† Changzhen Shang*† and Yajin Chen*†

*Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
†Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

Sorafenib has been globally approved as the standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, the response rate of HCC patients to sorafenib is limited because of tumor recurrence and metastasis. Therefore, seeking combined therapeutic strategies with sorafenib is necessary to improve the antitumor efficiency. Here we demonstrated that expression of MMP-2 is positively correlated with the migration ability of HCC cells. Cells with a higher MMP-2 expression (SK-HEP-1 cells) were less sensitive to sorafenib than those with lower MMP-2 expression (HepG2 cells). Cotreatment of cells with SB-3CT and sorafenib more strongly inhibited migration ability than with sorafenibtreatment alone in both HCC cells with high and low expression of MMP-2. In vivo cell metastasis experiments confirmed the synergistic effects of sorafenib and SB-3CT in reducing lung metastasis of SK-HEP-1 cells. Mechanistically, we showed that the synergistic antitumor effect may be attributed to inhibition of the PI3K/AKT/mTOR signaling pathway, but not the RAF/MEK/ERK signaling pathway. With these results taken together, the current study demonstrates that inhibiting MMP-2 expression can enhance the antitumor effect of sorafenib in HCC cells with a high MMP-2 expression, which may provide a novel strategy to improve therapeutic efficiency in HCC.

Key words: Hepatocellular carcinoma (HCC); Sorafenib; Matrix metalloproteinase-2 (MMP-2); SB-3CT; PI3K/AKT/mTOR pathway

1These authors provided equal contribution to this work.
Address correspondence to Changzhen Shang, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, No. 107 Yanjian West Road, Yuexiu District, Guangzhou, Guangdong 510120, P.R. China. Tel: +86-20-3407-0701; Fax: +86-20-3407-1091; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Yajin Chen, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Guangzhou 510120, P.R. China. Tel: +86-20-3407-0701; Fax: +86-20-3407-1091; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1555-1566, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14897158009178
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Knockdown of E2F3 Inhibits Proliferation, Migration, and Invasion and Increases Apoptosis in Glioma Cells

Zhi-Gang Shen,*1 Xiao-Zhou Liu,†1 Chang-Xiu Chen‡ and Jing-Min Lu§

*Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, P.R. China
†Department of Neurology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
‡Department of Pediatrics, 97th Hospital of PLA, Xuzhou, P.R. China
§Department of Neurology, Huai’an Second People’s Hospital and The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, P.R. China

E2F3a, as a member of the E2F family, is essential for cell division associated with the progression of many cancers. However, the biological effect of E2F3a on glioma is not understood as well. To investigate the functional mechanism of E2F3a in glioma, we examined the expression of E2F3a in glioma tissue and cell lines. We found that E2F3a was upregulated in glioma tissue compared with adjacent tissue, and this was associated with a poor survival rate. E2F3a was highly expressed in glioma cell lines compared with normal HEB cell lines. Knockdown of E2F3a significantly inhibited cell proliferation, promoted G0/G1 phase arrest, elevated apoptosis rates, and suppressed cell migration and invasion. However, overexpression of E2F3a markedly promoted cell proliferation, migration, and invasion and inhibited apoptosis. Moreover, in vivo studies showed that knockdown of E2F3a expression dramatically inhibited U373 tumor growth in a nude mouse model. Results of real-time PCR and Western blot showed that the depletion of E2F3a upregulated the expression levels of cell apoptosis-related proteins and downregulated migration-related proteins. Conversely, E2F3a overexpression downregulated the expression levels of cell apoptosis-related proteins and upregulated migration-related proteins. In conclusion, our results highlight the importance of E2F3a in glioma and provide new insights into the diagnostics and therapeutics of gliomas.

