Regulation and functional significance of CDC42 alternative splicing in ovarian cancer.

Abstract

Our previous study found that splicing factor polypyrimidine tract-binding protein 1 (PTBP1) had a role in tumorigenesis but the underlying mechanism remained unclear. In this study, we observed that knockdown of PTBP1 inhibited filopodia formation. Subsequently, we found that PTBP1 regulated the alternative splicing of CDC42, a major regulator of filopodia formation. Two CDC42 variants, CDC42-v1 and CDC42-v2, can be generated through alternative splicing. Knockdown of PTBP1 increased the expression of CDC42-v2. Ectopic expression of individual variants showed that CDC42-v2 suppressed filopodia formation, opposite to the effect of CDC42-v1. Quantitative RT-PCR revealed that CDC42-v2 was expressed at lower levels in ovarian cancer cell lines and ovarian tumor tissues than in normal control cells and tissues. Further, CDC42-v2 was observed to have inhibitory effects on ovarian tumor cell growth, colony formation in soft agar and invasiveness. In contrast, these inhibitory effects were not found with CDC42-v1. Taken together, above results suggest that the role of PTBP1 in tumorigenesis may be partly mediated by its regulation of CDC42 alternative splicing and CDC42-v2 might function as a tumor suppressor.

• Authors: Xiaolong He, Chengfu Yuan, Jilai Yang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 30 Pg. 29651-63 (Oct 06 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26336992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterogeneous-Nuclear Ribonucleoproteins
• PTBP1 protein, human
• Protein Isoforms
• Polypyrimidine Tract-Binding Protein
• cdc42 GTP-Binding Protein

Topics

• Alternative Splicing
• Animals
• Base Sequence
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Heterogeneous-Nuclear Ribonucleoproteins (genetics, metabolism)
• Humans
• Mice
• Molecular Sequence Data
• NIH 3T3 Cells
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Polypyrimidine Tract-Binding Protein (genetics, metabolism)
• Protein Isoforms (genetics, metabolism)
• Pseudopodia (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Stem Cell Assay
• cdc42 GTP-Binding Protein (genetics, metabolism)