journal contribution
posted on 2023-04-03, 16:08 authored by Tieju Liu, Huizhi Sun, Dongwang Zhu, Xueyi Dong, Fang Liu, Xiaohui Liang, Chen Chen, Bing Shao, Meili Wang, Yi Wang, Baocun Sun Supplementary Figure legends; Table S1, S4, S7, S8, and RSRC2 minigene sequence. Table S1: The increased splicing factors expression induced by PTX treatment in MDA-MB-231 cells; Table S4. All AS events selected for validation were confirmed by VeriQuest SYBR Green qPCR; Table S7: The relationship of TRA2A, CALUl, CALUs, RSRC2l, RSRC2s, PALMl, PALMs mRNA and TRA2A protein expression with PTXR of TNBC; Table S8: The relationship of TRA2A, CALUl, CALUs, RSRC2l, RSRC2s, PALMl and PALMs mRNA with TRA2A protein expression.
Funding
National Natural Science Foundation of China
National Undergraduate Training Program for Innovation and Entrepreneurship
History
ARTICLE ABSTRACT
Treatment of triple-negative breast cancer (TNBC) has been challenging, and paclitaxel resistance is one of the major obstacles to the better prognosis. Deregulation of alternative splicing (AS) may contribute to tumor progression and chemotherapy resistance. Human AS factor TRA2 has two separate gene paralogs encoding TRA2A and TRA2B proteins. TRA2B is associated with cancer cell survival and therapeutic sensitivity. However, the individual role of TRA2A in cancer progression has not been reported. Here we report that TRA2A facilitates proliferation and survival and migration and invasion of TNBC cells. In addition, TRA2A promotes paclitaxel resistance of TNBC by specifically controlling cancer-related splicing, which is independent of other splicing factors. TRA2A overexpression could promote AS of CALU, RSRC2, and PALM during paclitaxel treatment of TNBC cells. The isoform shift of RSRC2 from RSRC2s to RSRC2l leads to a decreased RSRC2 protein expression, which could contribute to TNBC paclitaxel resistance. TRA2A can regulate RSRC2 AS by specifically binding upstream intronic sequence of exon4. Strikingly, TRA2A expression is increased dramatically in patients with TNBC, and has a close relationship with decreased RSRC2 expression; both are associated with poor survival of TNBC. Collectively, our findings suggest that paclitaxel targets the TRA2A–RSRC2 splicing pathway, and deregulated TRA2A and RSRC2 expression may confer paclitaxel resistance. In addition to providing a novel molecular mechanism of cancer-related splicing dysregulation, our study demonstrates that expression of TRA2A in conjunction with RSRC2 may provide valuable molecular biomarker evidence for TNBC clinical treatment decisions and patient outcome. Mol Cancer Ther; 16(7); 1377–88. ©2017 AACR.