Key words: Glioma; E2F3a; Apoptosis; Migration

1Co-first authors.
Address correspondence to Jing-Min Lu, Department of Neurology, Huai’an Second People’s Hospital and The Affiliated Huai’an Hospital of Xuzhou Medical University, 62 Huaihai South Road, Qinghe District, Huai’an 223002, P.R. China. Tel: +86-0517-83943591; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1567-1578, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14897173032733
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Clinical Value of Capecitabine-Based Combination Adjuvant Chemotherapy in Early Breast Cancer: A Meta-Analysis of Randomized Controlled Trials

Guanling Chen,1 Zhaoze Guo,1 Minfeng Liu, Guangyu Yao, Jianyu Dong, Jingyun Guo, and Changsheng Ye

Breast Center, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China

Capecitabine has consistently demonstrated high efficacy and acceptable tolerability in salvage chemotherapy for advanced breast cancer. However, there remains no consensus on its role in adjuvant chemotherapy for early breast cancer (EBC). To estimate the value of capecitabine-based combination adjuvant treatment in EBC, eight randomized controlled trials with 14,072 participants were analyzed. The efficacy and safety outcomes included disease-free survival (DFS), overall survival (OS), relapse, breast cancer-specific survival (BCSS), and grades 3–5 adverse events. Capecitabine-based combination adjuvant chemotherapy demonstrated a 16% increase in BCSS (HR = 0.84, 95% CI = 0.71–0.98, p = 0.03) in the overall analysis and a 22% improvement in DFS (HR = 0.78, 95% CI = 0.64–0.96, p = 0.02) in the hormone receptor-negative (HR) subgroup. However, there were no significant differences in DFS (HR = 0.96, 95% CI = 0.89–1.05, p = 0.38), OS (HR = 0.91, 95% CI = 0.82–1.00, p = 0.06), or relapse between capecitabine-based and capecitabine-free combination adjuvant chemotherapy. Analogous results were observed in the subgroup analyses of HR+, HER2, HER2+, and triple-negative EBC. Regarding safety, reduced myelosuppression and hand–foot syndrome development were observed in capecitabine-treated patients. Capecitabine-based combination adjuvant chemotherapy might provide some BCSS benefit compared with capecitabine-free regimens in EBC, but the absolute survival gain is small, and the survival benefit appears to be restricted to patients with HR− EBC, which may indicate a target population for capecitabine-based combination adjuvant chemotherapy.

Key words: Early breast cancer (EBC); Capecitabine; Adjuvant chemotherapy; Meta-analysis

1These authors provided equal contribution to this work.
Address correspondence to Changsheng Ye, Breast Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China. Tel: +8615625107905; Fax: 020-62877176; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1579-1587, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14900505020895
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Targeting CD47 Enhances the Efficacy of Anti-PD-1 and CTLA-4 in an Esophageal Squamous Cell Cancer Preclinical Model

Hua Tao, Pudong Qian, Feijiang Wang, Hongliang Yu, and Yesong Guo

Radiotherapy Oncology Department, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu, P.R. China

Esophageal squamous cell cancer is a highly aggressive cancer with a dismal 5-year survival rate. CD47 is a cell transmembrane protein that is involved in cell apoptosis, proliferation, adhesion, migration, and antigen presentation in the immune system. By interacting with signal regulatory protein-a expressed in antigen-presenting cells (APCs), CD47 acts as an antiphagocytic mechanism to inhibit APC-dependent antigen presentation. Overexpression of CD47 was found in various types of cancer. However, its role in esophageal squamous cell cancer is not yet clear. Anti-CD47 is an antagonist of CD47 signaling pathways by competing with its ligand. In the current study, we investigated the effects of anti-CD47 treatment on the antitumor immune response in an esophageal squamous cell cancer preclinical model. We found that anti-CD47 treatment enhanced proinflammatory responses and increased CD8+ T-cell infiltration in tumor tissue in the animal model. T cells in anti-CD47-treated tumors showed higher PD-1 and CTLA-4 expression, indicating T-cell activation and the rationale of combining anti-CD47 with anti-PD-1 and CLTA-4. The combinatory treatment showed the best antitumor response, implying a novel treatment strategy. The effects of anti-CD47 depended on dendritic cell function. In patient samples, expression of CD47 was negatively correlated with CD8+ T-cell infiltration in esophageal squamous cell cancer patients. Taken together, CD47 might be a novel target to enhance anti-PD-1 and CLTA-4 efficacy in esophageal squamous cell cancer.

