Protein tyrosine phosphatase PTPN3 promotes drug resistance and stem cell-like characteristics in ovarian cancer.

Shuqin Li,Qian Luo,Guantai Ni,Wei Zhang,Hongping Xia,Man Wang,Fan Zhang,Jian Cao,Xiang Tao

doi:10.1038/srep36873

Abstract

The current standard treatment for ovarian cancer is aggressive surgery followed by platinum-based combination chemotherapy. Recurrence and chemotherapeutic drug resistance are the two main factors that account for the high mortality of most ovarian cancers. Liposomal doxorubicin is primarily used for the treatment of ovarian cancer when the disease has progressed after platinum-based chemotherapy. However, relatively little is known about the genomic changes that contribute to both cisplatin and doxorubicin resistance in high-grade serous ovarian cancer (HGSC) under the selective pressure of chemotherapy. Here, we found that protein tyrosine phosphatase PTPN3 gene expression was substantially increased in both cisplatin and doxorubicin-resistant ovarian cancer cells. Silencing of PTPN3 restored sensitivity to cisplatin and doxorubicin in resistant ovarian cancer cells. Down-regulation of PTPN3 also inhibited cell cycle progression, migration, stemness in vitro and the tumorigenicity of resistant ovarian cancer cells in vivo. Meanwhile, the expression of PTPN3 was found to be regulated by miR-199 in resistant ovarian cancer cells. These findings suggest that PTPN3 promotes tumorigenicity, stemness and drug resistance in ovarian cancer, and thus is a potential therapeutic target for the treatment of ovarian cancer.

Highlights

Ovarian cancer, the most common cause of gynaecologic cancer-associated death, is responsible for approximately 14,000 deaths in the United States annually[1]
Among the panel of significantly different genes, protein tyrosine phosphatase non-receptor type 3 (PTPN3) was significantly overexpressed in both A2780CIS and A2780ADR cells compared to A2780 cells (Table S1)
The results reported here provide evidence that PTPN3 regulates sensitivity to cisplatin and doxorubicin in ovarian cancer cells

Summary

Introduction

The most common cause of gynaecologic cancer-associated death, is responsible for approximately 14,000 deaths in the United States annually[1]. Acquired chemotherapy resistance is mainly associated with the inactivation of tumour suppressors such as RB1, NF1, RAD51B and PTEN, germline BRCA1 or BRCA2 mutations, loss of BRCA1 promoter methylation, and overexpression of the drug efflux pump MDR12. Liposome-encapsulated form of doxorubicin, is primarily used for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy[5]. PTPN3 silencing restored the sensitivity of resistant ovarian cancer cells to cisplatin and doxorubicin. Silencing of PTPN3 inhibited cell cycle progression, migration and stemness, and reduced the tumorigenicity of resistant ovarian cancer cells. These findings identify PTPN3 as a potential therapeutic target for ovarian cancer treatment and for overcoming cisplatin and doxorubicin resistance

Methods

Results

Conclusion