Remodeling of hepatic stellate cells orchestrated the stroma-derived oxaliplatin-resistance through CCN3 paracrine in hepatocellular carcinoma

Xia Liao,Fan Chang,Fengan Jia,Qingan Jia,Mei Zhang,Ge Song,Xuelian Xiao,Yang Bu,Pengbo Ning

doi:10.1186/s12885-019-6362-1

Abstract

BackgroundHepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. However, the precise role of HSCs trending, infiltration and paracrine in orchestrating the stroma-derived oxaliplatin-resistance in HCC is still vague.MethodsThe chemo-resistant models were established to explore the correlation between HSC cells and the condition of chemoresistance. The HCC clinical samples were collected to confirm this phenomenon. Then, the relationship between secretory CCN3 from oxaliplatin-resistant HCC and the infiltration of HSCs in associated HCC microenvironment was evaluated. Finally, the role and mechanism of HSCs remodeling in the orchestration of oxaliplatin-resistant HCC were explored.ResultsThe increased infiltration of HSCs and collagen accumulation were found in the microenvironment of oxaliplatin-resistant HCC. The cDNA profiles of the oxaliplatin-resistant HCC was reanalyzed, and CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then the enhanced abilities of migration and proliferation of HSCs, and elevation of the cytokines paracrine from HSCs relating to HCC malignancy were proved in vitro and in vivo, and which were related to CCN3-ERK signaling pathway activation.ConclusionsHSCs remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.

Highlights

Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression
We proved expression of CCN3 is upregulated in oxaliplatinresistant HCC, which may be the cause of increased infiltration of HSC after treated by oxaliplatin
We proved the expression levels of CCN3 and α-SMA are positively correlated, and the high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis in HCC

Summary

Introduction

Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. The precise role of HSCs trending, infiltration and paracrine in orchestrating the stroma-derived oxaliplatin-resistance in HCC is still vague. The most ubiquitous function of the CCN3 is its ability to orchestrate the inflammatory microenvironment [4]. The expression of CCN3 in HCC, and the precise physiological function and mechanism of action of CCN3 remain elusive. It is important to explore the role and mechanism of CCN3 paracrine in the remodeling of HSCs in HCC microenvironment

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