Effect of miR‐182 on hepatic fibrosis induced by Schistosomiasis japonica by targeting FOXO1 through PI3K/AKT signaling pathway

Abstract

The study aimed to investigate the impact of miR-182 and FOXO1 on S. japonica-induced hepatic fibrosis. Microarray analysis was performed to screen out differential expressed miRNAs and mRNAs. Rat hepatic fibrosis model and human hepatocellular cell line LX-2 were used to study the effect of miR-182 and FOXO1. qRT-PCR and Western blot were used to detect the expression of miR-182, FOXO1 or other fibrosis markers. The targeting relationship between FOXO1 and miR-182 was verified by luciferase reporter assay. Immunohistochemistry or immunofluorescence staining was conducted to detect FOXO1 or α-SMA in rat hepatic tissues. Cell viability and apoptosis were detected by MTT assay and flow cytometry. The expression of PI3K/AKT pathway-related proteins was detected by Western blot. miR-182 was highly expressed in liver fibrosis samples, and FOXO1 expression was negatively correlated with miR-182 expression. After transfection of miR-182, FOXO1 expression was down-regulated, with the results of LX-2 cells proliferation inhibition and apoptosis induction, as well as the aggravation of rat hepatic fibrosis. The expression of p-AKT/AKT and p-S6/S6 was increased, meaning that the PI3K/AKT signal pathway was activated. The results were reversed when treated with Wortmannin (PI3K inhibitor). After transfection of miR-182 inhibitor, FOXO1 expression was up-regulated, LX-2 cell proliferation was inhibited, and apoptosis rate was increased. High-expressed miR-182 and low-expressed FOXO1 promoted proliferation and inhibiting apoptosis on liver fibrosis cells, stimulating the development of S. japonica-induced hepatic fibrosis through feeding back to PI3K/AKT signaling pathway.

Higher levels of TNF and IL‐4 cytokines and low miR‐182 expression in visceral leishmaniasis‐HIV co‐infected patients

“…13,45 In the present study, miR-182 expression was found to be significantly higher in the HIV mono-infected group, which has already been studied as a noninvasive biomarker for a number of infectious diseases. [28][29][30][31] One of these studies showed that upon Schistosoma mansoni infection, the IL-4 cytokine upregulates miR-182 expression Th2-Treg cells, thereby suppressing IL-2 secretion of the Th1 response. 30 Another found the IL-4 cytokine in significantly higher levels in HIV mono-infected subjects.…”

“…miR‐182 has thus been described as a noninvasive biomarker for a number of infectious diseases, such as HIV, HCV, sepsis and schistosomiasis . In the specific case of leishmaniasis, miR‐210 upregulation plays a role in apoptotic signalling pathway and miR‐122 downregulation is related to VL pathogenesis .…”

“…[21][22][23][24][25][26] miR-182 has thus been described as a noninvasive biomarker for a number of infectious diseases, such as HIV, 27 HCV, 28 sepsis 29 and schistosomiasis. 30,31 In the specific case of leishmaniasis, miR-210 upregulation plays a role in apoptotic signalling pathway 32 and miR-122 downregulation is related to VL pathogenesis. 33 However, no studies of their role as biomarkers of infection in VL-HIV co-infected patients have been carried out directly on serum samples.…”

Inhibition of miR-182-5p attenuates pulmonary fibrosis via TGF-β/Smad pathway

“…14 Moreover, other possible miRNAs related to IPF are also under study. miR-182-5p was found to have significant upregulated expression in hepatic fibrosis [15][16][17] and peritoneal fibrosis. 18 Huang et al found that overexpressed miR-182 can regulate FOXO1 negatively and prompt the development of hepatic fibrosis.…”

“…18 Huang et al found that overexpressed miR-182 can regulate FOXO1 negatively and prompt the development of hepatic fibrosis. 15 Liu et al found that miR-182 might play an important role in the process of peritoneal fibrosis. 18 However, the potential effect of miR-182-5p on pulmonary fibrosis has not been reported yet.…”