Inhibition of ERK1/2 attenuates tumor-stromal interaction of hepatocellular carcinoma by regulating fibrosis and extracellular matrix remodeling

Extracellular signal-regulated kinases (ERKs) have been related to various human biochemical signals and affect the processes of cell proliferation, differentiation, autophagy and senescence in multiple gastrointestinal cancers.In the present study, we investigated the involvement of ERK1/2 in activation of hepatic stellate cell (HSC). We identified ERK1/2 phosphorylation on activated HSC of HCC samples. We found tumor cells promoted the migration and invasion capacity of HSC by activating ERK1/2 phosphorylation. By using a specific ERK1/2 inhibitor SCH772984, we accessed the IC50 value on tumor cells and HSCs. Interestingly, activated HSCs exhibited remarkably upregulated sensitivity to the inhibitor. By high-throughput transcriptome sequencing analysis, we found ERK1/2-inhibition altered genes significantly correlated to signaling pathways involved in extracellular matrix remodeling, collagen metabolic and focal adhesion in both tumor cells and HSCs. Meantime, adhesion abilities of both tumor cells and HSC were suppressed following ERK1/2 inhibition. Moreover, inhibition of ERK1/2 suppressed tumor cell-induced enhancement of HSC migration and invasion by regulating fibrosis marker FAP, FN1 and COL1A1 expression. In a tumor cell and HSC splenic co-transplanted xenograft mouse model, inhibition of ERK1/2 suppressed liver tumor formation by downregulating tumor fibrosis, indicating ERK1/2 inhibition suppressed tumor-stromal interaction in vivo.