Oncology Research 25(5) Abstracts

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Oncology Research, Vol. 25, pp. 651-661, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14752792816791
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Exosomes Derived From Hypoxic Colorectal Cancer Cells Promote Angiogenesis Through Wnt4-Induced β-Catenin Signaling in Endothelial Cells

Zhe Huang and Yong Feng

Department of 11th General Surgery, Shengjing Hospital of China Medical University, Shenyang, P.R. China

Cancer cell-derived exosomes have been actively released into the tumor microenvironment with pleiotropic roles in tumor growth and metastasis, including angiogenesis and immune modulation. However, the functions and underlying mechanisms of exosomes shed by colorectal cancer (CRC) cells under hypoxic conditions remain unknown. Here we found that exosomes derived from hypoxic CRC cells promoted the proliferation and migration of endothelial cells. Suppression of exosome secretion through RAB27a knockdown in CRC cells inhibited exosomal-induced proliferation and migration of endothelial cells. Furthermore, we discovered that these exosomes enriched with Wnt4 were dependent on HIF1α. Exosomal Wnt4 increased β-catenin nuclear translocation in endothelial cells. The induction of β-catenin signaling is critical for the proliferation and migration of endothelial cells, which could be abolished by the inhibitor ICG001. The in vivo animal study further revealed the tumorpromoting effects of CRC cell-derived exosomes with enhanced tumor growth and angiogenesis. Taken together, our study indicates that CRC cells promote angiogenesis through exosome-mediated Wnt/β-catenin signaling in endothelial cells under hypoxia, which might be a new mechanism in CRC development.

Key words: Colorectal cancer (CRC); Exosome; Wnt; Catenin; Angiogenesis

Address correspondence to Yong Feng, Department of 11th General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang 110004, P.R. China. Tel: 00-86-024-96615; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 663-671, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14761384026719
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

PAQR3 Inhibits the Proliferation and Tumorigenesis in Esophageal Cancer Cells

Fang Zhou,*1 Shunchang Wang,†1 and Jianjun Wang*

*Department of Oncology, Huaihe Hospital of Henan University, Kaifeng, P.R. China
†Department of Surgery, Huaihe Hospital of Henan University, Kaifeng, P.R. China

Progestin and adipoQ receptor family member III (PAQR3), a member of the PAQR family, is frequently downregulated in different types of human cancer. However, its expression and functions in esophageal cancer are still unknown. This study aimed to explore the expression of PAQR3 in esophageal cancer cell lines and to investigate the role of PAQR3 in the development of esophageal cancer. Our data showed that PAQR3 is expressed in low amounts in human esophageal cancer cell lines. Overexpression of PAQR3 significantly suppressed the proliferation, migration, and invasion of esophageal cancer cells. In addition, overexpression of PAQR3 downregulated the protein expression levels of RAF1, p-MEK1, and p-ERK1/2 in esophageal cancer cells. Furthermore, overexpression of PAQR3 attenuated the tumor growth in a tumor xenograft model. In conclusion, we demonstrated that overexpression of PAQR3 suppresses cell proliferation, migration, and invasion in esophageal cancer in vitro and in vivo. Therefore, PAQR3 may act as a therapeutic target for human esophageal cancer.

Key words: Progestin and adipoQ receptor family member III (PAQR3); Esophageal cancer; Proliferation; Invasion

1These authors provided equal contribution to this work.
Address correspondence to Jianjun Wang, Department of Oncology, Huaihe Hospital of Henan University, No. 8 Baobei Road, Kaifeng 475000, Henan Province, P.R. China. Tel: +86-0378-3155122; Fax: +86-0378-3155122; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 673-679, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14786040691928
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated According to Uridine Diphosphate Glucuronosyltransferase 1A1 Genotyping in Patients With Metastatic Colorectal Cancer

Cheng-Jen Ma,*†‡ Ching-Wen Huang,*‡§ Yung-Sung Yeh,*†¶ Hsiang-Lin Tsai,*§#** Huang-Ming Hu,††‡‡ I-Chen Wu,††‡‡ Tian-Lu Cheng,§§¶¶ and Jaw-Yuan Wang*†‡§**¶¶

*Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
†Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
‡Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
§Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
¶Division of Trauma and Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
#Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
**Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
††Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
‡‡Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
§§Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
¶¶Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan

We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade ≥3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0–21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes.

