TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing
TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing
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TRA2A 通过调节选择性剪接促进三阴性乳腺癌的紫杉醇耐药性和肿瘤进展
DOI：
10.1158/1535-7163.mct-17-0026
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发表时间：
2017-07-01
影响因子：
5.7
通讯作者：
Sun, Baocun
中科院分区：
文献类型：
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作者：
Liu, Tieju;Sun, Huizhi;Sun, Baocun
三阴性乳腺癌(TNBC)的治疗一直具有挑战性，紫杉醇耐药是影响其预后的主要因素之一。选择性剪接(AS)的解除调控可能导致肿瘤进展和化疗耐药。人类AS因子TRA2有两个编码TRA2A和TRA2B蛋白的基因序列。TRA2B与癌细胞存活和治疗敏感性有关。然而，TRA2A在癌症进展中的个体作用还没有报道。在此，我们报道TRA2A促进TNBC细胞的增殖、存活、迁移和侵袭。此外，TRA2A通过特异性地控制与癌症相关的剪接而促进了TNBC对紫杉醇的耐药性，这种剪接独立于其他剪接因子。在紫杉醇作用于TNBC细胞过程中，TRA2A过表达可促进CALU、RSRC2和Palm的AS表达。RSRC2从RSRC2s向RSRC2l的异构体转移导致RSRC2蛋白表达下降，这可能是导致TNBC紫杉醇耐药的原因之一。TRA2A通过特异性结合外显子4的上游内含子序列来调节RSRC2 AS。值得注意的是，TRA2A在TNBC患者中的表达显著增加，并与RSRC2的表达降低密切相关；两者都与TNBC的生存不良有关。综上所述，我们的研究结果表明，紫杉醇靶向TRA2A-RSRC2剪接途径，而TRA2A和RSRC2表达失控可能导致紫杉醇耐药。除了提供一种新的癌症相关剪接失调的分子机制外，我们的研究还表明，TRA2A和RSRC2的表达可能为TNBC的临床治疗决策和患者预后提供有价值的分子生物标志物证据。摩尔癌症杂志；16(7)；1377-88。©2017 AACR。
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.