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TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating
Tieju Liu1,2, Huizhi Sun1, Dongwang Zhu3
1Department of Pathology, Tianjin Medical University, Tianjin, China.
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.
Insights
The splicing factor TRA2A promotes triple-negative breast cancer (TNBC) progression and paclitaxel resistance by altering RSRC2 splicing. Increased TRA2A and decreased RSRC2 expression correlate with poor TNBC survival.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Triple-negative breast cancer (TNBC) treatment is challenging, with paclitaxel resistance a major obstacle.
- Alternative splicing (AS) deregulation is implicated in tumor progression and chemotherapy resistance.
- The role of TRA2A, a paralog of the AS factor TRA2B, in cancer progression was previously unreported.
Purpose of the Study:
- To investigate the role of TRA2A in TNBC proliferation, survival, migration, invasion, and paclitaxel resistance.
- To elucidate the molecular mechanisms by which TRA2A influences paclitaxel resistance in TNBC.
- To assess the clinical significance of TRA2A and RSRC2 expression in TNBC patients.
Main Methods:
- Investigated TRA2A's effects on TNBC cell proliferation, survival, migration, and invasion.
- Analyzed TRA2A-mediated alternative splicing of CALU, RSRC2, and PALM during paclitaxel treatment.
- Examined TRA2A binding to RSRC2 and correlated TRA2A/RSRC2 expression with TNBC patient survival data.
Main Results:
- TRA2A significantly facilitates TNBC cell proliferation, survival, migration, and invasion.
- TRA2A promotes paclitaxel resistance by controlling specific cancer-related splicing events, including RSRC2 isoform shifts.
- TRA2A directly regulates RSRC2 alternative splicing by binding to an intronic sequence.
- Elevated TRA2A expression and decreased RSRC2 expression are observed in TNBC patients and associated with poor survival.
Conclusions:
- TRA2A plays a critical role in TNBC progression and paclitaxel resistance via the TRA2A-RSRC2 splicing pathway.
- The TRA2A-RSRC2 axis represents a novel molecular mechanism for cancer-related splicing dysregulation in TNBC.
- TRA2A and RSRC2 expression levels may serve as valuable biomarkers for TNBC clinical treatment decisions and predicting patient outcomes.