Reversal of microRNA-blocked tumor suppressors by biphenyldicarboxylate impedes endotoxin-induced hepatic hyperplasia

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumor and the leading cause of cancer-related death worldwide. Biphenyldicarboxylate (BPDC), an intermediate of schisandrin C from Schisandra chinensis, has been used as a hepatoprotective agent that compromises hepatic injuries in China for decades. Whether BPDC is also implicated in the prevention of HCC remains understood. Here, we report that the bacterial endotoxin lipopolysaccharide (LPS) promotes hepatic inflammation and hyperplasia, during which the common tumor markers, alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA), were unregulated, whereas the tumor suppressors, PTEN, FOXO1 and MEN1, were downregulated through increasing the microRNAs, miR-21, miR-122 and miR-24. In contrast, BPDC dampened hepatic inflammation and hyperplasia accompanied by the upregulation of PTEN, FOXO1 and MEN1 through decreasing miR-21, miR-122 and miR-24. However, BPDC failed to downregulate the tumor marker AEG-1 via increasing miR-195. Taken together, BPDC exerts anti-tumor effects by upregulating tumor suppressors upon decreases of miRNAs rather than downregulating tumor markers by increases of miRNAs.Key words: Biphenyldicarboxylate, lipopolysaccharide, microRNA, tumor suppressor, hepatic inflammation upregulating tumor suppressors rather than downregulating tumor markers/oncogenes.These results should shed light on exploiting the exact mechanism of BPDC in the prevention and treatment of NAFLD and HCC, and would be also beneficial to elucidating the implication of miRNAs in the development of metastasis of hepatic hyperplasia and other hepatic pathogenesis. Materials and methodsAnimals and treatment procedures. Bal b/c mice, belonging to an inbred mouse population, were purchased from the Experimental Animal Centre of Guangzhou University of Chinese Medicine in China (Certificate No. 44005800007512). All mice were housed in a controlled room at the temperature of 24±2°C and the relative humidity of 55%±10% in a 12-h light: 12-h dark cycle with free diet consumption and water drinking. After feeding for one week, mice were randomly divided into three groups: (1) a group of the normal control (NC) of mice; (2) a group of mice administering LPS (LPS); (3) a group of mice given LPS and BPDC (LPS+BPDC).NC mice were intraperitoneally injected with neutral saline. LPS mice were intraperitoneally injected with LPS at 0.25mg/kg every other day for eleven weeks.LPS+BPDC mice were administered BPDC by intragastrical gavage at a dose of 100 mg/kg every day after eight weeks of intraperitoneal injection of LPS. LPS