Abstract
BackgroundLong 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.MethodsDifferentially 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 pull-down, 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.ResultsWe 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 N6-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.ConclusionsOur results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target.
Highlights
With 841,080 new cases and 781,631 deaths annually, hepatocellular carcinoma (HCC) ranks the sixth most commonly diagnosed malignancy and the fourth leading cause of death worldwide [1]
Our results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target
LINC00958 is highly expressed in HCC and predicts overall survival With a stringent filter of logFC > 2.0 and P value < 0.005, we established the profile of differentially expressed Long noncoding RNAs (lncRNA) in HCC based on TCGA data
Summary
With 841,080 new cases and 781,631 deaths annually, hepatocellular carcinoma (HCC) ranks the sixth most commonly diagnosed malignancy and the fourth leading cause of death worldwide [1]. Long non-coding RNAs (lncRNAs), a class of functional non-coding RNA transcripts > 200 nt in length, are engaged in diverse biological processes across every branch of life. Specific patterns of lncRNA expression coordinate cell differentiation, development, and pathogenesis. In HCC, lncRNAs have been reported to affect various malignant phenotypes, such as cell proliferation, motility, and glucose metabolism reprogramming [3,4,5]. LncRNA HULC activates the acyl-CoA synthetase subunit ACSL1 in a miR-9dependent manner to promote lipogenesis and function as an oncogene in hepatoma cells [7]. 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
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