Key words: CD47; Dendritic cells; PD-1; CTLA-4; Esophageal squamous cell cancer

Address correspondence to Pudong Qian, Radiotherapy Oncology Department, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, 42 Baiziting, Xuanwu District, Nanjing, Jiangsu 210009, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Feijiang Wang, Radiotherapy Oncology Department, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, 42 Baiziting, Xuanwu District, Nanjing, Jiangsu 210009, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1589-1599, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14897896412027
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

LINC00052 Promotes Gastric Cancer Cell Proliferation and Metastasis via Activating the Wnt/β-Catenin Signaling Pathway

Yuqiang Shan,1 Rongchao Ying,1 Zhong Jia, Wencheng Kong, Yi Wu, Sixin Zheng, and Huicheng Jin

Department of General Surgery, Hangzhou First People’s Hospital, Hangzhou, P.R. China

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. The etiology of GC is complex, and much more attention should be paid to genetic factors. In this study, we explored the role and function of LINC00052 in GC. We applied qRT-PCR and Northern blot to detect the expression of LINC00052 and found it was highly expressed during GC. We also investigated the effects of LINC00052 on tumor prognosis and progression and found that LINC00052 indicated poor prognosis and tumor progression. By performing MTT, colony formation, and Transwell assays, we found that LINC00052 promoted MGC-803 cell proliferation and metastasis. Pull-down and RIP assays showed that LINC00052 could interact with b-catenin and methyltransferase SMYD2, and immunoprecipitation detection showed that LINC00052 promoted β-catenin methylation to maintain its stability, so as to activate the Wnt/β-catenin pathway. Furthermore, XAV939 (inhibitor of β-catenin) was used to treat MGC-803 cells, and we found that LINC00052 promoted proliferation and metastasis, possibly by activation of the Wnt/β-catenin pathway. In conclusion, our research demonstrated a carcinogenic role for LINC000052 in GC, which may represent a new approach for the prevention and therapy of this cancer.

Key words: Gastric cancer (GC); LINC00052; Cell proliferation; Cell metastasis; Wnt/β-catenin pathway

1These authors provided equal contribution to this work.
Address correspondence to Yuqiang Shan, Department of General Surgery, Hangzhou First People’s Hospital, No. 261 Huansha Road, Hangzhou 310006, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Huicheng Jin, Department of General Surgery, Hangzhou First People’s Hospital, No. 261 Huansha Road, Hangzhou 310006, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1601-1606, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14928634401178
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Circulating Tumor Cells Predict Prognosis Following Tyrosine Kinase Inhibitor Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Patients

Baohong Yang,*1 Aiying Qin,†1 Kongyuan Zhang,‡ Haipeng Ren,* Shuzhen Liu,* Xiaolei Liu,§ Xiangpo Pan,¶ and Guohua Yu*

*Department of Oncology, Wei Fang People’s Hospital, Wei Fang, Shandong Province, P.R. China
†The Third Department of Oncology, Luoyang Central Hospital Affiliated with Zhengzhou University, Luoyang, P.R. China
‡Department of Radiology, Wei Fang People’s Hospital, Wei Fang, Shandong Province, P.R. China
§Respiratory Department, Weifang Medical University, Wei Fang, Shandong Province, P.R. China
¶Department of Medical Laboratory, Wei Fang People’s Hospital, Wei Fang, Shandong Province, P.R. China

