Mechanism Analysis of LINC00665 and Its Peptides CIP2A-BP in Hepatocellular Carcinoma

Abstract

Background: More and more studies show that long non-coding RNAs (lncRNAs) have miniature open reading frames that can be translated into short peptides. Here, we identify the long non-coding gene LINC00665 and its short peptides (CIP2A-BP) in hepatocellular carcinoma (HCC) and explore how they contribute to HCC progression.Materials and methods: First, GSE101728 data were acquired through the Gene Expression Omnibus for identification of differentially expressed genes (DEGs), and gene set enrichment analysis (GSEA) was conducted to find enriched biological pathways. Then, further bioinformatics analysis was carried out on the screened long non-coding genes, and LINC00665 expression was detected in HCC and normal liver samples. The relations between LINC00665 expression, HCC prognosis, and clinical characteristics were studied. Receiver operating characteristic (ROC) analysis was also applied to verify the LINC00665 prediction in HCC prognosis. In addition, pertinent experiments on LINC00665 and CIP2A-BP were also carried out to explore their roles in the progression of HCC.Results: As a result, we screened out 332 DEGs in total, including 130 upregulated and 202 downregulated DEGs. These DEGs were mainly enriched in posttranscriptional regulation of gene expression, RNA processing, nucleolus, and gene silencing biological pathways. In addition, we found that LINC00665 was increased in HCC samples, which substantially indicated its poor prognosis. Compared with normal tissues, LINC00665 had higher expression in the pathological stages III and IV, tumor-free groups, people no more than 60 years old, and stages T3, T4, N0, N1, and M1. ROC curve indicated that the variable INC00665 had certain accuracy in predicting overall survival (OS). Moreover, in functional experiments, LINC00665 knockdown could significantly decrease HCC cell proliferation, migration, and invasion, while overexpressed CIP2A-BP could markedly increase HCC cell proliferation, invasion, and migration.Conclusion: Our findings not only disclose a unique mechanism by which CIP2A-BP encoded by LINC00665 promotes HCC carcinogenesis but suggest that these long non-coding genes and short peptides could be used as biomarkers for HCC diagnosis and prognosis and new targets for HCC therapy.

Subcellular localization and relevant mechanisms of human cancer‐related micropeptides

“…Third, micropeptides affect various tumor phenotypes, including cell proliferation, metastasis, and invasion. The subtle and specific mechanisms remain to be further explored and can be expanded to other related fields by comprehensively elaborating the signaling pathways 48,49 . Furthermore, accurately analyzing the intracellular localization, translation level, functional mechanisms, and special structures of micropeptides is conducive to developing micropeptides as biological diagnostic and prognostic indicators and potential therapeutic tumor targets.…”

From Basic Science to Clinical Practice: The Role of Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A)/p90 in Cancer

“…A specificity protein 1 (SP1)-induced long non-coding RNA, DPPA2 upstream binding RNA (DUBR), upregulates CIP2A expression through E2F1-mediated transcription regulation, which also plays a role in upregulating CIP2A at the mRNA level by binding miR-520d-5p as a competing endogenous RNA (Liu et al, 2022). The knockdown of LINC00665 can also significantly decrease the cell proliferation, migration, and invasion of HCC, while overexpression of the short peptides of LINC00665 (CIP2A-BP) can markedly increase cell proliferation, invasion, and migration (Li et al, 2022).…”

A Concise Review on Dysregulation of LINC00665 in Cancers

“…Moreover, it can regulate the viability, apoptotic pathways, and autophagy of these cells through modulation of miR-186-5p/MAP4K3 [ 21 ] and Double-Stranded RNA–Activated Protein Kinase/NF-κB [ 22 ] axes. Another study in hepatocellular carcinoma cells has shown that LINC00665 silencing could decrease proliferation, migration, and invasion, whereas up-regulation the CIP2A-BP micropeptide enhances these features [ 36 ].…”

“…Moreover, up-regulation of LINC00665 has been associated with further development of the tumors, which has been closely correlated with clinical diagnosis. Accuracy of LINC00665 levels in prediction of overall survival has also been verified by ROC curve analyses [ 36 ].…”