Ginsenoside Rh4 inhibits inflammation-related hepatocellular carcinoma progression by targeting HDAC4/IL-6/STAT3 signaling

Abstract

This study aimed to investigate the effects of Ginsenoside Rh4 (Rh4) on inflammation-related hepatocellular carcinoma (HCC) progression and the underlying mechanism. HCC cells (HUH7 and LM3) were induced by lipopolysaccharide (LPS) to establish an inflammatory environment in the absence or presence of Rh4. CCK-8, wound healing and transwell assays were employed to analyze the viability, migration and invasion of HCC cells. Ki67 expression was detected by immunofluorescence method. Besides, the levels of glucose and lactic acid were tested by kits. The expression of proteins related to migration, glycolysis and histone deacetylase 4 (HDAC4)/IL-6/STAT3 signaling was measured with western blot. The transplantation tumor model of HCC in mice was established to observe the impacts of Rh4 on the tumor growth. Results indicated that Rh4 restricted the viability and Ki67 expression in HCC cells exposed to LPS. The elevated migration and invasion of HCC cells triggered by LPS were reduced by Rh4. Additionally, Rh4 treatment remarkably decreased the contents of glucose and lactic acid and downregulated LDHA and GLUT1 expression. The database predicated that Rh4 could target HDAC4, and our results revealed that Rh4 downregulated HDAC4, IL-6 and p-STAT3 expression. Furthermore, the enforced HDAC4 expression alleviated the effects of Rh4 on the proliferation, migration, invasion and glycolysis of HCC cells stimulated by LPS. Taken together, Rh4 could suppress inflammation-related HCC progression by targeting HDAC4/IL-6/STAT3 signaling. These findings clarify a new anti-cancer mechanism of Rh4 on HCC and provide a promising agent to limit HCC development.

TIMP-1 Promotes Expression of MCP-1 and Macrophage Migration by Inducing Fli-1 in Experimental Liver Fibrosis

“…After 48 h of co-culture, non-migratory macrophages were cleared from the upper chamber with a cotton swab, and the cells on the lower surfaces were fixed with 4% paraformaldehyde as previously described. 25 Macrophages were stained with DAPI and counted under a microscope in five randomly selected high-power fields.…”

Therapeutic Effects of Natural Products on Liver Cancer and Their Potential Mechanisms

“…Recent research has elucidated the therapeutic mechanisms through which ginsenosides combat liver cancer. For instance, ginsenoside Rh4 impedes the progression of inflammation-related hepatocellular carcinoma by targeting the HDAC4/IL-6/STAT3 signaling pathway [ 74 ]. In a DEN-induced SD rat model, ginsenoside CK may suppress liver cancer cell proliferation by downregulating Bclaf1 expression, thereby inhibiting the HIF-1α-mediated glycolytic pathway and proliferation [ 75 ].…”