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

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.

• Authors: Ruihui Xie, Xu Chen, Ziyue Chen, Ming Huang, Wen Dong, Peng Gu, Jingtong Zhang, Qianghua Zhou, Wei Dong, Jinli Han, Xisheng Wang, Hui Li, Jian Huang, Tianxin Lin
• Journal: Cancer letters (Cancer Lett) Vol. 449 Pg. 31-44 (05 01 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30742945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Heterogeneous-Nuclear Ribonucleoproteins
• Homeodomain Proteins
• MEIS2 protein, human
• PTBP1 protein, human
• Transcription Factors
• Polypyrimidine Tract-Binding Protein
• Pyruvate Kinase

Topics

• Alternative Splicing
• Animals
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heterogeneous-Nuclear Ribonucleoproteins (metabolism)
• Homeodomain Proteins (genetics)
• Humans
• Lymphatic Metastasis (genetics, pathology)
• Mice
• Neoplasm Grading
• Neoplasm Staging
• Neoplasm Transplantation
• Polypyrimidine Tract-Binding Protein (metabolism)
• Prognosis
• Pyruvate Kinase (genetics)
• Sequence Analysis, RNA
• Transcription Factors (genetics)
• Up-Regulation
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)