Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM
Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM
复制标题
多聚嘧啶束结合蛋白1通过MEIS2和PKM的选择性剪接促进膀胱癌的淋巴转移和增殖
DOI：
10.1016/j.canlet.2019.01.041
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Lin，Tianxin
中科院分区：
文献类型：
--
作者：
Xie，Ruihui;Chen，Xu;Lin，Tianxin
淋巴结（LN）转移是膀胱癌相关死亡的主要原因。剪接因子通过调节致癌变异促进癌症进展，但尚不清楚剪接因子是否以及如何调节膀胱癌淋巴结转移。本研究发现多聚嘧啶束结合蛋白1（PTBP1）表达与膀胱癌淋巴结转移相关，且与淋巴结转移状态、肿瘤分期、组织学分级及患者不良预后呈正相关。功能测定表明，PTBP1在体外促进膀胱癌细胞迁移、侵袭和增殖，在体内促进淋巴结转移和肿瘤生长。机制研究表明，PTBP1 上调 MEIS2-L 变体以促进转移，并增加 PKM2 变体的表达以通过调节选择性 mRNA 剪接来增强增殖。此外，MEIS2-L或PKM2的过表达可以在PTBP1敲低后分别挽救膀胱癌细胞的致癌能力以及MMP9或CCND1的表达。总之，我们的数据表明 PTBP1 通过替代剪接机制诱导膀胱癌 LN 转移和增殖。 PTBP1可能作为LN转移性膀胱癌的新预后标志物和治疗靶点。
Lymph node (LN) metastasis is the leading cause of bladder cancer-related mortality. Splicing factors facilitate cancer progression by modulating oncogenic variants, but it is unclear whether and how splicing factors regulate bladder cancer LN metastasis. In this study, Polypyrimidine tract binding protein 1 (PTBP1) expression was found to relate to bladder cancer LN metastasis, and was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that PTBP1 promoted bladder cancer cell migration, invasion, and proliferationin vitro, as well as LN metastasis and tumor growthin vivo. Mechanistic investigations revealed that PTBP1 upregulated MEIS2-L variant to promote metastasis and increased expression of PKM2 variant to enhance proliferation by modulating alternative mRNA splicing. Moreover, overexpression of MEIS2-L or PKM2 could rescue the oncogenic abilities of bladder cancer cells and the expression of MMP9 or CCND1 respectively after PTBP1 knockdown. In conclusion, our data demonstrate that PTBP1 induces bladder cancer LN metastasis and proliferation through an alternative splicing mechanism. PTBP1 may serve as a novel prognostic marker and therapeutic target for LN-metastatic bladder cancer.