Hedyotis diffusa Willd suppresses hepatocellular carcinoma tumor-stromal interactions by inactivating cancer-associated hepatic stellate cells.

[BACKGROUND] Hedyotis diffusa Willd (HDW) has the effects of clearing the heat, removing the toxins, restoring the circulation, eliminating the stasis and promoting the process of diuresis. Variety formulations of HDW various formulas involving HDW show remarkable clinical effects and have become second-lines anticancer drugs in China. However, its underlying mechanism against hepatocellular carcinoma (HCC) remains unclear. The objective of this study is to investigate the functional effect of HDW in the treatment of HCC, and to clarify the mechanism of HDW in suppression of tumor-stromal interaction.

[METHODS] Therapeutic effects of HDW on HCC cells and cancer-associated hepatic stellate cells (HSCs) were investigated in vitro and in vivo. Potential targets of HDW were predicted and signaling pathway analyses were conducted using network pharmacology. The HDW-target gene set (HDW-TGS) was systematically screened to investigate the mechanisms by which HDW influences tumor-stromal interactions and to identify target genes with significant clinical value.

[RESULTS] HDW induced HCC cells apoptosis via reactive oxygen species (ROS) induction. HDW-TGS significantly correlated to prognosis in The Cancer Genome Atlas (TCGA) HCC samples. HDW suppressed activated-HSC migration and invasion by regulating expression of fibrosis markers α-SMA and p-ERK1/2. In an HCC cell and HSC splenic co-transplanted xenograft mouse model, HDW suppressed liver tumor formation by downregulating fibrosis, indicating that HDW inhibited tumor-stromal interactions in vivo. Finally, we revealed a potential downstream target of HDW in HCC. We proposed that HDW might interrupt tumor-stromal interaction via ADH4.

[CONCLUSIONS] This study provides a new perspective for the treatment of HCC with HDW, demonstrating the feasibility of ADH4 as an HCC treatment target.