Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR-134-5p/FOXM1 axis

Abstract

Background Highly upregulated in liver cancer (HULC), the specifically overexpressed long non-coding RNA (lncRNA) in human hepatocellular carcinoma (HCC), can promote the growth and metastasis of HCC cells. Therefore, it will be benefit to HCC treatment by effectively downregulating HULC. Liver X receptor (LXR), a member of nuclear receptor superfamily, exerts anti-tumor effects on various human malignancies including HCC. However, it is unclear whether the anti-HCC function of LXR is involved in the regulation of HULC. Methods Quantitative real-time PCR and Western blot were used to separately examine RNA and protein levels in HCC cells. Cell counting kit-8 assay was used to detect the growth of HCC cells in vitro. Dual-luciferase reporter assays were performed to analyze the regulation of forkhead box M1 (FOXM1) by miR-134-5p and the regulation of miR-134-5p by HULC. Xenograft models were engaged to evaluate the growth of HCC cells in vivo. Results In this study, we found that activation of LXR could inhibit the growth of HCC cells by downregulating HULC. Mechanistically, LXR decreased HULC via suppressing its gene promoter activity. Moreover, HULC and FOXM1 were highly expressed while miR-134-5p was lowly expressed in HCC tissues, and the level of HULC was positively correlated with that of FOXM1 while negatively correlated with that of miR-134-5p. Additionally, miR-134-5p downregulated FOXM1 by targeting 3′untranslated region (UTR) of its mRNA, and HULC upregulated FOXM1 and its downstream target molecule cyclin D1 through sequestrating miR-134-5p. Furthermore, activation of LXR increased miR-134-5p while decreased FOXM1 by reducing HULC in HCC cells. The in vivo experiments showed that activation of LXR repressed the growth of HCC xenografts, and decreased HULC, FOXM1 and cyclin D1 while increased miR-134-5p in the xenografts. Conclusions Our results for the first time reveal that LXR can inhibit the growth of HCC cells by regulating HULC/miR-134-5p/FOXM1 axis. The novel pathway LXR/HULC/miR-134-5p/FOXM1 may serve as a promising target in HCC treatment. Background Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNAs with longer than 200

Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma

“…HULC knockdown increased the chemosensitivity to oxaliplatin through the repression of cell growth and the acceleration apoptosis in HCC cells. Further analysis confirmed its mode of action through the regulation of the miR-383-5p/vesicle-associated membrane protein-2 axis, the miR-377-5p/HIF-1α pathway, and the miR-134-5p/FOXM1 axis [41,42]. Emerging evidence provides new insights on the role of other lncRNAs in HCC development, such as NEAT1, ANRIL, SNHG1, or H19 [36,69].…”

“…Regulation of mitochondrial metabolism [38] HULC Growth of liver cancer stem cells [39] Chemosensitivity of anti-cancer drug oxaliplatin inhibition [40] Regulation of miR-383-5p/vesicle-associated membrane protein-2 pathway; miR-377-5p/HIF-1α pathway and miR-134-5p/FOXM1 pathway [41,42] On the contrary, hypermethylation may disturb the function of another group of genes. One of the signaling pathways affected by hypermethylation is the WNT/β-catenin signaling.…”

Propofol induces apoptosis of hepatocellular carcinoma cells by upregulating miR-134 expression

“…Additionally, miR-134 was found to have a connection to liver cancer. He et al ( 26 ) found that miR-134 targets FOXM1 to inhibit HCC cell proliferation. In this study, we observed that propofol promoted caspase-3 activity, while miR-134 deficiency induced by transfecting miR-134 inhibitor reserved this situation.…”

Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer

“…In previous studies, FOXM1 has been proven to play a promoting role in a variety of tumors, including HCC [186][187][188]. Therefore, LXR can inhibit the growth of HCC cells by reducing HULC, increasing miR-134-5p and reducing FOXM1 [185].…”

“…He et al found that LXRα can bind to the lncRNA HULC promoter region and inhibit the transcriptional activity of the HULC gene promoter. HULC can inhibit miR-134-5p targeting the 3'-UTR of FOXM1 to upregulate the expression of FOXM1 [185]. In previous studies, FOXM1 has been proven to play a promoting role in a variety of tumors, including HCC [186][187][188].…”