Epithelial growth factor receptor (EGFR) mutations are present in 10%–26% of non-small cell lung cancer (NSCLC) tumors and are associated with the response to tyrosine kinase inhibitors (TKIs). This study aimed to detect and quantify the presence of circulating tumor cells (CTCs) in EGFR-mutant NSCLC patients and investigate their possible role in providing prognostic information. Enrolled patients received erlotinib (150 mg) or gefitinib (250 mg) orally once daily as the first-line treatment. Serial blood samples were taken at baseline (CTC-d0) and on day 28 (CTC-d28) following the initiation of erlotinib/gefitinib for detection of CTCs using the CellSearch system. CTCs ≥ 2 were found in 47/107 (44%) and CTCs ≥ 5 in 17/107 (15%). The CTC measurements were dichotomized as favorable (<5 CTCs) and unfavorable (≥5 CTCs) groups. The median progression-free survival (PFS) interval for patients in the favorable group at baseline was 11.1 months, significantly longer than the median PFS time of 6.8 months achieved by patients in the unfavorable group ( p = 0.009). Patients in the favorable group on day 28 exhibited significantly longer PFS compared with patients in the unfavorable group (11.6 vs. 6.3 months; p < 0.0001). In univariate analysis, CTC-d0 ≥ 5 versus CTC-d0 = 0–4 was significantly associated with poor PFS and time-to-treatment failure (TTF). CTC-d28 ≥ 5 versus CTC-d28 = 0–4 was significantly associated with a poor PFS outcome. CTC-d0 and CTC-d28 remained independent poor prognostic markers in the stepwise multivariate analysis. Our study indicates that the CTC count is a prognostic factor for PFS and TTF outcomes in patients with advanced EGFR-mutant NSCLC.

Key words: EGFR-mutant non-small cell lung cancer (NSCLC); Circulating tumor cells (CTCs); Prognostic marker

1These authors provided equal contribution to this work.
Address correspondence to Xiangpo Pan, Department of Medical Laboratory, Wei Fang People’s Hospital, Yuhe Road, Kuiwen District, Wei Fang City, Shandong Province 261041, P.R. China. Tel: 86-15253698767; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1607-1616, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14938093512742
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Inhibition of ERK1/2 Signaling Impairs the Promoting Effects of TGF-β1 on Hepatocellular Carcinoma Cell Invasion

and Epithelial–Mesenchymal Transition

Ling Liu, Nianfeng Li, Qi Zhang, Jixiang Zhou, Ling Lin, and Xinxin He

Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China

Transforming growth factor-β (TGF-β) and ERK signaling have been implicated in various human cancers including hepatocellular carcinoma, but the underlying mechanism remains largely unclear. In this study, we aimed to explore the role of ERK1/2 in the regulation of TGF-β’s promoting and suppressive activities in HCC cells. Our data showed that treatment with TGF-b1 enhanced invasion and epithelial–mesenchymal transition (EMT) in HCC HepG2 cells, accompanied with increased MMP9 production and activation of Smad2/3 and ERK1/2, but inhibited tumor cell proliferation. These effects were eliminated by treatment with SB431542, a TGF-β inhibitor. Afterward, treatment with the MEK1/2 inhibitor U0126 reduced the TGF-β1-induced invasion and vimentin and MMP9 secretion in HepG2 cells, without affecting the inhibitory effects of TGF-β1 on HepG2 cell proliferation. Moreover, inhibition of Smad2/3 expression attenuated TGF-β1-induced cell invasion, ERK1/2 phosphorylation, and MMP9 production in HepG2 cells. However, knockdown of Slug only reduced cell invasion but did not affect ERK1/2 activation and MMP9 secretion in HepG2 cells. These data indicate that TGF-β1 activates ERK1/2 in HepG2 cells through the Smad2/3 pathway but not the Slug pathway. In summary, our study demonstrates that inhibition of ERK1/2 signaling attenuates the promoting effects of TGF-β1 on the metastatic phenotypes of HCC cells without affecting its suppressive effects on HCC cell proliferation. Therefore, we suggest that ERK1/2 may be used as a molecular target for the treatment of TGF-β-responsive HCC.

