Oncology Research 25(7) Abstracts

Return to Oncology Research>

Oncology Research, Vol. 25, pp. 1039-1046, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14813914187138
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Overexpression of Hepatocyte Cell Adhesion Molecule (hepaCAM) Inhibits the Proliferation, Migration, and Invasion in Colorectal Cancer Cells

Hai-tao Geng,* Rui-juan Cao,* Lei Cheng,† and Chun-yuan Liu†

*Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, P.R. China
†Department of General Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, P.R. China

Hepatocyte cell adhesion molecule (hepaCAM), a new type of CAM, belongs to the immunoglobulin superfamily. Recently, hepaCAM was reported to be implicated in cancer development, and many researchers investigated its biological function in the tumorigenesis of various cancers. However, what kind of role hepaCAM plays in colorectal cancer (CRC) remains unknown. In this study, we found that hepaCAM was downregulated in CRC tissues and cell lines. Overexpression of hepaCAM inhibited CRC cell proliferation, migration, and invasion in vitro. Furthermore, the tumorigenesis assay showed that increased expression of hepaCAM suppressed CRC tumor growth and metastasis in vivo. We also demonstrated that overexpression of hepaCAM reduced the protein expression levels of β-catenin, cyclin D1, and c-Myc, indicating its inhibitory effect on the Wnt/β-catenin signaling pathway. In conclusion, our study results suggest hepaCAMas a promising therapeutic target for CRC and provide a better understanding for the molecular basis of CRC progression.

Key words: Hepatocyte cell adhesion molecule (hepaCAM); Proliferation; Migration; Invasion; Colorectal cancer (CRC)

Address correspondence to Chun-yuan Liu, Department of General Surgery, Binzhou Medical University Hospital, 661 Yellow River Road, Binzhou 256603, Shandong, 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. 1047-1059, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14813899000565
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Upregulation of CD147 Promotes Metastasis of Cholangiocarcinoma by Modulating the Epithelial-to-Mesenchymal Transitional Process

Paweena Dana,*†‡ Ryusho Kariya,‡ Kulthida Vaeteewoottacharn,*† Kanlayanee Sawanyawisuth,*† Wunchana Seubwai,†§ Kouki Matsuda,‡ Seiji Okada,‡ and Sopit Wongkham*†

*Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
†Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
‡Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
§Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

CD147 is a transmembrane protein that can induce the expression and activity of matrix metalloproteinases (MMPs). Expression of CD147 has been shown to potentiate cell migration, invasion, and metastasis of cancer. In this study, the critical role of CD147 in metastasis was elucidated using CD147-overexpressing cholangiocarcinoma (CCA) cells in vitro and in vivo. The molecular mechanism, demonstrated herein, supported the hypothesis that metastasis increased in CD147-overexpressing cells. Five CD147-overexpressing clones (Ex-CD147) were established from a low CD147-expressing CCA cell line, KKU-055, using lentivirus containing pReceiver-Lenti-CD147. The metastatic capability was determined using the tail vein injection mouse model and an in vitro 3D invasion assay. Liver colonization was assessed using anti-HLA class I immunohistochemistry. Adhesion abilities, cytoskeletal arrangements, MMP activities, the expressions of adhesion molecules, and epithelial–mesenchymal transitional markers were analyzed. All Ex-CD147 clones exhibited a high CD147 expression and high liver colonization in the tail vein-injected mouse model, whereas parental cells lacked this ability. Ex-CD147 clones exhibited metastatic phenotypes (i.e., an increase in F-actin rearrangement) and cell invasion and a decrease in cell adhesion. The molecular mechanisms were shown to be via the induction of MMP-2 activity and enhancement of epithelial–mesenchymal transitions. An increase in mesenchymal markers Slug, vimentin, and N-cadherin, and a decrease in epithelial markers E-cadherin and claudin-1, together with suppression of the adhesion molecule ICAM-1, were observed in the Ex-CD147 clones. Moreover, suppression of CD147 expression using siCD147 in two CCA cell lines with high CD147 expression significantly decreased cell migration and invasion of these CCA cells. These findings emphasize the essential role of CD147 in CCA metastasis and suggest CD147 as a promising target for the effective treatment of CCA.

