Hub Long Noncoding RNAs with m6A Modification for Signatures and Prognostic Values in Kidney Renal Clear Cell Carcinoma

Abstract

Background: N6-methyladenosine (m6A)–modified long noncoding RNAs (m6A-lncRNAs) have been proven to be involving in regulating tumorigenesis, invasion, and metastasis for a variety of tumors. The present study aimed to screen lncRNAs with m6A modification and investigate their biological signatures and prognostic values in kidney renal clear cell carcinoma (KIRC).Materials and Methods: lncRNA-seq, miRNA-seq, and mRNA-seq profiles of KIRC samples and the clinical characteristics of corresponding patients were downloaded from The Cancer Genome Atlas (TCGA). The R package “edgeR” was utilized to perform differentially expressed analysis on these profiles to gain DElncRNAs, DEmiRNAs, and DEmRNAs, respectively. The results of intersection of DElncRNAs and m6A-modified genes were analyzed by the weighted gene co-expression network analysis (WGCNA) to screen hub m6A-lncRNAs. Then, WGCNA was also used to construct an lncRNA-miRNA-mRNA (ceRNA) network. The Cox regression analysis was conducted on hub m6A-lncRNAs to construct the m6A-lncRNAs prognostic index (m6AlRsPI). Receiver operating characteristic (ROC) curve was used to assess the predictive ability of m6AlRsPI. The m6AlRsPI model was tested by internal and external cohorts. The molecular signatures and prognosis for hub m6A-lncRNAs and m6AlRsPI were analyzed. The expression level of hub m6A-lncRNAs in KIRC cell lines were quantified by qRT-PCR.Results: A total of 21 hub m6A-lncRNAs associated with tumor metastasis were identified in the light of WGCNA. The ceRNA network for 21 hub m6A-lncRNAs was developed. The Cox regression analysis was performed on the 21 hub m6A-lncRNAs, screening two m6A-lncRNAs regarded as independent prognostic risk factors. The m6AlRsPI was established based on the two m6A-lncRNAs as follows: (0.0006066 × expression level of LINC01820) + (0.0020769 × expression level of LINC02257). The cutoff of m6AlRsPI was 0.96. KM survival analysis for m6AlRsPI showed that the high m6AlRsPI group could contribute to higher mortality. The area under ROC curve for m6AlRsPI for predicting 3- and 5-year survival was 0.760 and 0.677, respectively, and the m6AlRsPI was also tested. The mutation and epithelial–mesenchymal transition (EMT) analysis for m6AlRsPI showed that the high m6AIRsPI group had more samples with gene mutation and had more likely caused EMT. Finally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for mRNAs interacted with the two m6A-lncRNAs, showing they were involved in the process of RNA splicing and regulation of the mRNA surveillance pathway. qRT-PCR analysis showed that the two m6A-lncRNAs were upregulated in KIRC.Conclusion: In the present study, hub m6A-lncRNAs were determined associated with metastasis in KIRC, and the ceRNA network demonstrated the potential carcinogenic regulatory pathway. Two m6A-lncRNAs associated with the overall survival were screened and m6AlRsPI was constructed and validated. Finally, the molecular signatures for m6AlRsPI and the two m6A-lncRNAs were analyzed to investigate the potential modulated processes in KIRC.

Estradiol mediates the interaction of LINC01541 and miR-429 to promote angiogenesis of G1/G2 endometrioid adenocarcinoma in-vitro: A pilot study

“…In conclusion, alterations in METTL3 expression may significantly affect miRNA expression in various human cancers (32)(33)(34). In addition, m6A-lncRNAs have been proven to be involving in regulating tumorigenesis and m6A is likely to participate in the construction of the lncRNA-miRNA-mRNA (ceRNA) interaction regulatory network (35)(36)(37). We hypothesized that the interaction between LINC01541 and miR-429 assessed in our study may therefore be m6A-dependent.…”

Construction and Validation of a Novel Prognosis Model in Colon Cancer Based on Cuproptosis-Related Long Non-Coding RNAs

“…Consistent with our study, several previous studies demonstrated that LINC02257 was a prognostic marker for patients with colon adenocarcinoma or renal clear cell carcinoma. In detail, high expression of LINC02257 in tumor tissues is associated with poor prognosis by regulating PI3K/AKT signaling pathway [ 47 , 48 ]. Furthermore, Zhou et al [ 49 ] showed that LncRNA FARSA-AS1 promoted proliferation, stemness, and metastasis of colorectal cancer cells through upregulating FARSA and SOX9, which was different from our study.…”

LncRNA LINC02257: A Potential Biomarker for Diagnosis and Prognosis of Colorectal Cancer

“…For LINC02257, we have looked up a lot of literature. Only some studies reported that LINC02257 was highly expressed in some tumors, such as kidney renal clear cell carcinoma and CRC [ 13 , 14 ]. However, there was no in vivo or in vitro experimental study on its function.…”

“…To date, the study of LINC02257 on tumors was rarely reported. Its expression and prognostic value were just reported in kidney renal clear cell carcinoma and CRC [ 13 , 14 ]. However, the studies are limited.…”