Key words: Hepatocellular carcinoma (HCC); Transforming growth factor-β1 (TGF-β1); ERK1/2; Migration; Epithelial–mesenchymal transition (EMT)

Address correspondence to Lin Liu, M.D., Ph.D., Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, Hunan 410008, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1617-1624, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14905635363102
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Different Cell Cycle Modulation in SKOV-3 Ovarian Cancer Cell Line by Anti-HIV Drugs

Angelica Perna,*† Angela Lucariello,*† Carmine Sellitto,* Iolanda Agliata,† Maria Aurora Carleo,‡ Vincenzo Sangiovanni,‡ Vincenzo Esposito,§ Germano Guerra,† Luigi Cobellis,¶ and Antonio De Luca*

*Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, Università degli Studi della Campania “L. Vanvitelli”, Naples, Italy
†Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
‡III UOC of Infectious Diseases P.O. Cotugno, AO Ospedale dei Colli, Naples, Italy
§V UOC of Infectious Diseases P.O. Cotugno, AO Ospedale dei Colli, Naples, Italy
¶Department of Gynecology, Obstetric and Reproductive Science, Università degli Studi della Campania “L. Vanvitelli”, Naples, Italy

Antiretroviral drugs used for the treatment of human immunodeficiency virus (HIV) have proven to be effective even against cancer. Drawing from this background, the aim of our research project was to evaluate the effects of anti-HIV drugs that belong to the nucleoside and nucleotide reverse transcriptase inhibitor [NRTI; abacavir (ABC) and tenofovir (TDF)], nonnucleoside reverse transcriptase inhibitor [NNRTI; efavirenz (EFV) and etravirine (ETR)], and protease inhibitor [PI; darunavir (DRV)] categories on ovarian adenocarcinoma cell line SKOV-3. Using FACS analysis, we observed that treatment with NRTIs and NNRTIs showed a block in the G0/G1 phase. In particular, ETR displayed a relevant block in the progression of the G0/G1 phase of the cell cycle compared with the other examined drugs, and it also induced differentiation of SKOV-3 cells. In contrast, FACS analysis demonstrated that ABC and the PI inhibitor DRV showed no effect on the proliferation of cancer cells. DAPI (4′,6-diamidino-2-phenylindole) staining demonstrated that cells treated with NNRTIs (EFV and ETR) presented more DNA damage compared with other treatments. Immunoblotting analysis demonstrated that TDF, EFV, and ETR were able to obtain a reduction in the expression of cyclin D1 and Rb hypophosphorylation, and an increase in p21 concentration. Finally, we observed that ETR also induced differentiation, as demonstrated by Western blot, with high levels of E-cadherin expression. Therefore, our study provides additional evidence supporting the in vitro cytotoxic effects of ETR and EFV. Furthermore, it promotes the hypothesis for their potential use as therapeutic agents in ovarian cancer.

Key words: Cell cycle; Ovarian cancer; Antiretroviral drugs; Antineoplastic effect

Address correspondence to Antonio De Luca, Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, Università degli Studi della Campania “L. Vanvitelli”, Sezione di Anatomia Umana, Via L. Armanni 5, 80138 Napoli, Italy. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1625-1631, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15012905098071
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Self-Reported Adherence to Capecitabine on XELOX Treatment as Adjuvant Therapy for Colorectal Cancer

Kazuyoshi Kawakami,* Takashi Yokokawa,* Kazuo Kobayashi,* Takahito Sugisaki,* Kenichi Suzuki,* Mitsukuni Suenaga,† Kensei Yamaguchi,† Ayaka Inoue,‡ Yoshiaki Machida,‡ Toshiharu Yamaguchi,† and Toshihiro Hama*

*Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
†Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
‡Section for Practical Education, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan

Adherence has become an important issue in modern oncology treatment. Most studies have included heterogeneous target tumor types, regimens, and therapy settings. Our study focused on capecitabine during capecitabine plus oxaliplatin(XELOX) treatment as an adjuvant therapy for colorectal cancer. The main aims of this study were to evaluate real-life adherence to capecitabine and to investigate candidate factors that might decrease adherence. We studied 338 consecutive patients who received XELOX treatment between December 1, 2011, and April 30, 2015, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Our study assessed adherence to capecitabine through patient-reported treatment diaries and interviewed nonadherents to determine the reasons for not taking capecitabine at a pharmaceutical outpatient clinic. We calculated the adherence rate in a cycle as: number of times the patient took capecitabine/28. Relative dose intensities and factors associated with deteriorating adherence to capecitabine were retrospectively surveyed from electronic patient records. Uni- and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence. The study covered 282 patients who received 2,055 cycles of XELOX. Median adherence rate was 94.0% in the first cycle, and median relative dose intensity of capecitabine was 77.8%. The most common reasons for nonadherence were nausea/vomiting and diarrhea. The presence of the following factors was not significantly associated with adherence: ECOG performance status ≥1 (p = 0.715), clinical stage (p = 0.408), primary tumor site (p = 0.576), age ³70 years at study entry (p = 0.757), female gender (p = 0.504), and not living alone (p = 0.579). The adherence rate from this study was significantly higher than the adherence from metastatic settings. Adherence-enhancing interventions for capecitabine in XELOX treatment as adjuvant therapy comprised management of nausea/vomiting and diarrhea.

