Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

Abstract

As potential biomarkers and therapeutic targets, long noncoding RNAs (lncRNAs) are involved in the tumorigenesis of various tumors. Genetic variation in long noncoding regions can lead to lncRNA dysfunction and even cancer. Nevertheless, studies on the association between lncRNA‐associated single‐nucleotide polymorphisms (SNPs) and the risk of head and neck squamous cell carcinoma (HNSCC) remain inadequate. Here, we aimed to explore the association between SNPs in LINC01614 and HNSCC risk, and the potential role of LINC01614 in tumorigenesis. In this study, we found that rs16854802 A > G (odds ratio [OR] = 1.42, 95% confidence interval [CI]: 1.22–1.77, p < 0.001) and rs3113503 G > C (OR = 1.38, 95% CI: 1.15–1.64, p < 0.001) in LINC01614 increased the risk of HNSCC in the Chinese population. Functional bioinformatic analysis and luciferase reporter assay revealed that rs3113503 G > C variant disrupted the binding of miRNA‐616‐3p to LINC01614, which resulted in the increased expression of LINC01614. Further analysis of the TCGA database demonstrated that the upregulated LINC01614 in HNSCC cancer tissues was associated with poor prognostic in HNSCC patients. In vitro experiments showed that knockdown of LINC01614 inhibited the proliferation, invasion, and migration ability of HNSCC cells. Mechanistically, allele C of rs3113503 in LINC01614 was more effective than allele G in activating the PI3K/AKT signaling pathway. Moreover, the reduced expression of LINC01614 also inhibited the activation of the PI3K/AKT signaling pathway. In summary, our findings revealed that the risk SNP rs3113503 G > C in LINC01614 altered the binding to miR‐616‐3p, which led to increased LINC01614 expression and promoted HNSCC progression by activating the PI3K/AKT signaling pathway.

PERK-mediated induction of miR-5p and miR-3p arms of miR-616 regulates cell growth by targeting c-MYC

“…However, our results show that miR-616 expression attenuates the Furthermore, we observed that expression of miR-616 was reduced in human breast cancers as compared to tumour adjacent normal tissue (Fig 9). In agreement with our results miR-616-3p has been shown to potentiate apoptosis in HUVECs (16), inhibit head and neck squamous cell carcinoma progression (17) and inhibit cell growth and mammosphere formation of breast cancer cells (18,25). Any small RNA having G-rich 6mer seed sequence (nt 2-7 of the guide strand) can reduce viability of cells when associated with RNA-induced silencing complex.…”

“…This cluster maps to a region frequently amplified in Burkitt’s lymphoma, diffuse large B-cell lymphoma, follicular lymphoma and lung cancer (26, 43). The expression of miR-17-92 is reduced in prostate cancer (17) and miR-17-92 expression in intestinal epithelial cells inhibited colon cancer progression by suppressing tumour angiogenesis (17).…”

“…However, miR-616-3p has been reported to reduce XIAP expression and potentiate apoptosis in HUVECs (16). LINC01614 promotes head and neck squamous cell carcinoma progression via PI3K/AKT signalling pathway and miR-616-3p can inhibit cancer progression by downregulating LINC01614 expression (17). Ye et al reported that miR-616-3p inhibited cell growth and mammosphere formation of breast cancer cells by suppressing GLI1 (18), while Yuan reported that miR-616-3p promoted breast cancer cell migration and invasion by targeting TIMP2 and regulating MMP signalling (19).…”

Identification and expression of the target gene SLC24A2 of oar-miR-377 and its novel SNPs effects on wool traits in sheep

“…However, because the thermodynamics of RNA-RNA binding plays a crucial role in the interaction of miRNA with target mRNA, it can be expected that sequence variants such as SNP in miRNA binding sites may affect the expression of miRNA targets. There was also evidence that SNPs in miRNA binding sites may be associated with disease, such as SNP identi ed at miRNA binding sites in oncogenes are associated with increased gene expression in papillary thyroid cancer (Hou et al 2022). Due to the mutation of SLC24A5 gene, the golden mutation is accompanied by the decreased pigmentation of the skin melanophore and the retinal epithelium, and the number and density of melanosomes are reduced, resulting in the delay and reduction of melanin deposition (Reis et al 2020).…”

SNP-Target Genes Interaction Perturbing the Cancer Risk in the Post-GWAS

“…Moreover, the SNP rs11655237 allele G in LINC00673 exon can create a miRNA binding site that increases the function of LINC00667 expression ( Figure 2 e). Furthermore, rs67311347 in RCC [ 109 ], rs12982687 in CRC [ 110 ], and rs16854802 in neck squamous cell carcinoma (HNSCC) [ 111 ] are SNPs in lncRNA sequences that affect target gene expression by binding with miRNA. If a SNP occurs within miRNA, it will consequently affect the binding affinity of the miRNA to target genes.…”