Key words: Extracellular matrix metalloproteinase inducer (EMMPRIN); Cell invasion; Metastasis; Epithelial–mesenchymal transition (EMT); Matrix metalloproteinase (MMP)

Address correspondence to Professor Seiji Okada, Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. Tel: +81-96-373-6522; Fax: +81-96-373-6523; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Professor Sopit Wongkham, Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mittapap Road, MuangKhon Kaen 40002, Thailand. Tel: +66-4334-8386; Fax: +66-4334-8386; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1061-1068, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14830466773541
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Silencing of Ribosomal Protein L34 (RPL34) Inhibits the Proliferation and Invasion of Esophageal Cancer Cells

Huijie Fan,*1 Jing Li,*1 Yongxu Jia,* Jingjing Wu,* Long Yuan,† Mingjun Li,* Jiangqi Wei,‡ and Benling Xu§

*Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
†Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, P.R. China
‡Department of Surgery, The First Renmin Hospital of Xinxiang City, Xinxiang, P.R. China
§Department of Cancer Biotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, P.R. China

Ribosomal protein L34 (RPL34) belongs to the L34E family of ribosomal proteins and contains a zinc finger motif. Aberrant expression of RPL34 has been reported in several human malignancies. However, the precise role and potential underlying mechanisms of RPL34 in human esophageal cancer remain largely unknown. Thus, the objective of this study was to investigate the role of RPL34 in esophageal cancer progression. Our results showed that the expression of RPL34 at both the mRNA and protein levels was frequently upregulated in esophageal cancer cell lines. Knockdown of RPL34 efficiently inhibited esophageal cancer cell proliferation, migration, and invasion in vitro. Mechanistically, knockdown of RPL34 significantly downregulated the protein expression level of p-PI3K and p-Akt in esophageal cancer cells. Finally, knockdown of RPL34 attenuated tumor growth in nude mice. In conclusion, our study revealed that RPL34 functions as an oncogene that modulates the proliferation and metastasis of esophageal cancer cells, in part, by the inactivation of the PI3K/Akt signaling pathway. Thus, these findings suggest that RPL34 may serve as a potential therapeutic target for the treatment of esophageal cancer.

Key words: Ribosomal protein L34 (RPL34); Esophageal cancer; Proliferation; Invasion; PI3K/Akt pathway

1These authors provided equal contribution to this work.
Address correspondence to Huijie Fan, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, P.R. China. Tel: +86-0371-66295542; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1069-1079, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14829256525028
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


miR-92a Inhibits Proliferation and Induces Apoptosis by Regulating Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) Expression in Acute Myeloid Leukemia

Yueli Gu,* Jinchun Si,† Xichun Xiao,* Ying Tian,* and Shuo Yang*

*Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
†Department of Surgery Teaching and Research Section, Shangqiu Medical College, Shangqiu, P.R. China

Aberrant expression of microRNA-92a (miR-92a) has been investigated in various cancers. However, the function and mechanism of miR-92a in acute myeloid leukemia (AML) remain to be elucidated. Our data showed that miR-92a was evidently downregulated and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was remarkably upregulated in AML cell lines HL-60 and THP-1. Dual luciferase reporter assay revealed that MTHFD2 was a direct target of miR-92a. Gain- and loss-of-function analysis demonstrated that MTHFD2 knockdown or miR-92a overexpression notably inhibited proliferation and promoted apoptosis of AML cell lines. Restoration of MTHFD2 expression reversed proliferation inhibition and apoptosis induction of AML cells triggered by miR-92a. Moreover, an implanted tumor model in mice indicated that miR-92a overexpression dramatically decreased tumor growth and MTHFD2 expression in vivo. Taken together, our results suggest that miR-92a inhibits proliferation and induces apoptosis by directly regulating MTHFD2 expression in AML. miR-92a may act as a tumor suppressor in AML, providing a promising therapeutic target for AML patients.

Key words: miR-92a; Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2); Acute myeloid leukemia (AML); Proliferation; Apoptosis

Address correspondence to Yueli Gu, Department of Hematology, Shangqiu First People’s Hospital, No. 292 Kaixuan Road, Shangqiu 476000, P.R. China. Tel: +86-0370-3255762; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1081-1087, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14831120463349
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


miR-5195-3p Inhibits Proliferation and Invasion of Human Bladder Cancer Cells by Directly Targeting Oncogene KLF5

Zhangjie Jiang,*1 Yida Zhang,†1 Runfu Cao,† Li Li,‡ Kezhao Zhong,† Qingsheng Chen,† and Jianjun Xiao†

*Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
†Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
‡Department of Anesthesiology, Ganzhou Renmin Hospital, Ganzhou, P.R. China

miRNAs play a key role in the carcinogenesis of many cancers, including bladder cancer. In the current study, the role of miR-5195-3p, a quite recently discovered and poorly studied miRNA, in the proliferation and invasion of human bladder cancer cells was investigated. Our data displayed that, compared with healthy volunteers (control) and SU-HUC-1 normal human bladder epithelial cells, miR-5195-3p was sharply downregulated in bladder cancer patients and five human bladder cancer cell lines. The oligo miR-5195-3p mimic or miR-5195-3p antagomir was subsequently transfected into both T24 and BIU-87 bladder cancer cell lines. The miR-5195-3p mimic robustly increased the miR-5195-3p expression level and distinctly reduced the proliferation and invasion of T24 and BIU-87 cells. In contrast, the miR-5195-3p antagomir had an opposite effect on miR-5195-3p expression, cell proliferation, and invasion. Our data from bioinformatics and luciferase reporter gene assays identified that miR-5195-3p targeted the mRNA 3′-UTR of Kruppel-like factor 5 (KLF5), which is a proven proto-oncogene in bladder cancer. miR-5195-3p sharply reduced KLF5 expression and suppressed the expression or activation of its several downstream genes that are kinases improving cell survival or promoting cell cycle regulators, including ERK1/2, VEGFA, and cyclin D1. In conclusion, miR-5195-3p suppressed proliferation and invasion of human bladder cancer cells via suppression of KLF5.

Key words: Bladder cancer; miR-5195-3p; Cell proliferation; Cell invasion; Krüppel-like factor 5 (KLF5)

1These authors provided equal contribution to this work.
Address correspondence to Yida Zhang, Department of Urology, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Street, Nanchang 330000, P.R. China. Tel: +86-0797-8112320; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1089-1095, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14784668796788
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Downregulation of Homeobox B7 Inhibits the Tumorigenesis and Progression of Osteosarcoma

Lei Yang,* Fei Xie,† and Shuangqing Li‡

*The Third Department of Orthopedics, Cangzhou Central Hospital, Cangzhou, P.R. China
†Department of Pediatrics, Cangzhou Central Hospital, Cangzhou, P.R. China
‡Department of Orthopedics, Cangzhou Central Hospital, Cangzhou, P.R. China

Homeobox B7 (HOXB7), a member of the HOX gene family, plays a role in tumorigenesis. However, until now the expression status and role of HOXB7 in osteosarcoma remain unclear. Therefore, the present study aimed to investigate the functional role and mechanism of HOXB7 in osteosarcoma. Our results demonstrated that HOXB7 was overexpressed in osteosarcoma cell lines. Downregulation of HOXB7 significantly inhibited osteosarcoma cell proliferation in vitro, as well as attenuated xenograft tumor growth in vivo. Downregulation of HOXB7 also inhibited the migration and invasion of osteosarcoma cells. Furthermore, downregulation of HOXB7 significantly suppressed the protein expression levels of p-PI3K and p-Akt in U2OS cells. In summary, our data demonstrated that downregulation of HOXB7 inhibited proliferation, invasion, and tumorigenesis, partly through suppressing the PI3K/Akt signaling pathway in osteosarcoma cells. Our findings provide new insights into the role of HOXB7 in osteosarcoma and new therapeutic targets for the treatment of osteosarcoma.

Key words: Homeobox B7 (HOXB7); Osteosarcoma; Proliferation; Invasion; PI3K/Akt pathway

Address correspondence to Lei Yang, The Third Department of Orthopedics, Cangzhou Central Hospital, No. 16 Xinhua Distinct, Cangzhou 061000, P.R. China. Tel: +86-0317-2075627; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1097-1107, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14836170586829
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


MicroRNA-409-3p Represses Glioma Cell Invasion and Proliferation by Targeting High-Mobility Group Nucleosome-Binding Domain 5

Yidong Cao,*1 Liang Zhang,*1 Minghao Wei,* Xue Jiang,† and Dong Jia*

*Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
†Operating Room, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, P.R. China

Emerging evidence has suggested that aberrantly expressed microRNAs (miRNAs) are associated with glioma development and progression. The aberrant expression of miR-409-3p has been reported in several human cancers. However, little is known about the function of miR-409-3p in gliomas. The aim of this study was to investigate the specific role and molecular mechanism of miR-409-3p in gliomas. In the present study, we found that miR-409-3p was downregulated in glioma tissue and cell lines. Overexpression of miR-409-3p inhibited glioma cell invasion and proliferation, whereas suppression of miR-409-3p promoted glioma cell invasion and proliferation. High-mobility group nucleosome-binding domain 5 (HMGN5), a well-known oncogene in gliomas, was identified as a functional target of miR-409-3p using bioinformatics, dual-luciferase reporter assay, real-time quantitative polymerase chain reaction, and Western blot analysis. Furthermore, miR-409-3p was found to regulate the expression of matrix metalloproteinase 2 and cyclin D1. Restoration of HMGN5 expression significantly reversed the inhibitory effects of miR-409-3p overexpression on glioma cell invasion and proliferation. Taken together, our results suggest that miR-409-3p inhibits glioma cell invasion and proliferation by targeting HMGN5, representing a potential therapeutic target for glioma.

