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Long noncoding RNA lnc-H2AFV-1 promotes cell growth by regulating aberrant m6A RNA modification in head and neck squamous cell carcinoma.

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor in the oral and maxillofacial regions, and long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and progression of HNSCC. The lncRNA lnc-H2AFV-1 was found to be upregulated in HNSCC tissues; however, the function of lnc-H2AFV-1 in regulating HNSCC proliferation and the potential molecular mechanism is unclear. The present study evaluated the expression of lnc-H2AFV-1 in HNSCC tissues using quantitative real-time PCR (qPCR) and associated abundant lnc-H2AFV-1 expression with tumor size. Functionally, lnc-H2AFV-1 significantly promoted the proliferation of HNSCC cells in vitro and in vivo. Quantified N6-methyladenosine (m6A) RNA methylation and dot blot assays revealed that total m6A methylation in HNSCC cells was accompanied by lnc-H2AFV-1 expression. Western blotting showed that the expression of methyltransferase-like (METTL) 3 and METTL14 was consistent with that of lnc-H2AFV-1, whereas the expression of demethylase fat mass and obesity-associated (FTO) was contrary to that of lnc-H2AFV-1. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-qPCR revealed that lnc-H2AFV-1 overexpression led to the elevated expression and maximal m6A methylation of intraflagellar transport (IFT) 80 in HNSCC. In addition, METTL3/14 knockdown decreased IFT80 expression. Thus, our findings suggested that lnc-H2AFV-1 might be a biomarker that alters m6A modification by regulating the m6A methylases METTL3/14 and FTO and then mediating the downstream target IFT80 to promote HNSCC progression.

SUBMITTER: Chen X

PROVIDER: S-EPMC9207353 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveHead and neck squamous cell carcinoma (HNSCC) is a highly heterotopic malignant tumor. Alternative splicing (AS) and RNA modification have been reported to be involved in tumorigenesis. Therefore, we constructed RNA modification-associated AS (RMA-AS) signature model to predict the prognosis of HNSCC.MethodsAS events and RNA-modified gene expression information were downloaded from TCGA-HNSCC database. Univariate Cox regression analysis was employed for analyzing prognosis-related AS events. RMA-AS events were obtained by constructing a coexpression network between RNA modification-associated genes and AS events using WGCNA package. The prognostic signatures were analyzed by LASSO, univariate Cox, and multivariate Cox regression. Kaplan-Meier survival analysis, proportional hazard model, and ROC curve were performed to verify the prognostic value. "ESTIMATE" R package, ssGSEA algorithm, and CIBERSORT method were used to detect immune microenvironment in HNSCC. Cytoscape was utilized to build a regulatory network of splicing factor-regulated RMA-AS.ResultsThere were 16,574 prognostic AS events and 4 differentially expressed RNA modification-associated genes in HNSCC. Based on RMA-AS events, we obtained a risk model consisting of 14 AS events, named RMA-AS_Score. The samples were divided into RMA-AS_Score high- and RMA-AS_Score low-risk groups, according to the risk score. The RMA-AS_Score high group was related to poor prognosis. Moreover, the RMA-AS_Score signature was an independent prognostic predictor and was related to tumor grade. Meanwhile, the AUC value of RMA-AS_Score was 0.652, which is better than other clinical characteristics. Besides, a nomogram prediction model of quantitative prognosis has also been developed, which has robust effectiveness in predicting prognosis. In addition, the prognostic signature was observably related to immune microenvironment and immune checkpoint. Finally, 14 splicing factors were identified and constructed into a network of splicing factor-regulated RMA-AS.ConclusionWe identified the RMA-AS signature of HNSCC. This signature could be treated as an independent prognostic predictor.

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Long noncoding RNA lnc-H2AFV-1 promotes cell growth by regulating aberrant m6A RNA modification in head and neck squamous cell carcinoma.

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