PTBP1 enhances exon11a skipping in Mena pre-mRNA to promote migration and invasion in lung carcinoma cells |
| |
| Institution: | 1. Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China;2. Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;3. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of pharmacy, Jinan University, Guangzhou 510632, China;4. Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;5. Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China;6. Department of Internal Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, MDC 19, Tampa, FL 33612, USA;1. Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, PR China;2. Teaching Center for Preventive Medicine Experiments, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, PR China;3. Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China;4. Department of Nutrition and Food Hygiene, Harbin Medical University, Harbin, Heilongjiang Province, PR China;1. Clinical Laboratory, The First Affiliated Hospital of Xi''an Jiaotong University, Xi''an, Shaanxi 710061, PR China;2. Center for Translational Medicine, The First Affiliated Hospital of Xi''an Jiaotong University, Xi''an, Shaanxi 710061, PR China;3. Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi''an Jiaotong University, Xi''an, Shaanxi 710061, PR China;1. Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University 11451, Riyadh, Saudi Arabia;2. Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University 11451, Riyadh, Saudi Arabia;3. Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates;4. Department of Biomedical Sciences, University of Westminster, London, W1W 6UW, UK;5. Translational Research Institute, School of Medicine, Henan Provincial People''s Hospital, Henan University, Zhengzhou, China |
| |
| Abstract: | Alternative splicing (AS) events occur in the majority of human genes. AS in a single gene can give rise to different functions among multiple isoforms. Human ortholog of mammalian enabled (Mena) is a conserved regulator of actin dynamics that plays an important role in metastasis. Mena has been shown to have multiple splice variants in human tumor cells due to AS. However, the mechanism mediated Mena AS has not been elucidated. Here we showed that polypyrimidine tract-binding protein 1 (PTBP1) could modulate Mena AS. First, PTBP1 levels were elevated in metastatic lung cancer cells as well as during epithelial-mesenchymal transition (EMT) process. Then, knockdown of PTBP1 using shRNA inhibited migration and invasion of lung carcinoma cells and decreased the Mena exon11a skipping, whereas overexpression of PTBP1 had the opposite effects. The results of RNA pull-down assays and mutation analyses demonstrated that PTBP1 functionally targeted and physically interacted with polypyrimidine sequences on both upstream intron11 (TTTTCCCCTT) and downstream intron11a (TTTTTTTTTCTTT). In addition, the results of migration and invasion assays as well as detection of filopodia revealed that the effect of PTBP1 was reversed by knockdown of Mena but not Mena11a+. Overexpressed MenaΔ11a also rescued the PTBP1-induced migration and invasion. Taken together, our study provides a novel mechanism that PTBP1 modulates Mena exon11a skipping, and indicates that PTBP1 depends on the level of Mena11a− to promote lung cancer cells migration and invasion. The regulation of Mena AS may be a potential prognostic marker and a promising target for treatment of lung carcinoma. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