Key words: Glioma; High-mobility group nucleosome-binding domain 5 (HMGN5); miR-409-3p; Invasion; Proliferation

1These authors provided equal contribution to this work and are co-first authors.
Address correspondence to Dong Jia, Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, No. 1 Xinsi Road, Xi’an, Shaanxi 710038, 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. 1109-1116, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14800889609439
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


miR-133b Inhibits Cell Growth, Migration, and Invasion by Targeting MMP9 in Non-Small Cell Lung Cancer

Yan Zhen,*1 Jia Liu,*†1 Yujie Huang,*†1 Yajun Wang,* Wen Li,*† and Jun Wu*†

*Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, P.R. China
†Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, P.R. China

Although increasing evidence indicates that the deregulation of microRNAs (miRNAs) contributes to tumorigenesis and invasion, little is known about the role of miR-133b in human non-small cell lung cancer (NSCLC). In the present study, we revealed that the introduction of miR-133b dramatically suppressed NSCLC cell growth, migration, and invasion in vitro. On the contrary, miR-133b inhibitors promoted cell growth, migration, and invasion in vitro. Further studies revealed that matrix metallopeptidase 9 (MMP9) is a direct target gene of miR-133b. Silencing MMP9 inhibited cell growth, migration, and invasion of NSCLC cells, which was consistent with the effect of miR-133b overexpression. In clinical specimens, reduced miR-133b was an unfavorable factor and negatively correlated with MMP9 expression. Our studies demonstrate that miR-133b inhibits cell growth, migration, and invasion by targeting MMP9 in NSCLC.

Key words: miR-133b; Matrix metallopeptidase 9 (MMP9); Non-small cell lung cancer (NSCLC); Cell growth; Migration and invasion

1These authors provided equal contribution to this work.
Address correspondence to Wen Li, Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Ren Min Road South 57, Zhanjiang 524001, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Jun Wu, Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Ren Min Road South 57, Zhanjiang 524001, 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. 1117-1127, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14821952695683
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1

Tinghui Jiang,* Mengfan Li,† Qiuyin Li,‡ Zhiqiang Guo,§ Xianjun Sun,‡ Xufeng Zhang,§ Yan Liu,‡ Wenyi Yao,‡ and Ping Xiao*

*Key Laboratory of Nanobiological Technology, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
†Department of Vascular Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
‡Department of Interventional Radiology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
§Department of Thoracic Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China

Some microRNAs (miRs) have been demonstrated to play promoting or tumor-suppressing roles in the development and progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism of miR-98-5p in HCC still remains largely unclear. In the present study, our data showed that miR-98-5p was significantly downregulated in 84 cases of HCC tissues compared to the matched adjacent nontumor tissues. In addition, downregulation of miR-98-5p was associated with tumor size, portal vein tumor embolus, node metastasis, and clinical stage in HCC. HCC patients with low expression of miR-98-5p showed a shorter survival time compared with those with high miR-98-5p levels. Moreover, the expression of miR-98-5p was also reduced in HCC cell lines (HepG2, Hep3B, LM3, and SMCC7721) compared to the normal liver cell line THLE-3. Overexpression of miR-98-5p significantly decreased LM3 cell growth by inducing cell cycle arrest at the G1
stage and cell apoptosis. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was then identified as a novel target gene of miR-98-5p, and its protein expression was negatively regulated by miR-98-5p in LM3 cells. Overexpression of IGF2BP1 eliminated the effects of miR-98-5p overexpression on the proliferation, cell cycle, and apoptosis of LM3 cells. Finally, we found that IGF2BP1 was upregulated in HCC, and its expression was negatively correlated to miR-98-5p levels. In summary, we demonstrate that miR-98-5p could inhibit HCC cell proliferation while inducing cell apoptosis, partly at least, via inhibition of its target gene IGF2BP1, and we suggest that miR-98-5p may become a promising therapeutic candidate for HCC treatment.