Key words: UGT1A1; Regorafenib; FORFIRI; Dose escalation; Metastatic colorectal cancer (mCRC)

Address correspondence to Professor Jaw-Yuan Wang, Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung 807, Taiwan. Tel: +886-7-3121101; Fax: +886-7-3213931; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 681-689, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14771034190471
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

FOXR2 Promotes the Proliferation, Invasion, and Epithelial–Mesenchymal Transition in Human Colorectal Cancer Cells

Sheng-Qiang Lu,*1 Yan Qiu,†1 Wei-Jie Dai,‡ and Xiao-Yu Zhang§

*Department of Anesthesiology, Hubei Cancer Hospital, Wuhan, P.R. China
†Department of Clinical Laboratory, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
‡Department of Gastroenterology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, P.R. China
§Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, P.R. China

Forkhead box R2 (FOXR2), a member of the FOX gene family, has not been very well investigated for its role in cancer. A recent study has shown that FOXR2 is highly expressed in breast cancer samples and is associated with poor prognosis. In addition, FOXR2 was identified as an oncogene in medulloblastoma. Nevertheless, whether FOXR2 plays a role in colorectal cancer (CRC) remains unclear. In the present study, we conducted several in vitro and in vivo studies to investigate the expression and effect of FOXR2 in CRC. The study results demonstrated that FOXR2 was upregulated in CRC tissues and cells. Downregulation of FOXR2 inhibited CRC cell proliferation, invasion, and the epithelial–mesenchymal transition (EMT) phenotype in vitro and also suppressed CRC cell growth and metastasis in vivo. Furthermore, downregulation of FOXR2 remarkably reduced the protein expression of Shh, Gli1, and Ptch1 in SW480 cells. Taken together, our data suggested that FOXR2 significantly promoted proliferation, invasion, and EMT of CRC cells. All these findings provided evidence for the role of FOXR2 as an oncogene in CRC development.

Key words: Forkhead box R2 (FOXR2); Proliferation; Invasion; Epithelial–mesenchymal transition (EMT); Colorectal cancer (CRC)

1These authors are co-first authors.
Address correspondence to Xiao-Yu Zhang, Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, No. 62 Huaihai South Road, Huai’an 223300, 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. 691-699, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14774897404770
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

TRIM11 Upregulation Contributes to Proliferation, Invasion, and EMT of Hepatocellular Carcinoma Cells

Zewei Zhang,*1 Chao Xu,†1 Xiafang Zhang,†1 Lulu Huang,† Cheng Zheng,‡ Haitao Chen,† Yan Wang,† Haixing Ju,§ and Qinghua Yao†

*Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou, P.R. China
†Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, P.R. China
‡Zhejiang Institute for Food and Drug Control, Hangzhou, P.R. China
§Department of Colorectal Surgery, Zhejiang Cancer Hospital, Hangzhou, P.R. China

The tripartite motif-containing protein 11 (TRIM11), a member of the TRIM protein family, has attracted much attention because of its involvement in the development of the central nervous system. It has gained renewed focus because of its newly found function in promoting tumors. However, little is known about its role in hepatocellular carcinoma (HCC). In the present study, we found TRIM11 to be overexpressed in HCC tissues and cell lines. Downregulation of TRIM11 inhibited HCC cell proliferation and invasion in vitro and in vivo as well as suppressed the epithelial–mesenchymal transition (EMT) process. In addition, downregulation of TRIM11 decreased the protein expression levels of p-PI3K and p-Akt in HCC cells and thus inhibited activation of the PI3K/Akt signaling pathway. Based on these results, we suggest the importance of TRIM11 in HCC progression and the potential of TRIM11 as a therapeutic target for HCC.

Key words: Tripartite motif-containing protein 11 (TRIM11); Proliferation; Invasion; Epithelial–mesenchymal transition (EMT); Hepatocellular carcinoma (HCC)

1These authors provided equal contribution to this work.
Address correspondence to Haixing Ju, Department of Colorectal Surgery, Zhejiang Cancer Hospital, 1st East Banshan Road, Hangzhou 310022, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Qinghua Yao, Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, 1st East Banshan Road, Hangzhou 310022, 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. 701-708, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772378087005
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Forkhead Box A2 (FOXA2) Inhibits Invasion and Tumorigenesis in Glioma Cells

Bingqian Ding,*1 Huimin Liang,†1 Ming Gao,* Zhenjiang Li,* Chenyang Xu,* Shaokang Fan,* and Na Chang†

*Department of Neurosurgery, Huaihe Hospital of Henan University, Kaifeng, P.R. China
†Department of Neurology, Huaihe Hospital of Henan University, Kaifeng, P.R. China

The forkhead box A2 (FOXA2) is the key transcriptional factor that plays an important role in tumorigenesis. However, until now the expression pattern and role of FOXA2 in glioma have yet to be elucidated. Therefore, the aim of this study was to evaluate the expression of FOXA2 in glioma and investigate its role in glioma cells. Our data showed that FOXA2 was significantly downregulated in human glioma cell lines. Forced expression of FOXA2 suppressed the ability of glioma cells to proliferate, migrate, and invade and influenced the expression level of EMT-associated proteins. In addition, forced expression of FOXA2 attenuated tumor growth of glioma in a nude mouse xenograft model. Mechanistically, we disclosed that forced expression of FOXA2 greatly downregulated the expression of b-catenin, cyclin D1, and c-Myc in glioma cells. Taken together, these results show that FOXA2 may play an important role in proliferation, invasion, and tumorigenesis in glioma cells. Thus, FOXA2 may be a potential therapeutic target for the treatment of glioma.

