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Cancer Lett. 2019 May 1;449:31-44. doi: 10.1016/j.canlet.2019.01.041. Epub 2019 Feb 10.

Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM.

Author information

1
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
2
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: chenx457@mail.sysu.edu.cn.
3
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
4
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
5
Department of Urology, Shenzhen Longhua District Central Hospital, Shenzhen, China. Electronic address: 18923877315@163.com.
6
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
7
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: huangj8@mail.sysu.edu.cn.
8
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: lintx@mail.sysu.edu.cn.

Abstract

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 proliferation in vitro, as well as LN metastasis and tumor growth in 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.

KEYWORDS:

Alternative splicing; Bladder cancer; Lymph node metastasis; MEIS2; PKM2; PTBP1

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