Abstract
Involvement of long non-coding RNAs (lncRNAs) in hepatocarcinogenesis has been largely documented. Mitochondrial dynamics is identified to impact survival and metastasis in tumors including hepatocellular carcinoma (HCC), but the underlying mechanism remains poorly understood. This study planned to explore the regulation of lncRNA LL22NC03-N14H11.1 on HCC progression and mitochondrial fission. Dysregulated lncRNAs in HCC are identified through circlncRNAnet and GEPIA bioinformatics tools. Biological function of LL22NC03-N14H11.1 in HCC was detected by CCK-8 assay, flow cytometry analysis, transwell invasion, and wound healing assays. Molecular interactions were determined by RNA immunoprecipitation, RNA pull-down, and co-immunoprecipitation assays. Results showed that LL22NC03-N14H11.1 was upregulated in HCC tissues and cells. Functionally, LL22NC03-N14H11.1 contributed to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC. Moreover, LL22NC03-N14H11.1 facilitated mitochondrial fission in HCC cells. Mechanistically, LL22NC03-N14H11.1 recruited Myb proto-oncogene (c-Myb) to repress the transcription of leucine zipper-like transcription regulator 1 (LZTR1), so as to inhibit LZTR1-mediated ubiquitination of H-RAS (G12V), leading to the activation of mitogen-activated protein kinase (MAPK) signaling and induction of p-DRP1 (Serine 616). In conclusion, this study firstly revealed that lncRNA LL22NC03-N14H11.1 promoted HCC progression through activating H-RAS/MAPK pathway to induce mitochondrial fission, indicating LL22NC03-N14H11.1 as a novel potential biomarker for HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is the third most fatal malignancy globally, taking up 90% of primary liver cancer cases[1]
To identify the dysregulated long non-coding RNAs (lncRNAs) in HCC, we browsed circlncRNAnet and identified 2667 upregulated lncRNAs in HCC samples (P < 0.05, log 2 fold change (FC) > 1). We analyzed these lncRNAs in the GEPIA database (Gene Expression Profiling Interactive Analysis), finding that three lncRNAs, LL22NC03N14H11.1, LINC00152, and RP11-620J15.3, presented significant upregulation in liver HCC (LIHC) samples and had potential prognostic values in LIHC patients (Fig. 1a)
RTqPCR data revealed that both LL22NC03-N14H11.1 and LINC00152 were highly expressed in 62 HCC samples vs. the matched adjacent non-tumor samples, and the upregulation of LL22NC03-N14H11.1 was more significant than LINC00152 (Fig. 1b)
Summary
Hepatocellular carcinoma (HCC) is the third most fatal malignancy globally, taking up 90% of primary liver cancer cases[1]. Yi et al Cell Death and Disease (2020)11:832 the mechanism varies depending on the cellular location of lncRNAs12. We firstly discovered a novel lncRNA LL22NC03-N14H11.1 located at chr22:16,154,073–. 16,154,766 via bioinformatics analysis, and the results showed that LL22NC03-N14H11.1 was upregulated and had poor prognostic significance in HCC samples. The morphology of mitochondria is highly dynamic and varies constantly through fission and fusion, helping cells adjust their morphology to satisfy the variable need of cells and adapt to the cellular environment[13]. Facilitated mitochondrial fission can aggravate cancer metastasis through promoting migration and invasion[17,18]. Huang et al.[19] stated that mitochondrial fission was increased in HCC and promoted HCC cell survival and autophagy. Whether LL22NC03-N14H11.1 played a part in HCC via its regulation on mitochondrial fission has never been explored
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