Key words: Glioma; Forkhead box A2 (FOXA2); Migration; Invasion

1These authors provided equal contribution to this work.
Address correspondence to Na Chang, Department of Neurology, Huaihe Hospital of Henan University, No. 8 Baobei Road, Kaifeng 475000, P.R. China. Tel: +86-0371-23906530; Fax: +86-0371-23906058; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 709-719, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772331883976
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Overexpression of PER3 Inhibits Self-Renewal Capability and Chemoresistance of Colorectal Cancer Stem-Like Cells via Inhibition of Notch and β-Catenin Signaling

Feng Zhang,* Hong Sun,† Sai Zhang,† Xin Yang,‡ Guogang Zhang,* and Tao Su†

*Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, P.R. China
†The Medical Research Center of Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
‡Department of General Surgery, The Third Hospital of Changsha, Changsha, P.R. China

PER3, a circadian clock gene, plays an important role in colorectal cancer, but its action and underlying mechanism in colorectal cancer stem-like cells (CSCs) remain unclear. In this study, the colorectal CSCs were enriched in colorectal HCT-116 sphere-forming cells, expressing lower levels of stem cell markers CD133, CD44, LGR5, and SOX2 compared with HCT-116 cells. A drug-resistant strain from HCT-116 was established. Western blot and qRT-PCR analysis showed that PER3 was downregulated in colorectal CSCs and drug-resistant HCT-116. Overexpression of PER3 could strengthen 5-FU-induced inhibitory effects on colorectal CSCs, but knockdown of PER3 decreased its inhibition of colorectal CSCs. In addition, overexpression of PER3 in colorectal CSCs resulted in reduced colony formation efficiency in a soft agar medium and self-renewal efficiency. Inversely, knockdown of PER3 enhanced self-renewal of colorectal CSCs. Overexpression of PER3 decreased stemness markers and Notch1, Jagged1, β-catenin, c-Myc, and LGR5 in colorectal CSCs. When Notch or β-catenin signaling was inhibited, the chemoresistance and self-renewal capability of colorectal CSCs were decreased. It was confirmed that PER3 can reduce chemoresistance and self-renewal capability of colorectal CSCs via inhibition of Notch and β-catenin signaling. Our results reveal that PER3 plays a critical role in maintaining the stemness of colorectal CSCs and may be a promising target for elimination of CSCs.

Key words: Colorectal cancer stem-like cells (CSCs); Circadian clock; PER3; Self-renewal; Chemoresistance

Address correspondence to Guogang Zhang, Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, P.R. China. Tel: +86-731-84327695; Fax: +86-731-84327695; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Tao Su, The Medical Research Center of Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, P.R. China. Tel: 86-0731-84327628; Fax: +86-731-84327332; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 721-731, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772375848616
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Knockdown of Cyclin-Dependent Kinase Inhibitor 3 Inhibits Proliferation and Invasion in Human Gastric Cancer Cells

Yan Li,* Shan Ji,† Li-Ye Fu,* Tao Jiang,* Di Wu,* and Fan-Dong Meng*

*Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, P.R. China
†Department of Endocrinology, The Fifth People’s Hospital of Shenyang, Shenyang, P.R. China

Cyclin-dependent kinase inhibitor 3 (CDKN3) has been reported to promote tumorigenesis. Since it is unclear whether CDKN3 participates in the development of human gastric cancer, this study assessed the association between CDKN3 expression and cell biological function and demonstrated the clinical significance and prognosis of CDKN3 in human gastric cancer. In this study, we found that CDKN3 showed a high expression in 35 paired human gastric cancer tissues and was correlated with poor patient survival, AJCC clinical staging, and recurrence. Silencing of CDKN3 in human gastric cancer cells can significantly reduce proliferation, migration, invasion, and adhesion abilities. Also, silencing of CDKN3 in human gastric cancer cells can induce G0–G1 cell cycle arrest and apoptosis. Detection of cell cycle marker expression showed that CDKN3 knockdown promotes cell cycle arrest by decreasing the expression of CDK2, CDC25A, CCNB1, and CCNB2 in human gastric cancer cells. The results of this study will help elucidate the oncogene function of CDKN3 in human gastric cancer.

