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

Abstract

Introduction

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

Data Sharing Statement

All data generated or analyzed during this study are included in this published article.

Ethics Approval and Consent to Participate

The National Health Research Institute Biobank and its associated institutions or providing the biological specimen and related clinical data (all of which have been deidentified) for our research. The doxorubicin-treated HCC patient specimens were obtained from the human biobank of National Cheng Kung University Hospital.

Consent for Publication

The authors agree to publish.

Acknowledgments

We would like to thank the National Health Research Institute Biobank and its associated institutions for providing the biological specimen and related clinical data (all of which have been deidentified) for our research. The National Health Research Institute Biobank is supported by grants from the Ministry of Health and Welfare, Ministry of Science and Technology and National Health Research Institutes, Taiwan. We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine and Cancer Data Bank of National Cheng Kung University Hospital. This work was supported by a grant from the Ministry of Science and Technology of the Republic of China (MOST 109-2320-B-006-067 to C.-Y.C.) and a grant from National Cheng Kung University Hospital (NCKUH-11102040), An Nan Hospital, China Medical University (ANHRF111-11). We would like to thank Ching-Chuan Hsieh and Pin-Jia Huang for performing experiments, acquisition of data, analysis and interpretation for manuscript revision.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Chao-Jen Li and Hung-Wen Tsai are co-first authors for this study. The authors declare no conflicts of interest in this work.

Additional information

Funding

This work was supported by a grant from the Ministry of Science and Technology of the Republic of China (MOST 109-2320-B-006-067, MOST 111-2320-B-006-024, MOST 111-2634-F-006-012 to C.-Y.C.) and a grant from National Cheng Kung University Hospital (NCKUH-11102040), An Nan Hospital, China Medical University (ANHRF111-11).