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TGF-β1 Causes EMT by Regulating N-Acetyl Glucosaminyl Transferases via Downregulation of Non Muscle Myosin II-A through JNK/P38/PI3K Pathway in Lung Cancer

[ Vol. 17 , Issue. ]

Author(s):

Ghulam Jilany Khan, Yingsheng Gao, Ming Gu, Lai Wang, Sara Khan, Farah Naeem, Herve Semukunzi, Debmalya Roy, Shengtao Yuan and Li SunPages 1-11 (11)

Abstract:


Background: Epithelial to mesenchymal transition (EMT) is a major determinant of cancer metastasis and is closely linked with TGF-β1. Intracellular proteins, including E. Cadherin, N. Cadherin and Vimentin are directly related to EMT that affect cell migration and adhesion; on the other hand, non muscle myosin (NM) has a central role in cytokinesis, migration and adhesion. Objective: We aimed to explore the association of EMT and metastasis with TGF-β1 through regulation of non-muscle myosin II-A (NMII-A) and its interaction with Hexosamine Biosynthesis Pathway (HBP).

Method: Protein expression changes were assessed by western blotting and immunofluorescent staining while transcription level changes were assessed by qRT-PCR. EMT was assessed by phenotypic analysis, wound healing, proliferation and transwell migration assay in vitro while in vivo studies were conducted in BALB/c nude mice for lung orthotopic and tail vein metastasis models.

Results: We demonstrated that regulation of JNK/ P38/PI3K by TGF-β1 led to down expression of NMII-A which promoted EMT and lung cancer metastasis. This down expression of NMII-A conversely upregulated the expression of Core 2 N-acetyl Glucosaminyl Transferase mucin type (C2GnT-M) and further facilitated up-regulation and down-regulation of N-acetylglucosaminyltransferase (GnT) -V and -III respectively; moreover, NMII-A K.D cells showed 3 times more tendency to migrate towards brain in vivo.

Conclusion: The study reports a novel pathway through which NMII-A negatively regulates EMT and metastasis via up regulation of C2GnT-M, GnT-V and down expression of GnT-III. These findings of lung cancer may further be required to study other cancer types.

Keywords:

NMII-A, EMT, C2GnT-M, GnT-III, GnT-V, GlcNAc, HBP, Lung cancer metastasis

Affiliation:

Jiangsu key laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, Jiangsu key laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, University College of pharmacy, University of the Punjab, Lahore , Institute of Chemical Sciences and Engineering, University of Engineering and Technology, Lahore, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, Jiangsu key laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, Jiangsu key laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009



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