Key words: Gastric cancer; Cyclin-dependent kinase inhibitor 3 (CDKN3); Cell cycle; Motility

Address correspondence to Fan-Dong Meng, Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, No. 92 Beier Street, Heping District, Shenyang 110001, 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. 733-742, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772362173376
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Long Noncoding RNA LINC00261 Suppresses Cell Proliferation and Invasion and Promotes Cell Apoptosis in Human Choriocarcinoma

Yinan Wang,* Kai Xue,† Yonghong Guan,* Yuemei Jin,* Shanshan Liu,* Yichao Wang,* Shuyan Liu,* Ling Wang,* and Liying Han*

*Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, P.R. China
†Department of Otolaryngology, The Second Hospital of Jilin University, P.R. China

Choriocarcinoma is one of the gestational trophoblastic neoplasias (GTNs) that originate in the chorionic villi and the extravillous trophoblast. Long noncoding RNAs (lncRNAs) are a type of non-protein-coding RNAs that have recently been implicated in human tumorigenesis. The present study investigated the role of the lncRNA LINC00261 in cell proliferation, metastasis, and apoptosis in choriocarcinoma cell lines. The transcription level of LINC00261 was significantly lower in choriocarcinoma tissues and in choriocarcinoma cell lines. Overexpression of LINC00261 caused a decrease in cell proliferation and arrested the cell cycle at the G0/G1 phase. Furthermore, overexpression of LINC00261 inhibited cell migration and invasion. Meanwhile, it promoted cell apoptosis and the relative activities of caspase 3 and caspase 9 in choriocarcinoma JEG-3 and JAR cells. These data suggested that LINC00261 promotes cell proliferation and metastasis in choriocarcinoma. Our data might provide novel insight into the early diagnosis and treatment of choriocarcinoma in clinics.

Key words: Choriocarcinoma; LINC00261; Proliferation; Metastasis; Apoptosis

Address correspondence to Liying Han, M.D., Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun City, Jilin Province 130041, P.R. China. Tel: +86-0431-88796114; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 743-751, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772395226335
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Downregulation of Ubiquitin-Specific Protease 22 Inhibits Proliferation, Invasion, and Epithelial–Mesenchymal Transition in Osteosarcoma Cells

Dengfeng Zhang,1 Feng Jiang,1 Xiao Wang, and Guojun Li

Orthopedics Department, Huaihe Hospital of Henan University, Kaifeng, P.R. China

Ubiquitin-specific protease 22 (USP22), a novel deubiquitinating enzyme, belongs to an extended family of proteins that have ubiquitin hydrolase activity. Recently, USP22 has attracted widespread attention because of its implication in carcinogenesis. However, there have been no studies, to our knowledge, investigating the expression of USP22 in osteosarcoma (OS) and its association with OS progression. In this study, we explored the role of USP22 in OS. We demonstrated that USP22 was highly expressed in OS tissue and cell lines. Downregulation of USP22 inhibited OS cell proliferation, invasion, and epithelial–mesenchymal transition (EMT) in vitro. In addition, downregulation of USP22 suppressed OS tumor growth and metastasis in vivo. We also found that the PI3K/Akt signaling pathway was involved in the tumor-promoting effect of USP22 on OS progression. Taken together, we suggest USP22 as a novel therapeutic target for OS.

Key words: Ubiquitin-specific protease 22 (USP22); Proliferation; Invasion; Epithelial–mesenchymal transition (EMT); Osteosarcoma (OS)

1These authors provided equal contribution to this work.
Address correspondence to Dengfeng Zhang, Orthopedics Department, Huaihe Hospital of Henan University, No. 8 Baobei Road, Kaifeng 475000, Henan Province, P.R. China. Tel: +86-0371-3906000; Fax: +86-0371-3906000; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 753-761, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
114772342320617
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Downregulation of MicroRNA-449 Promotes Migration and Invasion of Breast Cancer Cells by Targeting Tumor Protein D52 (TPD52)

Zhiling Zhang, Jiawei Wang, Runfang Gao, Xuan Yang, Yafen Zhang, Jie Li, Jing Zhang, Xingjuan Zhao, Chunfang Xi, and Xiaoting Lu

Department of Breast Surgery, Shanxi Provincial People’s Hospital, Taiyuan, P.R. China

