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

Abstract

Long non-coding RNAs (lncRNAs) have recently gained attention due to their important roles in human cancer types, such as breast and gastric cancer. The present study measured alterations in muskelin 1 antisense RNA (MKLN1-AS) expression in hepatocellular carcinoma (Hcc) and evaluated its clinical value in patients with Hcc. Additionally, the current study investigated the effects of MKLN1-AS on the malignant features of Hcc cells. The detailed molecular mechanisms underlying the cancer-promoting activities of MKLN1-AS in Hcc cells were also elucidated. MKLN1-AS expression in Hcc tissues and cell lines was detected using reverse-transcription quantitative PCR (RT-qPCR). Cell Counting Kit-8 assays and flow cytometry were used to determine the roles of MKLN1-AS in Hcc cell proliferation and apoptosis. Migration and invasion assays, as well as tumor xenograft experiments were conducted to analyze migration and invasion in vitro and tumor growth in vivo, respectively. The interaction among microRNA-654-3p (miR-654-3p), MKLN1-AS and hepatoma-derived growth factor (HdGF) in Hcc was investigated using luciferase reporter assay, RNA immunoprecipitation assay, RT-qPcR, western blotting and rescue experiments. MKLN1-AS was upregulated in Hcc tissues and cell lines, and a high MKLN1-AS expression was associated with shorter overall survival and disease-free survival in patients with Hcc. Functionally, the knockdown of MKLN1-AS impaired Hcc cell proliferation, migration and invasion, as well as induced cell apoptosis in vitro. Knockdown of MKLN1-AS expression also inhibited cell proliferation in vivo. The results indicated that MKLN1-AS functioned as a competing endogenous RNA by sponging miR-654-3p in Hcc cells. Additionally, miR-654-3p targeting of HdGF was positively modulated by MKLN1-AS, and miR-654-3p knockdown partially abrogated this effect. Rescue experiments demonstrated that knockdown of miR-654-3p and overexpression of HdGF both abolished MKLN1-AS knockdown-induced cellular processes in Hcc. In summary, MKLN1-AS induced pro-oncogenic effects during Hcc progression by serving as a molecular sponge for miR-654-3p to increase HdGF expression. Therefore, the MKLN1-AS/miR-654-3p/HdGF axis may offer a novel target for the diagnosis, prognosis, prevention and treatment of Hcc.

Genome-Wide Screening Identifies Prognostic Long Noncoding RNAs in Hepatocellular Carcinoma

“…Among these lncRNAs, RHPN1-AS1 was reported to act as an oncogene in multiple human cancers, including nonsmall cell lung cancer [19], uveal melanoma [20], and breast cancer [21]. LINC01134 and MKLN1-AS were found to promote HCC progression or metastasis by previous studies [24][25][26][27][28], suggesting that the two lncRNAs might be more specific in HCC, while NRAV and CMB9-22P13.1 were 13 BioMed Research International rarely reported as an oncogene in cancers. Similar with RHPN1-AS1, MAPKAPK5-AS1 was frequently reported to act as tumor-promoting lncRNAs in multiple cancers like thyroid cancer, colorectal cancer, glioma, lung cancer, and HCC [29][30][31][32][33].…”

Development and Validation of a Pyroptosis-Related Long Non-coding RNA Signature for Hepatocellular Carcinoma

“…MKLN1-AS was overexpressed and contributed to poor prognosis in HCC patients ( Guo et al, 2021 ). In addition, MKLN1-AS increases HDGF expression by functioning as a molecular sponge for miR-654-3p, resulting in a cancer-promoting effect during the HCC process ( Gao et al, 2020 ). MIR4435-2HG can promote immunometabolic activities of primary myeloid dendritic cells by targeted epigenetic modifications of a part of mTOR signaling pathway ( Hartana et al, 2021 ).…”

Identifying a Hypoxia-Related Long Non-Coding RNAs Signature to Improve the Prediction of Prognosis and Immunotherapy Response in Hepatocellular Carcinoma

“…DUXAP8 promotes the growth and proliferation of HCC cell lines by suppressing Krüppel-like factor 2 (KLF2) expression ( Jiang, et al, 2019 ). ( Gao, et al, 2020 ) revealed that MKLN1-AS promoted HCC progression by acting on miR-654-3p, and down-regulation of MKLN1-AS inhibits the aggressive phenotype of HCC cells. RHPN1-AS1 enhances the proliferation and invasion process of HCC cells by targeting miR-7-5p ( Song, et al, 2020 ).…”