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

Title: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

Volume: 18 Issue: 2

Author(s): Ghulam Jilany Khan, Yingsheng Gao, Ming Gu, Lai Wang, Sara Khan, Farah Naeem, Herve Semukunzi, Debmalya Roy, Shengtao Yuan*Li Sun*

Affiliation:

• Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009,China

• Jiangsu key laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009,China

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

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.

Cite this article as:

Khan Jilany Ghulam, Gao Yingsheng, Gu Ming, Wang Lai, Khan Sara, Naeem Farah , Semukunzi Herve , Roy Debmalya , Yuan Shengtao *, Sun Li *, 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, Current Cancer Drug Targets 2018; 18 (2) . https://dx.doi.org/10.2174/1568009617666170807120304