Our study aimed to investigate whether microRNA-449 (miR-449) plays a key role in regulating the migration and invasion of breast cancer cells via targeting tumor protein D52 (TPD52). The results of the qRT-PCR and Western blotting showed that, in comparison with normal breast tissues and cells, miR-449 was significantly downregulated in breast cancer tissues and cells, while TPD52 was markedly upregulated. After transfection with an miR-449 inhibitor, suppression of miR-449 significantly promoted cell migration and invasion. Also, when miR-449 was overexpressed by transfection with miR-449 mimics, E-cadherin expression significantly increased, and the expression of N-cadherin and vimentin were markedly decreased, whereas the opposite effects were obtained when miR-449 was suppressed by transfection with an miR-449 inhibitor. TPD52 was also confirmed as the direct target of miR-449 via luciferase reporter analysis. Knockdown of TPD52 significantly alleviated the effects of miR-449 overexpression on cell migration and invasion, as well as the expression of E-cadherin, N-cadherin, and vimentin. Our results indicate that downregulation of miR-449 may promote the migration and invasion of breast cancer cells by targeting TPD52. miR-449 may serve as a potential target in the therapy of breast cancer.

Key words: Breast cancer; MicroRNA-449 (miR-449); Cell proliferation; Cell migration; Cell invasion; Tumor protein D52 (TPD52)

Address correspondence to Zhiling Zhang, Department of Breast Surgery, Shanxi Provincial People’s Hospital, No. 29 Shuangtasi Avenue, Taiyuan 030012, 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. 763-771, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772402056137
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Knockdown of SALL4 Inhibits Proliferation, Migration, and Invasion in Osteosarcoma Cells

Dengfeng Zhang,1 Feng Jiang,1 Xiao Wang, and Guojun Li

Orthopedics Department, Huaihe Hospital of Henan University, Kaifeng, P.R. China

Sal-like protein 4 (SALL4) is a zinc finger transcription factor that has been reported to be aberrantly expressed in several human malignancies and identified as an oncogene. However, the potential role of SALL4 in osteosarcoma remains to be elucidated. In this study, we explored the biological functions of SALL4 in osteosarcoma. We found that SALL4 was overexpressed in osteosarcoma tissues and cell lines. Knockdown of SALL4 inhibited osteosarcoma cell proliferation, migration, and invasion in vitro. In addition, SALL4 knockdown suppressed osteosarcoma growth and metastasis in vivo. We also showed that SALL4 knockdown decreased the protein expression of Wnt3a and b-catenin in osteosarcoma cells. Taken together, our study showed that SALL4 plays an important role in regulating the proliferation, migration, and invasion of osteosarcoma cells. Thus, SALL4 may represent a potential therapeutic target in the treatment of osteosarcoma.

Key words: Sal-like protein 4 (SALL4); Proliferation; Invasion; Osteosarcoma

1These authors provided equal contribution to this work.
Address correspondence to Dengfeng Zhang, Orthopedics Department, Huaihe Hospital of Henan University, No. 8 Baobei Road, Kaifeng 475000, Henan Province, P.R. China. Tel: +86-0378-3906000; Fax: +86-0378-3906000; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 773-779, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14774889687280
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
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Tumor Protein D52 (TPD52) Inhibits Growth and Metastasis in Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway

Zhenhua Zhao,1 Hui Liu,1 Junqing HouTieqiang Li, Xinyi Du, Xiaolei Zhao, Wenchao Xu, Weibo Xu, and Junkai Chang

Department of Urology, Huaihe Hospital of Henan University, Kaifeng, P.R. China

Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial–mesenchymal transition (EMT) phenotype in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC.

Key words: Renal cell carcinoma (RCC); Tumor protein D52 (TPD52); Proliferation; Invasion

1These authors provided equal contribution to this work.
Address correspondence to Zhenhua Zhao, Department of Urology, Huaihe Hospital of Henan University, No. 8 Baobei Road, Kaifeng 475000, Henan Province, P.R. China. Tel: +86-0371-23906572; Fax: +86-0371-23906572; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 781-787, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772417575982
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Protease Serine S1 Family Member 8 (PRSS8) Inhibits Tumor Growth In Vitro and In Vivo in Human Non-Small Cell Lung Cancer

Chaonan Ma,*1 Wei Ma,*1 Nannan Zhou,* Na Chen,* Li An,† and Yijie Zhang*

*Respiratory Department, Huaihe Hospital of Henan University, Kaifeng, P.R. China
†Department of Medical Record, The First People’s Hospital of Lingbao City, Lingbao, P.R. China

