Abstract
N6-Methyladenosine (m6A) modification is one of the commonest chemical modifications in eukaryotic mRNAs, which has essential effects on mRNA translation, splicing, and stability. Currently, there is a rising concern on the regulatory role of m6A in tumorigenesis. As a known component in the m6A methyltransferase complex, METTL3 (methyltransferase-like 3) plays an essential role in m6A methylation. Till now, the functions of METTL3 in oral squamous cell carcinoma (OSCC) and its relative mechanism remain to be explored. In this research, through the GEPIA database, we found that high METTL3 expression has a correlation with poor prognosis of squamous cell carcinoma of head and neck. qRT-PCR displayed that METTL3 was highly expressed in OSCC cells. Functionally, METTL3 knockdown reduced the invasion, migration, and proliferation competence of OSCC cells and attenuated the activation of CD8+ T cells. In contrast, METTL3 overexpression resulted in opposite results. GEPIA, UALCAN, and SRAMP databases, PCR, western blot, and m6A RNA methylation assay confirmed the m6A modification of PRMT5 and PD-L1 mediated by METTL3. In conclusion, our results displayed that METTL3 intensified the metastasis and proliferation of OSCC by modulating the m6A amounts of PRMT5 and PD-L1, suggesting that METTL3 may be a therapeutic target for OSCC patients.
Highlights
Oral squamous cell carcinoma (OSCC) is the commonest head and neck malignancy and responsible for approximately 90% of malignant epithelial tumors in the oral and maxillofacial region [1,2,3,4]
METTL3 is highly expressed in most human cancers, and we found through the GEPEIA database that METTL3 has a close relation with the prognosis of squamous cell carcinoma of head and neck
Cell activation. (d, e) Cell Counting Kit-8 (CCK8) and EdU assays displayed that sh-METTL3 attenuated OSCC cell proliferation. (f) Wound healing assay displayed that sh-METTL3 suppressed the competence of OSCC cell migration. (g) Transwell assays displayed that sh-METTL3 suppressed the competence of OSCC cell invasion. ∗p < 0:05, ∗∗p < 0:01, and ∗∗∗p < 0:001
Summary
Oral squamous cell carcinoma (OSCC) is the commonest head and neck malignancy and responsible for approximately 90% of malignant epithelial tumors in the oral and maxillofacial region [1,2,3,4]. Countless studies have demonstrated that abnormal m6A RNA methylation exerts an essential influence in the pathogenesis of many human disorders including OSCC [14, 20, 21]. The deletion or abnormal expression of METTL3 will affect the level of m6A of intracellular RNA and affect the degradation and translation of mRNA and the generation of microRNA, which may lead to the occurrence of human diseases [24, 25]. METTL3 is highly expressed in most human cancers, and we found through the GEPEIA database (http://gepia.cancer-pku.cn/index .html) that METTL3 has a close relation with the prognosis of squamous cell carcinoma of head and neck. The low expression of METTL3 predicts a high free survival of disease of head and neck squamous cell carcinoma. We evaluated the function of METTL3 in OSCC and probed into the mechanism of METTL3’s involvement in OSCC
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