M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

Abstract

Background: Long non-coding RNAs (lncRNAs) possess significant regulatory functions in multiple biological and pathological processes, especially in cancer. Dysregulated lncRNAs in hepatocellular carcinoma (HCC) and their therapeutic applications remain unclear.Methods: Differentially expressed lncRNA profile in HCC was constructed using TCGA data. LINC00958 expression level was examined in HCC cell lines and tissues. Univariate and multivariate analyses were performed to demonstrate the prognostic value of LINC00958. Loss-of-function and gain-of-function experiments were used to assess the effects of LINC00958 on cell proliferation, motility, and lipogenesis. Patient-derived xenograft model was established for in vivo experiments. RNA immunoprecipitation, dual luciferase reporter, biotin-labeled miRNA pulldown, fluorescence in situ hybridization, and RNA sequencing assays were performed to elucidate the underlying molecular mechanisms. We developed a PLGA-based nanoplatform encapsulating LINC00958 siRNA and evaluated its superiority for systemic administration. Results:We identified a lipogenesis-related lncRNA, LINC00958, whose expression was upregulated in HCC cell lines and tissues. High LINC00958 level independently predicted poor overall survival. Functional assays showed that LINC00958 aggravated HCC malignant phenotypes in vitro and in vivo. Mechanistically, LINC00958 sponged miR-3619-5p to upregulate hepatoma-derived growth factor (HDGF) expression, thereby facilitating HCC lipogenesis and progression. METTL3-mediated N 6 -methyladenosine modification led to LINC00958 upregulation through stabilizing its RNA transcript. A PLGA-based nanoplatform loaded with si-LINC00958 was developed for HCC systemic administration. This novel drug delivery system was controlled release, tumor targeting, safe, and presented satisfactory antitumor efficacy.

The role of long noncoding RNAs in hepatocellular carcinoma

“…Mechanistic studies revealed that m6A frequently regulates the degradation of modified lncRNAs, including those related with HCC. For example, m6A modification upregulates the stability of LINC00958, leading to its overexpression in HCC and promotes cell proliferation and invasion [172]. This effect may result from an enhanced binding of lncRNA with protective partner, or a disassociation with RNA decay machinery.…”

Joint analysis of lncRNA m6A methylome and lncRNA/mRNA expression profiles in gastric cancer

“…Dynamic RNA modifications are often enriched for quantitative traits and complex traits including common diseases, and thus m 6 A is potentially correlated with gene expression homeostasis [ 25 , 26 ]. For instance, METTL3-mediated m 6 A modification led to LINC00958 upregulation through stabilizing its RNA transcript, and LINC00968 sponged miR-3619-5p to upregulate HDGF expression thereby facilitating the lipogenesis and progression of hepatocellular carcinoma (HCC) [ 27 ]. Another investigation revealed that m 6 A demethylase ALKBH5 could suppress the degradation of lncRNA PVT1, and its overexpression promoted osteosarcoma cell proliferation in vitro and tumor growth in vivo [ 28 ].…”

Identification of Potential Prognostic Biomarkers for Tongue Squamous Cell Carcinoma

“…However, investigations on the functions of m 6 A in lncRNAs are lacking. One recent study revealed that the METTL3-mediated N 6methyladenosine modi cation led to LINC00958 upregulation by stabilizing its RNA transcript in hepatocellular carcinoma [40] . A similar study showed that in colorectal cancer cells, METTL14…”