Protease serine S1 family member 8 (PRSS8), a membrane-anchored serine protease, has been reported to be involved in the development of several human cancers. However, the role of PRSS8 in non-small cell lung cancer (NSCLC) pathogenesis remains unclear. The objective of this study was to investigate PRSS8 expression, biological function, and its related molecular mechanism in NSCLC. Our results showed that PRSS8 was expressed in a low amount in NSCLC cell lines. Ectopic expression of PRSS8 inhibited tumor growth in vitro and in vivo. Furthermore, ectopic expression of PRSS8 inhibited the migration and invasion of NSCLC cells. It also suppressed the EMT process in A549 cells. Mechanistically, we found that the ectopic expression of PRSS8 downregulated the protein expression levels of p-JAK1, p-JAK2, and p-STAT3 in A549 cells. Taken together, our study showed that PRSS8 plays an important role in the growth and metastasis of NSCLC. Thus, PRSS8 may be a novel therapeutic target for NSCLC.

Key words: Non-small cell lung cancer (NSCLC); Protease serine S1 family member 8 (PRSS8); Proliferation; Metastasis

1These authors provided equal contribution to this work.
Address correspondence to Yijie Zhang, Respiratory Department, Huaihe Hospital of Henan University, No. 115 of Ximen Street, Kaifeng 475000, P.R. China. Tel: +86-0371-23906609; Fax: +86-0371-23906609; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 789-798, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14783677992682
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Long Noncoding RNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation and Invasion in Gastric Cancer via Negatively Modulating miRNA-145-5p

Kewei Ren,*†‡ Zhen Li,*†‡ Yahua Li,*†‡ Wenzhe Zhang,*†‡ and Xinwei Han*†‡

*Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
†Interventional Institute of Zhengzhou University, Zhengzhou, P.R. China
‡Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, P.R. China

Long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) is involved in the development and carcinogenesis of various tumors, suggesting the diagnostic potential of TUG1 in these cancers. However, the exact role of TUG1 and its underlying mechanism in gastric cancer (GC) remain unknown. In this study, the expression of TUG1 and miR-145-5p in GC cell lines and nonmalignant gastric epithelial cell lines was detected by qRT-PCR. BGC-823 and SGC-7901 cells were transfected with si-TUG1, pcDNA 3.1-TUG1, miR-145-5p mimics, or matched controls. The biological function of TUG1 and miR-145-5p in GC cell proliferation and invasion in vitro and tumor growth in vivo was investigated by MTT assay, Transwell invasion assay, and tumor xenograft experiments. The regulating relationship between TUG1 and miR-145-5 was confirmed by luciferase reporter assay. The results showed that TUG1 was significantly overexpressed and miR-145-5p was dramatically downregulated in GC cell lines. TUG1 knockdown strikingly inhibited cell proliferation and invasion in vitro and markedly suppressed tumor growth in vivo. Furthermore, TUG1 could directly bind to miR-145-5p and repress miR-145-5p expression. TUG1 overexpression significantly relieved the inhibition on GC cell proliferation and invasion in vitro and tumor growth in vivo, mediated by miR-145-5p overexpression. In conclusion, TUG1 promotes cell proliferation and invasion in GC via negatively modulating miRNA-145-5p, which undoubtedly contributes to understanding the mechanism of GC occurrence and development.

Key words: Gastric cancer (GC); Long noncoding RNA (lncRNA); Taurine-upregulated gene 1 (TUG1); miRNA-145-5p; Proliferation; Invasion

Address correspondence to Xinwei Han, Department of Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, P.R. China. Tel: +86037166862161; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 799-808, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14783691306605
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Oxysterol-Binding Protein-Related Protein 8 Inhibits Gastric Cancer Growth Through Induction of ER Stress, Inhibition of Wnt Signaling, and Activation of Apoptosis

Xiaohe Guo,* Lanfang Zhang,* Yingying Fan,* Dezhong Zhang,† Lei Qin,* Shuping Dong,* and Guangyan Li*

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

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. Oxysterol-binding proteinrelated protein 8 (ORP8) functions as a sterol sensor that regulates a number of cellular functions. We showed that ORP8 expression was significantly lower in GC tissues and cells. Overexpression of ORP8 significantly inhibited GC cell proliferation in several GC cells. The formation of colonies in AGS cells was inhibited by the overexpression of ORP8. Moreover, overexpression of ORP8 significantly decreased implanted tumor growth in nude mice. Overexpression of ORP8 resulted in a significant increase in CHOP and GRP78 expression and the phosphorylation of PERK, indicating the occurrence of ER stress. Inhibition of ER stress by 4-PBA notably suppressed overexpression of ORP8-induced decrease of GC cell proliferation, formation of colonies, and implanted tumor growth. Overexpression of ORP8 resulted in a significant decrease in Wnt3a and b-catenin expression, and activation of Wnt signaling by HLY78 markedly blocked overexpression of ORP8-induced decrease in GC cell proliferation, formation of colonies, and implanted tumor growth. 4-PBA inhibited overexpression of ORP8-induced decrease in Wnt signaling. Furthermore, overexpression of ORP8 resulted in significant activation of mitochondrial apoptotic events and increase in apoptosis, which was inhibited by 4-PBA and HLY78. Induction of ER stress, inhibition of Wnt signaling, and apoptotic cell death were involved in ORP8-induced inhibition of GC cell proliferation. These findings indicate that downregulation of ORP8 plays a pivotal role in the progression of GC, and it may be a novel therapeutic target in the treatment of GC.

