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PTBP1 enhances exon11a skipping in Mena pre-mRNA to promote migration and invasion in lung carcinoma cells.
Biochim Biophys Acta Gene Regul Mech. 2019 08; 1862(8):858-869.BB

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.

Authors+Show Affiliations

Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.Department of Internal Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, MDC 19, Tampa, FL 33612, USA.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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.Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Pharmacodynamics Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China; 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. Electronic address: jnubiopharm@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31075540

Citation

Li, Shuaiguang, et al. "PTBP1 Enhances Exon11a Skipping in Mena pre-mRNA to Promote Migration and Invasion in Lung Carcinoma Cells." Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms, vol. 1862, no. 8, 2019, pp. 858-869.
Li S, Shen L, Huang L, et al. PTBP1 enhances exon11a skipping in Mena pre-mRNA to promote migration and invasion in lung carcinoma cells. Biochim Biophys Acta Gene Regul Mech. 2019;1862(8):858-869.
Li, S., Shen, L., Huang, L., Lei, S., Cai, X., Breitzig, M., Zhang, B., Yang, A., Ji, W., Huang, M., Zheng, Q., Sun, H., & Wang, F. (2019). PTBP1 enhances exon11a skipping in Mena pre-mRNA to promote migration and invasion in lung carcinoma cells. Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms, 1862(8), 858-869. https://doi.org/10.1016/j.bbagrm.2019.04.006
Li S, et al. PTBP1 Enhances Exon11a Skipping in Mena pre-mRNA to Promote Migration and Invasion in Lung Carcinoma Cells. Biochim Biophys Acta Gene Regul Mech. 2019;1862(8):858-869. PubMed PMID: 31075540.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PTBP1 enhances exon11a skipping in Mena pre-mRNA to promote migration and invasion in lung carcinoma cells. AU - Li,Shuaiguang, AU - Shen,Lianghua, AU - Huang,Luyuan, AU - Lei,Sijia, AU - Cai,Xingdong, AU - Breitzig,Mason, AU - Zhang,Bin, AU - Yang,Annan, AU - Ji,Wenzuo, AU - Huang,Meiyan, AU - Zheng,Qing, AU - Sun,Hanxiao, AU - Wang,Feng, Y1 - 2019/05/07/ PY - 2018/06/11/received PY - 2019/04/16/revised PY - 2019/04/18/accepted PY - 2019/5/11/pubmed PY - 2019/11/26/medline PY - 2019/5/11/entrez KW - Alternative splicing KW - Invasion KW - Lung carcinoma KW - Mena KW - Migration KW - Polypyrimidine Tract-Binding Protein 1 SP - 858 EP - 869 JF - Biochimica et biophysica acta. Gene regulatory mechanisms JO - Biochim Biophys Acta Gene Regul Mech VL - 1862 IS - 8 N2 - 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. SN - 1876-4320 UR - https://www.unboundmedicine.com/medline/citation/31075540/PTBP1_enhances_exon11a_skipping_in_Mena_pre_mRNA_to_promote_migration_and_invasion_in_lung_carcinoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1874-9399(18)30248-7 DB - PRIME DP - Unbound Medicine ER -