Key words: Cell proliferation; Cell cycle; Cell apoptosis; Hepatocellular carcinoma (HCC); MicroRNAs (miRs); Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)

Address correspondence to Ping Xiao, Key Laboratory of Nanobiological Technology, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, Hunan 410008, P.R. China. Tel: +86-731-84327304; Fax: +86-731-84327388; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1129-1140, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14841698396900
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-Fluorouracil Antitumor Activity In Vitro and In Vivo

Antonello Di Paolo,1 Paola Orlandi,1 Teresa Di Desidero, Romano Danesi, and Guido Bocci

Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in the landscape of colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on human colon cancer cells exposed to 5-FU, calcium (CaLV), or disodium (NaLVlevofolinate or their simultaneous and sequential combination for 24 and 72 h. TYMS and SLC19A1 gene expression was performed with real-time PCR. In vivo experiments were performed in xenograftednude mice, which were treated with 5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24-h treatment in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 24 and 72 h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 24 h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed the enhanced antitumor activity of the 5-FU + NaLV simultaneous combination with a good toxicity profile, whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations potentiated the antiproliferative effects of the drugs.

Key words: Colon cancer; 5-Fluorouracil (5-FU); Calcium levofolinate (CaLV); Disodium levofolinate (NaLV); Synergism; Thymidylate synthetase (TYMS); SLC19A1

1These authors provided equal contribution to this work.
Address correspondence to Guido Bocci, M.D., Ph.D., Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126-Pisa, Italy. Tel: +39-050-2216756; Fax: +39-050-2216758; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1141-1152, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14841698396784
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Betulinic Acid Inhibits Cell Proliferation in Human Oral Squamous Cell Carcinoma via Modulating ROS-Regulated p53 Signaling

Huan Shen,*1 Li Liu,†1 Yongjin Yang,* Wenxing Xun,‡ Kewen Wei,‡ and Guang Zeng‡

*Department of Stomatology, The General Hospital of the Second Artillery Corps of Chinese PLA, Beijing, P.R. China
†Department of Stomatology, PLA Army General Hospital, Beijing, P.R. China
‡Department of Plastic and Burn Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, P.R. China

Oral squamous cell carcinoma (OSCC) is a common cancer of the head and neck. Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid. The present study was designed to explore the effects of BA on OSCC KB cell proliferation in vitro and on implanted tumor growth in vivo and to examine the possible molecular mechanisms. The results showed that BA dose-dependently inhibited KB cell proliferation and decreased implanted tumor volume. In addition, BA significantly promoted mitochondrial apoptosis, as reflected by an increase in TUNEL+
cells and the activities of caspases 3 and 9, an increase in Bax expression, and a decrease in Bcl-2 expression and the mitochondrial oxygen consumption rate. BA significantly increased cell population in the G0/G1 phase and decreases the S phase cell number, indicating the occurrence of G0/G1 cell cycle arrest. ROS generation was significantly increased by BA, and antioxidant NAC treatment markedly inhibited the effect of BA on apoptosis, cell cycle arrest, and proliferation. BA dose-dependently increased p53 expression in KB cells and implanted tumors. p53 reporter gene activity and p53 binding in the promoters of Bax were significantly increased by BA. Knockdown of p53 blocked BA-induced increase in apoptosis, cell cycle arrest, and inhibition of cell proliferation. NAC treatment suppressed BA-induced increase in p53 expression. Furthermore, phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased by BA. Taken together, the data demonstrated that ROS–p53 signaling was crucial for BA-exhibited antitumor effect in OSCC. BA may serve as a potential drug for the treatment of oral cancer.

Key words: Betulinic acid (BA); Oral squamous cell carcinoma (OSCC); Apoptosis; Cell cycle arrest; p53; Signal transducer and activator of transcription 3 (STAT3); Reactive oxygen species (ROS)

1These authors provided equal contribution to this work.
Address correspondence to Guang Zeng, Department of Plastic and Burn Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi’an 710038, 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. 1153-1159, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14845839228545
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


3-Phosphoinositide Dependent Protein Kinase-1 (PDK-1) Promotes Migration and Invasion in Gastric Cancer Cells Through Activating the NF-κB Pathway

Ning Wu,* Changyu He,† Bohui Zhu,* Jinling Jiang,† Yiwen Chen,* and Tao Ma†

*Department of Oncology, Shanghai Pudong New Area Gongli Hospital, Shanghai, P.R. China
†Department of Oncology, Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China

Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer deaths in the world. Many factors have been reported regarding the progression and development of GC. In this study, we aimed to investigate the correlation of 3-phosphoinositide dependent protein kinase-1 (PDK-1) with cell viability, migration, and invasion of GC. The expression of PDK-1 was measured in different GC cell lines. Thereafter, the expression of PDK-1 was interfered by small hairpin RNA (shRNA) and then incubated with or without the inhibitor of nuclear factor-κB (NF-κBpyrrolidine dithiocarbamate (PDTC). We then investigated the effects of PDK-1 aberrant expression on GC cell viability, migration, invasion, and the epithelial–mesenchymal transition (EMT) progress. The results showed that PDK-1 was highly expressed in GC cells, and PDK-1 promoted cell viability, migration, invasion, and EMT in GC. Moreover, we confirmed that PDK-1 activated the phosphatidylinositol 3-hydroxy kinase (PI3K)/AKT and NF-κB signaling pathways. However, administration of PDTC reversed the effects of overexpression of PDK-1 on cell migration and invasion. All these findings suggest that PDK-1 may be involved in progression of GC and could be a new therapeutic target for this disease.