Key words: Oxysterol-binding protein-related protein 8 (ORP8); Gastric cancer (GC); Endoplasmic reticulum (ER) stress; Wnt signaling; Mitochondrial apoptosis

Address correspondence to Guangyan Li, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road 88, Weihui 453100, 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. 809-817, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14799180778233
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Kallistatin Suppresses Cell Proliferation and Invasion and Promotes Apoptosis in Cervical Cancer Through Blocking NF-κB Signaling

Tao Wang, Fan Shi, JiQuan Wang, Zi Liu, and Jin Su

Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China

Kallistatin has been recognized as an endogenous angiogenesis inhibitor and exerts pleiotropic effects in inhibiting tumor growth, migration, apoptosis, and inflammation. The purpose of the present study was to investigate the potential role and mechanisms of kallistatin in cervical cancer. We demonstrated that kallistatin effectively inhibited cell proliferation and enhanced apoptosis in a dose-dependent manner. Additionally, kallistatin suppressed migration and invasion activities and markedly reduced the expression of matrix-degrading metalloproteinases, progelatinase (MMP-2), MMP-9, and urokinase-type PA (uPA). Kallistatin reversed the epithelial–mesenchymal transition (EMT) and caused the upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and vimentin. Moreover, kallistatin led to a marked decrease in the expression of vascular endothelial growth factor (VEGF) and HIF-1α. In a xenograft mouse model, kallistatin treatment reduced tumor growth. Importantly, kallistatin strikingly impeded NF-κB activation by suppressing IκBα degradation and the level of phosphorylation of p65. Interestingly, similar to kallistatin, treatment with PDTC (an inhibitor of NF-κB) also attenuated cell invasion and migration. Taken together, these findings suggest that kallistatinsuppresses cervical cancer cell proliferation, migration, and EMT and promotes cell apoptosis by blocking the NF-κB signaling pathway, suggesting that kallistatin may be a novel therapeutic target for cervical cancer treatment.

Key words: Cervical cancer; Kallistatin; Migration; Apoptosis; NF-κB signaling

Address correspondence to Tao Wang, Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yan Tower West Road, Xi’an 710061, P.R. China. Tel: +86-029-85324019; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 819-829, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14772349843854
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Silencing of Btbd7 Inhibited Epithelial–Mesenchymal Transition and Chemoresistance in CD133+ Lung Carcinoma A549 Cells

Li-Zhou Fang,* Jian-Qing Zhang,* Ling Liu,* Wei-Ping Fu,* Jing-Kui Shu,* Jia-Gang Feng,* and Xiao Liang†

*Department of Respiratory Medicine, The First Affiliated Hospital of Kunming University of Science and Technology, Kunming City, Yunnan Province, P.R. China
†Department of Infectious Diseases, The First People’s Hospital of Yunnan Province, Kunming City, Yunnan Province, P.R. China

Cancer stem cells (CSCs) are responsible for tumorigenesis and recurrence, so targeting CSCs is an effective method to potentially cure cancer. BTB/POZ domain-containing protein 7 (Btbd7) has been found in various cancers, including lung cancer and liver cancer, but the role of Btbd7 in non-small cell lung cancer (NSCLC), CSC self-renewal, and chemoresistance is still unknown. Therefore, in this study we found that the ratio of tumor sphere formation and stem cell transcription factors in CD133+ cells was dramatically enhanced compared to parental cells, which indicated successful sorting of CD133+ cells from A549. Meanwhile, Btbd7 and the markers of the epithelial–mesenchymal transition (EMT) process were more highly expressed in CD133+ cells than in parental cells. Silencing of Btbd7 significantly inhibited the self-renewal and EMT process in CD133+ cells. Furthermore, we found that downregulation of Btbd7 promoted cell apoptosis and increased the sensitivity to paclitaxel in CD133+ and parental cells. In conclusion, our results suggest that Btbd7 is a promising agent for the inhibition of survival and chemoresistance of cancer stem-like cells of NSCLC, which may act as an important therapeutic target in NSCLC.

