LncRNA LL22NC03-N14H11.1 promoted hepatocellular carcinoma progression through activating MAPK pathway to induce mitochondrial fission

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.

Mitochondrial Fission and Fusion in Tumor Progression to Metastasis

“…Another study showed the role of a long non-coding RNA (lncRNA)—L22NC03-N14H11.1—in the tumor progression of hepatocellular carcinoma ( Yi et al, 2020 ). L22NC03-N14H11.1 had increased expression in patients diagnosed with stage III/IV cancer compared to those diagnosed with stage I/II.…”

Comprehensive analysis of N6‐methyladenosine‐related long non‐coding RNAs for prognosis prediction in liver hepatocellular carcinoma

“…Therefore, LINC00152 can be used as a novel potential LIHC prognostic marker. As for RP11‐620J15.3, it was the former transcript of hepatocarcinogenesis (GIHCG), and its overexpression was related to poor prognosis and immune infiltration of hepatocellular carcinoma (HCC) 36,37 …”

“…As for RP11‐620J15.3, it was the former transcript of hepatocarcinogenesis (GIHCG), and its overexpression was related to poor prognosis and immune infiltration of hepatocellular carcinoma (HCC). 36 , 37 . However, the molecular regulatory mechanism of RP11‐620J15.3 on the prognosis of LIHC remains unclear.…”

MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

“…Of note, downregulation of BANCR via shRNA-mediated knockdown inactivated the MAPK/ERK signaling in HCC cells, leading to the suppression of cellular proliferation and migration [ 65 ]. Other lncRNAs, such as IGF2AS, LL22NC03-N14H11.1, and URHC, are upregulated in HCC and known to promote tumorigenesis in the liver by activating the MAPK/ERK signaling [ 66 , 67 , 68 ]. On the contrary, lncRNAs RUNX1-IT1 and CASC2 inactivate the MAPK/ERK signaling pathway and their expression is significantly downregulated in HCC [ 69 , 70 ].…”