Key words: 3-Phosphoinositide dependent protein kinase-1 (PDK-1); Gastric cancer; Migration; Invasion; Nuclear factor-κB (NF-κB)

Address correspondence to Tao Ma, Department of Oncology, Ruijin Hospital Shanghai Jiaotong University School of Medicine, No. 197 Ruijinger Road, Shanghai 200025, 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. 1161-1168, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14841698396829
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


MicroRNA-21 Inhibits the Apoptosis of Osteosarcoma Cell Line SAOS-2 via Targeting Caspase 8

Bin Xu, Hehuan Xia, Junming Cao, Zhihong Wang, Yipeng Yang, and Yongsheng Lin

Department of Orthopedics, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China

Currently
, multiple microRNAs (miRNAs) have been found to play vital roles in the pathogenesis of osteosarcoma. This study aimed to investigate the role of miR-21 in osteosarcoma. The level of miR-21 in 20 pairs of osteosarcoma and corresponding adjacent tissues was monitored by qPCR. Human osteosarcoma cell line SAOS-2 was transfected with either miR-21 mimic or miR-21 inhibitor, and then cell viability, survival, and apoptosis were measured by MTT, colony formation assay, and flow cytometry. A target of miR-21 was predicted by the microRNA.org database and verified in vitro by using luciferase reporter, qPCR, and Western blot analyses. Finally, cells were cotransfected with siRNA against caspase 8 and miR-21 inhibitor, and the apoptotic cell rate was determined again. Results showed that the mRNA level of miR-21 was highly expressed in osteosarcoma tissues compared with adjacent tissues. Overexpression of miR-21 improved cell viability and survival but suppressed apoptosis. Caspase 8 was a direct target of miR-21, and it was negatively regulated by miR-21. Moreover, miR-21 suppression attenuated caspase 8 silencing and induced the decrease in apoptosis. In conclusion, overexpression of miR-21 suppressed SAOS-2 cell apoptosis via directly targeting caspase 8.

Key words: MicroRNA-21; Osteosarcoma; Cell survival: Apoptosis: Caspase 8

Address correspondence to Yongsheng Lin, Department of Orthopedics, The Third Hospital of Hebei Medical University, No. 68 Xiangjiang Road, Shijiazhuang 050035, 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. 1169-1176, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14847395834985
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


MicroRNA-133a Inhibits Proliferation of Gastric Cancer Cells by Downregulating ERBB2 Expression

Chang Li,* Xiaoping Li,† Shuohui Gao,* Chang Li,‡ and Lianjun Ma§

*Department of Gastrointestinal Internal Medicine, China–Japan Union Hospital of Jilin University, Changchun, P.R. China
†Department of Pediatrics, The First Hospital of Jilin University, Changchun, P.R. China
‡Department of Cadre’s Ward, China–Japan Union Hospital of Jilin University, Changchun, P.R. China
§Endoscopy Center, China–Japan Union Hospital of Jilin University, Changchun, P.R. China

Gastric cancer is the fourth most common type of cancer and the second highest leading cause of cancer-related deaths worldwide. It has already been established that miR-133a is involved in gastric cancer. In this study, we investigated the molecular mechanisms by which miR-133a inhibits the proliferation of gastric cancer cells. We analyzed the proliferative capacity of human gastric cancer cells SNU-1 using an MTT assay. Cell apoptosis was determined using flow cytometry. The expression levels of ERBB2, p-ERK1/2, and p-AKT in SNU-1 cells were determined using Western blot analysis. To confirm that ERBB2 is a direct target of miR-133a, a luciferase reporter assay was performed. Results showed that miR-133a overexpression inhibited SNU-1 cell proliferation and increased apoptosis. ERBB2 was a direct target of miR-133a, and it was negatively regulated by miR-133a. Interestingly, ERBB2 silencing has a similar impact to miR-133a overexpression, in that it significantly induced apoptosis and inhibited ERK and AKT activation. Our study showed that miR-133a inhibits the proliferation of gastric cancer cells by downregulating the expression of ERBB2 and its downstream signaling molecules p-ERK1/2 and p-AKT. Therefore, miR-133a might be used as a therapeutic target for treating gastric cancer.