Key words: Capecitabine; Adherence; XELOX treatment; Pharmaceutical outpatient clinic; Oral anticancer drugs

Address correspondence to Kazuyoshi Kawakami, Department of Pharmacy, The Japanese Foundation for Cancer Research, Cancer Institute Hospital, 3-8-31 Ariake Koto-Ku, Tokyo 135-8550, Japan. Tel: +81-3-3570-0215 (direct); Fax: +81-3-3570-0216; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1633-1641, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14878528144150
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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YEATS Domain Containing 4 Promotes Gastric Cancer Cell Proliferation and Mediates Tumor Progression via Activating the Wnt/β-Catenin Signaling Pathway

Sheqing Ji,* Youxiang Zhang,† and Binhai Yang‡

*Department of Gastroenterology, Binzhou People’s Hospital, Binzhou, P.R. China
†Department of Pharmacy, Binzhou People’s Hospital, Binzhou, P.R. China
‡Department of Gastroenterology, Second People’s Hospital of Binzhou, Binzhou, P.R. China

Increased expression of YEATS domain containing 4 (YEATS4) has been reported to have a correlation with progression in many types of cancer. However, the mechanism by which it promotes the development of gastric cancer (GC) is rarely reported. This study aimed to investigate the effect of YEATS4 on cell proliferation and tumor progression. The mRNA and protein expressions of YEATS4 in GC tissues and cell lines were analyzed. BGC-823 cells then overexpressed or silenced YEATS4 by transfection of different plasmids. The regulatory effect of YEATS on cell viability, colony formation, cell apoptosis, and tumor growth in vivo was evaluated. Finally, we explored the underlying regulatory mechanism of YEATS4 on the Wnt/β-catenin pathway. YEATS4 was highly expressed in GC tissues and cell lines. Furthermore, Kaplan–Meier survival analysis and qRT-PCR analysis showed that the increased expression of YEATS4 indicated poor prognosis and tumor progression. The overexpression of YEATS4 significantly promoted cell proliferation and inhibited cell apoptosis, whereas the opposite trends were found upon the downregulation of YEATS4. Western blot analysis showed that the downregulation of YEATS4 inhibited protein expression and phosphorylation of β-catenin. In addition, decreased expressions of c-Myc, CDK6, CDK4, cyclin D1, and Bcl-2 and increased expression of Bax were observed in YEATS4 knockdown cells. Our results showed that increased expression of YEATS4 might play a critical role in promoting GC cell proliferation and apoptosis by activating the Wnt/β-catenin signaling pathway, indicating that the control of YEATS4 expression might be used as a promising therapy for GC.

Key words: YEATS domain containing 4 (YEATS4); Gastric cancer (GC); Proliferation; Apoptosis; Wnt/β-catenin pathway

Address correspondence to Sheqing Ji, Department of Gastroenterology, Binzhou People’s Hospital, No. 515 Huangheqi Road, Binzhou 256601, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1643-1651, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14908284471361
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

miR-1193 Suppresses the Proliferation and Invasion of Human T-Cell Leukemia Cells Through Directly Targeting the Transmembrane 9 Superfamily 3 (TM9SF3)

