Cisplatin or Doxorubicin Reduces Cell Viability via the PTPIVA3-JAK2-STAT3 Cascade in Hepatocellular Carcinoma

Abstract

Chao-Jen Li,1,* Hung-Wen Tsai,2,* Yi-Li Chen,3 Chun-I Wang,4 Yang-Hsiang Lin,5 Pei-Ming Chu,6,7 Hsiang-Cheng Chi,8,9 Yi-Ching Huang,3 Cheng-Yi Chen3 1Department of General & Gastroenterological Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan; 2Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 5Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan; 8Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Cheng-Yi Chen, Tel/Fax [phone]#5329, Email [email protected]: Hepatocellular carcinoma (HCC) accounts for 80% of all liver cancers and is the 2nd leading cause of cancer-related death in Taiwan. Various factors, including rapid cell growth, a high recurrence rate and drug resistance, make HCC difficult to cure. Moreover, the survival rate of advanced HCC patients treated with systemic chemotherapy remains unsatisfactory. Hence, the identification of novel molecular targets and the underlying mechanisms of chemoresistance in HCC and the development more effective therapeutic regimens are desperately needed.Methods: An MTT assay was used to determine the cell viability after cisplatin or doxorubicin treatment. Western blotting, qRT‒PCR and immunohistochemistry were utilized to examine the protein tyrosine phosphatase IVA3 (PTP4A3) level and associated signaling pathways. ELISA was utilized to analyze the levels of the inflammatory cytokine IL-6 influenced by cisplatin, doxorubicin and PTP4A3 silencing.Results: In this study, we found that PTP4A3 in the cisplatin/doxorubicin-resistant microarray was closely associated with the overall and recurrence-free survival rates of HCC patients. Cisplatin or doxorubicin significantly reduced cell viability and decreased PTP4A3 expression in hepatoma cells. IL-6 secretion increased with cisplatin or doxorubicin treatment and after PTP4A3 silencing. Furthermore, PTP4A3 was highly expressed in tumor tissues versus adjacent normal tissues from HCC patients. In addition, we evaluated the IL-6-associated signaling pathway involving STAT3 and JAK2, and the levels of p-STAT3, p-JAK2, STAT3 and JAK2 were obviously reduced with cisplatin or doxorubicin treatment in HCC cells using Western blotting and were also decreased after silencing PTP4A3. Collectively, we suggest that cisplatin or doxorubicin decreases HCC cell viability via downregulation of PTP4A3 expression through the IL-6R-JAK2-STAT3 cascade.Discussion: Therefore, emerging evidence provides a deep understanding of the roles of PTP4A3 in HCC cisplatin/doxorubicin chemoresistance, which can be applied to develop early diagnosis strategies and reveal prognostic factors to establish novel targeted therapeutics to specifically treat HCC.Keywords: hepatocellular carcinoma, chemoresistance, cisplatin, doxorubicin, PTP4A3, IL-6

Keywords

• hepatocellular carcinoma
• chemoresistance
• cisplatin
• doxorubicin
• ptp4a3
• il-6