Key words: MicroRNA-133a (miR-133a); Gastric cancer; ERBB2; p-ERK1/2; p-AKT

Address correspondence to Chang Li, Department of Cadre’s Ward, 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  or Lianjun Ma, Endoscopy Center, 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. 1177-1188, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14874349473815
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Leukemia Inhibitory Factor Promotes Aggressiveness of Chordoma

Sukru Gulluoglu,*† Mesut Sahin,‡ Emre Can Tuysuz,† Cumhur Kaan Yaltirik,§ Aysegul Kuskucu,* Ferda Ozkan,¶ Fikrettin Sahin,† Ugur Ture,§ and Omer Faruk Bayrak*

*Department of Medical Genetics, Yeditepe University Medical School, Istanbul, Turkey
†Department of Biotechnology, Institute of Science, Yeditepe University, Istanbul, Turkey
‡Department of Nanoscience and Nanoengineering, Institute of Science Ataturk University, Erzurum, Turkey
§Department of Neurosurgery, Yeditepe University Medical School, Yeditepe University, Istanbul, Turkey
¶Department of Medical Pathology, Yeditepe University Medical School, Yeditepe University, Istanbul, Turkey

Chordomas are rare tumors of the spine and skull base that are locally destructive and resistant to chemotherapy and radiation therapy, with a poor prognosis and limited therapeutic options. Chordoma patients have a long life expectancy with high mortality from the disease. Cancer stem cells, which are known to exist in chordomas, have extensive proliferative and self-renewal potential and are responsible for maintaining tumor heterogeneity along with chemotherapy and radiotherapy resistance. Leukemia inhibitory factor (LIF) has multiple functions in stem cell biology, the immune response, and cancer, and is potentially a key molecule that allows cancer stem cells to self-renew. The purpose of this study was to determine whether LIF increases the aggressive traits of chordoma cells and leads to a poor prognosis in patients. Chordoma cell lines were treated with LIF, and functional tests were done. Twenty skull base chordoma samples were checked for levels of LIF and a correlation with clinicopathological features. The whole transcriptome microarray was used to observe changes in gene expression. We observed increased migration, invasion, tumorosphere formation, colony formation, epithelial–mesenchymal transition, and chemoresistance accompanied by a dramatic elevation in inflammatory gene networks and pathways in chordomas. The expression of LIF was associated with tumor size and a poorer overall survival. Microarray and quantitative real-time polymerase chain reaction assessments suggest that LIF can facilitate tumor-promoting inflammation. Results indicate that LIF plays a role in maintaining cancer stem cells in chordomas.

Key words: Chordoma; Leukemia inhibitory factor (LIF); Tumor inflammation; Prognosis

Address correspondence to Omer Faruk BayrakYeditepe Universitesi Hastanesi Genetik Tani MerkeziKoftuncu Sokak AcıbademMahallesi Istek Vakfi 3, Kat 34718 No: 57/1 Kadikoy, Istanbul, Turkey. Tel: +905327280398; Fax: +902163265839; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1189-1197, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14865126670075
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Long Noncoding RNA LINC0086 Functions as a Tumor Suppressor in Nasopharyngeal Carcinoma by Targeting miR-214

Jie Guo,*† Jinqi Ma,‡ Guosheng Zhao,‡ Guocai Li,‡ Yunfeng Fu,‡ Yanwei Luo,‡ and Rong Gui

*Department of Preventive Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
†Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, P.R. China
‡Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, P.R. China

Nasopharyngeal carcinoma (NPC) is a distinct head and neck cancer, which is occurring at a high frequency in Southern China. Emerging studies have shown that long noncoding RNAs (lncRNAs) play a critical role in carcinogenesis and progression. In this study, we established a comprehensive lncRNA profile in NPC and found that 35 lncRNAs were differentially expressed in NPC. We found that LINC0086 was decreased in NPC patient serum samples and tissues. The Kaplan–Meier survival curve showed that patients with high LINC0086 expression had a higher survival rate than those with low LINC0086 expression. LINC0086 expression was associated with NPC histological grade, lymph node metastasis, and clinical stage. Upregulation of LINC0086 inhibited cancer cell proliferation and promoted apoptosis. In addition, upregulation of LINC0086 dramatically decreased the expression of miR-214, an oncogene in several cancers, in C666-1 and HK-1 cells. An miR-214 binding site was found in the 3′-UTR of LINC0086. We also validated that both miR-214 and LINC0086 presented in the RISC complex, demonstrating that LINC0086 could decrease miR-214 expression by directly interacting with miR-214. Furthermore, the suppressive effects of LINC0086 on NPC cell growth were reversed by overexpression of miR-214 in vitro and in vivo. Thus, our study reports a novel mechanism underlying NPC carcinogenesis and provides a potential novel diagnosis and treatment biomarker for NPC.

