Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2/AKT pathway

Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is the main cause for hepatocellular carcinoma (HCC). This study was intended to identify the function of long non-coding RNA (lncRNA) lncARSR in NAFLD and its role in human HCC cells (HepG2) proliferation and invasion. Methods LncARSR expression was detected both in high fatty acid-treated HepG2 cells and NAFLD mouse model. After gain- and loss-of-function approaches in high fatty acid-treated HepG2 cells and NAFLD mice, lipid accumulation in livers from NAFLD mice and high fatty acid-treated cells was determined by H&E staining, Oil Red-O staining or Nile Red staining respectively. Expression of YAP1, adipogenesis- (Fasn, Scd1 and GPA) and IRS2/AKT pathway-related genes was measured. Cell proliferation was monitored by MTT and soft-agar colony formation assays, cell cycle was analyzed by flow cytometry, and cell invasion was examined by transwell assay. The tumor weight and volume were then measured through in vivo xenograft tumor model after silencing lncARSR. Results LncARSR was highly expressed in high fatty diet (HFD)-fed mice and high fatty acid-treated HepG2 cells. LncARSR was observed to bind to YAP1, which inhibited phosphorylation nuclear translocation. LncARSR activated the IRS2/AKT pathway by reducing YAP1 phosphorylation, and further increased lipid accumulation, cell proliferation, invasion and cell cycle. Silencing lncARSR in HFD-fed mice alleviated NAFLD by regulating YAP1/IRS2/AKT axis. Conclusion Silencing lncARSR suppressed the IRS2/AKT pathway, consequently reducing HCC cell proliferation and invasion and inhibiting lipid accumulation in NAFLD mice by downregulating YAP1, which suggests a clinical application in treating NAFLD.

Long non‑coding RNA MKLN1‑AS aggravates hepatocellular carcinoma progression by functioning as a molecular sponge for miR‑654‑3p, thereby promoting hepatoma‑derived growth factor expression

“…lncRNAs have received increasing attention in the past decade due to their important roles in human cancer types (32,33). Numerous lncRNAs, such as ubiquitin conjugating enzyme E2 R2-AS1 (34), colorectal neoplasia differentially expressed (35) and snail family transcriptional repressor 3-AS1 (36), are differentially expressed in Hcc and are closely associated with clinicopathological factors and prognosis of patients with Hcc (37)(38)(39). For instance, these lncRNAs participate in the regulation of various aggressive cellular features during hepatocarcinogenesis and cancer progression (40)(41)(42).…”

Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression

“…Qu L et al revealed that lncARSR promoted AKT activation indirectly and led to Sunitinib resistance of renal cancer 10 . Li and colleagues, as well as Ying J et al, proved that lncARSR activated AKT via suppressing PTEN directly 13,30 Furthermore, lncARSR enhanced AKT activation by promoting YAP1/IRS2/AKT signaling pathways 31 . It is well documented that AKT activation was involved in chemoresistance in various cancer, including ovarian and endometrial cancer, breast cancer, non-small cell lung cell, and osteosarcoma 32 .…”

Long Non-Coding RNAs in Liver Cancer and Nonalcoholic Steatohepatitis

“…Taken together, these studies highlight the fact that transcriptional regulation via lncRNAs is an important mechanism to be investigated, although careful dissection of the gene regulatory networks by combining ChIP-seq and other methods (e.g., chromosome conformation capture techniques [37]) must be conducted in a genome-wide manner to record the influence of such lncRNAs on a number of genes, as many of these epigenetic and transcription factors (positively or negatively) regulate not only one but many genes. (YAP1) to inhibit its phosphorylation nuclear translocation, resulting in activation of the IRS2/AKT pathway, leading to increased lipid accumulation, cell proliferation, invasion and cell cycle [34]. The translation regulatory long non-coding RNA 1 (TRERNA1) binds the euchromatic histone lysine methyltransferase 2 (EHMT2) to dimethylate the promoter of cadherin 1 (CDH1) [35]; TSPOAP1, SUPT4H1 and RNF43 antisense RNA 1 (TSPOAP1-AS1, also known as BZRAP1-AS1) binds to DNA methyltransferase 3 beta (DNMT3B) to induce methylation of the promoter of thrombospondin 1 (THBS1), resulting in its inhibition [36] ( Figure 1B).…”