Key words: Btbd7; CD133+; Epithelial–mesenchymal transition (EMT); Chemoresistance; Non-small cell lung cancer (NSCLC)

Address correspondence to Liang Xiao, Department of Infectious Diseases, The First People’s Hospital of Yunnan Province, No. 157 Jinbi Road, Kunming City, Yunnan Province 650031, P.R. China. Tel: 86-871-63638520; E-mail; This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 25, pp. 831-842, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14816726393937
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

GGNBP2 Suppresses the Proliferation, Invasion, and Migration of Human Glioma Cells

Ao Zhan,* Bo Lei,* Honggang Wu,* YueTao Wen,† Liandong Zheng,* Shan Wang,* Xiaoqiang Wan,* and Zhenghong Wei*

*Department of Neurosurgery, The People’s Hospital of Leshan City, Leshan, Sichuan, P.R. China
†Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, P.R. China

Gliomas are the most common and aggressive type of primary adult brain tumors. Although GGNBP2 has previously been considered to be a tumor suppressor gene, little is known about the association between GGNBP2 and glioma. In this study, we clearly demonstrated that GGNBP2 was downexpressed in glioma tissues, and its downexpression is related to the pathological grade and overall survival of patients with gliomas. Overexpression of GGNBP2 suppressed the proliferation, migration, and invasion of glioma cells. Mechanistically, we demonstrated that the PI3K/Akt and Wnt/β-catenin signaling pathways were suppressed by GGNBP2 overexpression. In contrast, knockdown of GGNBP2 has precisely the opposite effect. Collectively, these data indicate that GGNBP2 shows tumor suppressive activity in human glioma cells and may stand out as a potential therapeutic target for glioma.

Key words: GGNBP2; Glioma; Proliferation; Invasion; Migration

Address correspondence to Zhenghong Wei, Department of Neurosurgery, The People’s Hospital of Leshan City, No. 238 White Tower Street, Leshan City, Sichuan Province 614000, 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. 843-852, 2017
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504016X
14813880882288
E-ISSN 1555-3906
Copyright ©2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Epithelial–Mesenchymal Transition via STAT3 Signaling Pathway in Non-Small Cell Lung Cancer Cells

Wenzhang Zhang,*1 Xin Wu,†1 Liang Hu,* Yuefan Ma,* Zihan Xiu,* Bingyu Huang,* Yun Feng,* and Xudong Tang*†‡

*Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, Guangdong, P.R. China
†Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, P.R. China
‡Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong, P.R. China

The human papillomavirus (HPV) infection may be associated with the development and progression of nonsmall cell lung cancer (NSCLC). However, the role of HPV-16 oncoproteins in the development and progression of NSCLC is not completely clear. Epithelial–mesenchymal transition (EMT), a crucial step for invasion and metastasis, plays a key role in the development and progression of NSCLC. Here we explored the effect of HPV-16 oncoproteins on EMT and the underlying mechanisms. NSCLC cell lines, A549 and NCI-H460, were transiently transfected with the EGFP-N1-HPV-16 E6 or E7 plasmid. Real-time PCR and Western blot analysis were performed to analyze the expression of EMT markers. A protein microarray was used to screen the involved signaling pathway. Our results showed that overexpression of HPV-16 E6 and E7 oncoproteins in NSCLC cells significantly promoted EMT-like morphologic changes, downregulated the mRNA and protein levels of EMT epithelial markers (E-cadherin and ZO-1), and upregulated the mRNA and protein levels of EMT mesenchymal markers (N-cadherin and vimentin) and transcription factors (ZEB-1 and Snail-1). Furthermore, the HPV-16 E6 oncoprotein promoted STAT3 activation. Moreover, WP1066, a specific signal transducer and activator of transcription 3 (STAT3) inhibitor, reversed the effect of HPV-16 E6 on the expression of ZO-1, vimentin, and ZEB-1 in transfected NSCLC cells. Taken together, our results suggest that overexpression of HPV-16 E6 and E7 oncoproteins enhances EMT, and the STAT3 signaling pathway may be involved in HPV-16 E6-induced EMT in NSCLC cells.

Key words: Human papillomavirus (HPV); Epithelial–mesenchymal transition (EMT); Signal transducer and activator of transcription 3 (STAT3); Non-small cell lung cancer (NSCLC)

1These authors provided equal contribution to this work.
Address correspondence to Professor Xudong Tang, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, 2 Wenming DongluXiashan, Zhanjiang, Guangdong 524023, P.R. China. Tel: +86-13226269146; Fax: +86-759-2284104; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it