ERK pathway activation contributes to the tumor-promoting effects of hepatic stellate cells in hepatocellular carcinoma.

BACKGROUND

Activated hepatic stellate cell (aHSC) play a critical role in hepatocellular carcinoma (HCC) progression crosstalking with cancer cell via various signaling pathways. The aim of our study is to explore the tumor-promoting effects of aHSCs on HCC via ERK pathway.

METHODS

α-SMA, p-ERK and p-JNK expression levels in tumoral and peritumoral tissues of HCC were assessed by immunohistochemical and western blotting. The protein and mRNA expression levels in human hepatoma cell treated with aHSC conditioned medium (CM) were determined by western blotting and real-time quantitative PCR, respectively. Cell migration and invasion abilities were assessed using transwell assays. The proliferation ability of HCC cells induced by aHSCs-CM was detected by CCK-8 assay and cell cycle analysis.

RESULTS

We found that aHSC number was positively correlated with p-ERK expression levels in tumoral tissues and aHSC-CM could time-dependently promote PCNA, p-ERK expression in HCC cells. Moreover, aHSC-CM enhanced HCC cells proliferation via ERK. Additionally, aHSC upregulated c-jun and cyclinD1 expression levels, accelerating the transition from G1 to the S phase of HCC cells, and this effect could be arrested by inhibiting ERK pathway. Furthermore, aHSC-CM promoted migration and invasion of HCC cells via ERK. Epithelial-mesenchymal transitions (EMT) phenomenon could be reversed by ERK suppression.

CONCLUSION

High expression of p-ERK and aHSCs may be associated with the aggressive behavior of HCC cells. Secretions from aHSCs could promote proliferation and EMT of HCC cells via ERK1/2/c-jun/cyclinD1 axis or ERK pathway.