LncRNA HOTAIR overexpression induced downregulation of c-Met signaling promotes hybrid epithelial/mesenchymal phenotype in hepatocellular carcinoma cells

Hande Topel,Gulsun Bagci,Nese Atabey,Dehan Comez,Ezgi Bagirsakci,Gulcin Cakan-Akdogan

doi:10.1186/s12964-020-00602-0

Abstract

BackgroundEpithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Recently, it is defined that cancer cells can attain a hybrid epithelial/mesenchymal (hybrid E/M) phenotype. Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and also more capable of initiating metastatic lesions. However, the mechanisms regulating hybrid E/M in HCC are not well described yet. In this study, we investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC.MethodsExpression of c-Met and lncRNA HOTAIR were defined in HCC cell lines and patient tissues through HCC progression. lncRNA HOTAIR was overexpressed in SNU-449 cells and its effects on c-Met signaling were analyzed. c-Met was overexpressed in SNU-398 cells and its effect on HOTAIR expression was analyzed. Biological significance of HOTAIR/c-Met interplay was defined in means of adhesion, proliferation, motility behavior, invasion, spheroid formation and metastatic ability. Effect of ectopic lncRNA HOTAIR expression on phenotype was defined with investigation of molecular epithelial and mesenchymal traits.ResultsIn vitro and in vivo experiments verified the pivotal role of lncRNA HOTAIR in acquisition of hybrid E/M phenotype through modulating expression and activation of c-Met and its membrane co-localizing partner Caveolin-1, and membrane organization to cope with the rate limiting steps of metastasis such as survival in adhesion independent microenvironment, escaping from anoikis and resisting to fluidic shear stress (FSS) in HCC.ConclusionsOur work provides the first evidence suggesting a role for lncRNA HOTAIR in the modulation of c-Met to promote hybrid E/M phenotype. The balance between lncRNA HOTAIR and c-Met might be critical for cell fate decision and metastatic potential of HCC cells.BCiVY--bidSCe2kP4myVdrVideo

Highlights

Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC)
Expression of HOX Transcript Antisense Intergenic RNA (HOTAIR) is low in HCC cells with high c-Met expression and activation To examine expression levels of HOTAIR and c-Met, we analyzed their mRNA expression in 10 HCC cell lines (FOCUS, SNU-449, SK-HEP-1, SNU-475, SNU-387, SNU-423, MAHLAVU, Hep-3B, HuH-7 and SNU-398)
RTqPCR analysis of HOTAIR mRNA expression levels and western blot analysis of c-Met protein expression revealed that HOTAIR expression is low in HCC cell lines with high c-Met protein expression (Fig. 1c)

Summary

Introduction

Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and more capable of initiating metastatic lesions. We investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC. HCC is reported to have complex and heterogeneous molecular features which is previously stressed out by integrative studies combining genomic characterization, exome sequencing, transcriptome analysis and clinical trials. Besides potential benefits in chronic liver diseases, c-Met contributes to initiation, development and progression of HCC. In addition to its contribution to HCC development and progression, c-Met is considered to be a key player in drug resistance [5]

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