Key words: Nasopharyngeal carcinoma (NPC); Long noncoding RNAs (lncRNAs); LINC0086; miR-214; Carcinogenesis

Address correspondence to Dr. Yanwei Luo, Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Changsha, 410013, P.R. China. Tel: +86-0731-88618513; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Prof. Rong Gui, Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Changsha, 410013, P.R. China. Tel: +86-0731-88618513; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 1199-1205, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14873444858101
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Gamma Irradiation Upregulates B-cell Translocation Gene 2 to Attenuate Cell Proliferation of Lung Cancer Cells Through the JNK and NF-κBPathways

Peihe Wang,* Yuanyuan Cai,* Dongju Lin,† and Yingxiao Jiang*

*Department of Radiotherapy, Weifang People’s Hospital, Weifang, P.R. China
†Department of Reproduction, Weifang People’s Hospital, Weifang, P.R. China

Gamma ray can promote cancer cell apoptosis and cell cycle arrest. It is often used in the clinical treatment of tumors, including lung cancer. In this study, we aimed to explore the role of gamma ray treatment and its correlation with BTG2 in cell proliferation, apoptosis, and cell cycle arrest regulation in a lung cancer cell line. A549 cell viability, apoptosis rate, and cell cycle were investigated after gamma ray treatment. We then used siRNA for BTG2 to detect the effect of BTG2 knockdown on the progress of gamma ray-treated lung cancer cells. Finally, we investigated the signaling pathway by which gamma ray might regulate BTG2. We found that gamma ray inhibited A549 cell viability and promoted apoptosis and cell cycle arrest, while BTG2 knockdown could relieve the effect caused by gamma ray on A549 cells. Moreover, we confirmed that the effect of BTG2 partly depends on p53 expression and gamma ray-promoting BTG2 expression through the JNK/NF-κB signaling pathway. Our study assessed the possible mechanism of gamma ray in tumor treatment and also investigated the role of BTG2 in gamma ray therapy. All these findings might give a deep understanding of the effect of gamma ray on the progression of lung cancer involving BTG2.

Key words: Lung neoplasms; Gamma ray; MAP kinase signaling system

Address correspondence to Yingxiao Jiang, Department of Radiotherapy, Weifang People’s Hospital, No. 151 Guangwen Street, Weifang 261000, 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. 1207-1214, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X
14886679715637
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved


Long Noncoding RNA CRNDE Promotes Multiple Myeloma Cell Growth by Suppressing miR-451

Yi-Bin Meng, Xin He, Yun-Fei Huang, Qi-Ning Wu, Yong-Cun Zhou, and Ding-Jun Hao

Hong-Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, Shanxi, P.R. China

It has been determined that long noncoding RNAs (lncRNAs) are identified as a potential regulatory factor in multiple tumors as well as multiple myeloma (MM). However, the role of colorectal neoplasia differentially expressed (CRNDE) in the pathogenesis of MM remains unclear. In this study, we found that the CRNDE expression level, in MM samples and cell lines, is higher than that in the control detected by real-time qPCR, which is also closely related to tumor progression and poor survival in MM patients. Knockdown of CRNDE significantly inhibits the proliferative vitality of MM cells (U266 and RPMI-8226), induces cell cycle arrest in the G0/G1
phase, and promotes apoptosis. After being transfected with siRNA, miR-451 expression observably increases. Bioinformatics analysis and luciferase assay reveal the interaction by complementary bonding between CRNDE and miR-451. Pearson’s correlation shows that CRNDE is negatively correlated to miR-451 expression in human MM samples. Subsequently, miR-451 inhibitor rescues the inhibited tumorigenesis induced by CRNDE knockdown. Our study illustrates that lncRNA CRNDE induces the proliferation and antiapoptosiscapability of MM by acting as a ceRNA or molecular sponge via negatively targeting miR-451, which could act as a novel diagnostic marker and therapeutic target for MM.

Key words: Colorectal neoplasia differentially expressed (CRNDE); miR-451; Long noncoding RNAs (lncRNAs); Multiple myeloma (MM)

Address correspondence to Ding-Jun Hao, M.D., Hong-Hui Hospital, Xi’an Jiaotong University College of Medicine, No. 76 Nanguo Road, Xi’an, Shanxi 710061, P.R. China. Tel: +86-029-87800002; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it