18β‐glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell‐mediated immunosuppression in mice

Abstract

Hepatic stellate cells (HSCs) have immunosuppressive capabilities and contribute to the occurrence and development of hepatocellular carcinoma (HCC). Thus, activated HSCs may be a suitable target for HCC therapy. Our study used mixed leukocyte reactions (MLR) in vitro to demonstrate that 18β‐glycyrrhetinic acid (GA) could reverse HSC‐mediated immunosuppression by reducing T‐cell apoptosis and regulatory T (Treg) cells expression, thereby enhancing the ability of T cells to attack tumor cells and attenuating HCC cell invasiveness. Moreover, we established a HCC orthotopic implantation model in immunocompetent C57BL/6 mice, which suggested that GA played a protective role in HCC development by reducing immunosuppression mediated by HSCs in the tumor microenvironment.

α-smooth muscle actin-positive fibroblasts correlate with poor survival in hepatocellular carcinoma

“…Activated HSCs that express extremely high levels of α-SMA have emerged as potent suppressors of hepatic immunity by affecting T-cell responses and thus, play a vital role in the progression of HCC (6,7,11,12). Previous studies have also indicated that activated HSCs are potential targets for HCC treatment (4). …”

“…These activated fibroblasts have been proposed to be important in promoting tumor progression and metastasis by releasing growth factors, extracellular matrix proteins and angiogenic factors (2,3). The hepatic stellate cell (HSC), an important hepatic stromal cell, is known to be activated or transdifferentiated into a myofibroblast-like cell through intercellular communication between HSCs and damaged hepatocytes in various liver tumors, including hepatocellular carcinoma (HCC) (4). These activated HSCs demonstrate a high expression of α-SMA and are considered to be a vital stromal component in HCC (5).…”

18 beta-glycyrrhetinic acid ameliorates the cognitive functions and decreases the recurrence rate of pituitary adenomas patients

“…DMBA/TPA-induced skin tumor formation could also be suppressed by GA (Agarwal et al, 1991[2]). In addition, GA played a protective role in hepatocellular carcinoma development by reducing immunosuppression mediated by hepatic stellate cells in the tumor microenvironment (Kuang et al, 2013[18]). While GA has been shown to exhibit anti-viral and anti-inflammatory effects, it also displays cytotoxic effects on human hepatocellular carcinoma, breast cancer (Wang et al, 2015[29]) and ovarian cancer (Yang et al, 2012[31]).…”

Hepatocellular carcinoma-targeted effect of configurations and groups of glycyrrhetinic acid by evaluation of its derivative-modified liposomes

“…13,14 18β-GA could reduce the amount of glucose release induced by glucagon in rat primary cultured hepatocytes, while 18α-GA did not. 15 Nevertheless, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a kind of microsomal enzyme belonging to the short-chain dehydrogenase/reductase family, which is highly expressed in many glucocorticoid target tissues, such as the liver, adipose tissue, skeletal muscle and macrophages.…”