Liyun Shen, Xingjun Du, Hongyan Ma, and Shunxi Mei

Hematological Department, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China

miRNAs have been involved in various types of cancer, including T-cell leukemia. In this study, the role of miR-1193 in the proliferation and invasion of T-cell leukemia cells was explored. First, we found that miR-1193 was sharply downregulated in T-cell leukemia cells when compared with normal T cells. miR-1193 markedly decreased the proliferation and invasion in Jurkat human T-cell leukemia cells. Transmembrane 9 superfamily 3 (TM9SF3) was then predicted to be a potential target gene of miR-1193, the levels of which displayed a strongly negative correlation with miR-1193 levels in T-cell leukemia patients. We confirmed that TM9SF3 was a target gene of miR-1193 by luciferase reporter gene assay. Finally, gene overexpression and knockdown experiments in Jurkat cells revealed that TM9SF3 positively regulated cell proliferation and invasion.

Key words: miR-1193; Cell proliferation and invasion; Transmembrane 9 superfamily 3 (TM9SF3); T-cell leukemia

Address correspondence to Shunxi Mei, Hematological Department, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Jinshui District, Zhengzhou, 450014 Henan Province, P.R. China. Tel: 86-371-63930334; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1653-1664, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14992942781895
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

Dina Polosukhina,* Harold D. Love,*† Harold L. Moses,‡§¶# Ethan Lee,**†† Roy Zent,†§**‡‡ and Peter E. Clark*‡

*Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
†Department of Medicine (Nephrology and Hypertension), Vanderbilt University Medical Center, Nashville, TN, USA
‡Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
§Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
¶Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
#Department of Medicine (Hematology–Oncology), Vanderbilt University Medical Center, Nashville, TN, USA
**Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
††Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
‡‡Veterans Affairs Hospital, Nashville, TN, USA

Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have shown that constitutive activation of β-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors, which resemble human WT. Here we demonstrate that pharmacologic inhibition of β-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide proof of the concept that the canonical Wnt/β-catenin pathway may be a novel therapeutic target in the management of WT.

Key words: β-Catenin; Pyrvinium; Wilms tumor (WT)

Address correspondence to Peter E. Clark, M.D., at his current address: Professor and Chair, Department of Urology, Chair, Urologic Oncology, Carolinas Healthcare System, Levine Cancer Institute, 1021 Morehead Medical Dr., 6th Floor-Suite 6149, Charlotte, NC 28204, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1665, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15078984695565
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved.

Erratum

This article was originally published in Volume 24, Number 3, pages 189-196 (http://dx.doi.org/10.3727/096504016X14641336229602). Author Lingfei Han was included in error in the original article. Below is shown the correct author contributors with Lingfei Han removed.

Knockdown of HVEM, a Lymphocyte Regulator Gene, in Ovarian Cancer Cells Increases Sensitivity to Activated T Cells

Ting Zhang,1 Lei Ye,1 Qizhi He, and Jianlong Zhu

Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China

Ovarian cancer is highly malignant with a gradually increasing incidence and a high mortality rate. Immunosuppression is induced in ovarian cancer, although the mechanism detail is not clear. It has been indicated that HVEM (herpesvirus entry mediator) B- and T-lymphocyte attenuator (BTLA) negatively regulates the immune responses of T lymphocytes. Here, HVEM mRNA was found to be elevated in ovarian cancer tissue samples and primary ovarian cancer cells in comparison with benign tissue samples. We then knocked down HVEM expression in an ovarian cancer cell line, OVCAR3, by lentivirus-based small hairpin RNA (shRNA). Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis showed that HVEM-shRNA had no effect on the proliferation, early apoptosis, or cell cycle distribution of OVCAR3. We then isolated activated T cells and performed coculture experiments in Transwell. Remarkably, HVEM-silenced ovarian cancer cells (primary ovarian cancer cells and OVCAR3) increased the number of T cells and the secretion of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), while activated T cells promoted the apoptosis of HVEM-silenced ovarian cancer cells. The current study partially explains the immune escape mechanism of ovarian cancer cells and provides a possible target for immunotherapy.

Key words: Herpesvirus entry mediator (HVEM); Ovarian cancer; T cells; Immunosuppression

1These authors provided equal contribution to this work.
Address correspondence to Jianlong Zhu, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536 Changle Road, Jing’an District, Shanghai 200040, China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it