Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition.

Catherine Vilpoux,Hicham Bouhlal,Jagadeesh Bayry,Constance Marié,Eric Nguyen-Khac,Grégory Fouquet,Ingrid Marcq,Mickaël Naassila,Louison Collet,Hakim Ouled-Haddou

doi:10.3390/cancers14040910

Abstract

Simple SummarySorafenib is a treatment for advanced HCC which demonstrated a poor objective response rate due to important induction of resistance. We demonstrated that induction of acquired-resistance to sorafenib in Huh-7 cell line leads to the loss of SLAMF3 expression, a tumor suppressor receptor in HCC. In these cells, the sorafenib-resistant phenotype is characterized by the increase of aggressiveness and induction of the epithelial-to-mesenchymal transition. Acquired-resistance to sorafenib induce a multipotent mesenchymal stem cells characteristic. Interestingly, SLAMF3 overexpression reversed the epithelial-to-mesenchymal transition and decreased metastatic potential in sorafenib-resistant cells through the control of ERK1/2 and mTOR signaling pathways. SLAMF3 seems to be a theranostics tools to the management of sorafenib treatment.Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients.

Highlights

Due to late diagnosis, only a minority of hepatocellular carcinoma (HCC) patients are eligible for curative treatment [1]
We show that signaling lymphocytic activation molecules family 3 (SLAMF3) expression is decreased in Res cells and corresponds with the sorafenib resistance profile
When we analyzed the expression of other markers of Mesenchymal stromal cells (MSCs) such as CD90 and CD133, we found no modifications in the mean fluorescence intensity (MFI) of CD90 while the percentage of cells positive for CD90 was significantly increased by 4.07-fold in Res cells (N = 3; p = 0.008)

Summary

Introduction

Only a minority of hepatocellular carcinoma (HCC) patients are eligible for curative treatment [1]. Numerous mechanisms are proposed to be associated with the high resistance rate to sorafenib, of which epithelial-to-mesenchymal transition (EMT) has a major role [5]. EMT is associated with the poor prognosis of HCC [6] This aggressive phenotype of HCC, acquired during the sorafenib resistance process, is associated with the loss of epithelial markers such as E-cadherin, and the simultaneous acquisition of vimentin, a major mesenchymal phenotype protein [7]. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients

Methods

Results

Conclusion