Functional diversity of miR-146a-5p and TRAF6 in normal and oral cancer cells

Abstract

Numerous studies implicate miR-146a as pleiotropic regulator of carcinogenesis; however, its roles in carcinogenesis are not fully understood. A clue from expression analyses of miR-146a-5p in all 13 oral squamous cell carcinoma (OSCC) cell lines examined and in OSCC tissues, whole blood and whole saliva of OSCC patients in vivo revealed that miR‑146a-5p expression was highly upregulated. Particularly, we widened the view of its upregulation in saliva, implicating that high miR-146a-5p expression is not only correlated closely to the development of human oral cancer, but also to a possible candidate as a diagnostic marker of OSCC. Indeed, further examination showed that exogenous miR-146a-5p expression showed pleiotropic effects on cell proliferation and apoptosis which were partially based on the contextual responses of activation of JNK, downstream of TRAF6 that was targeted by miR-146a-5p in normal human keratinocytes and OSCC cell lines. TRAF6 suppression by a TRAF6-specific siRNA resulted in contradictory consequences on cellular processes in normal and OSCC cells. Notably, TRAF6 downregulation by both miR-146a-5p and TRAF6-specific siRNA deactivated JNK in SCC-9, but not in normal human keratinocytes. In support of the proliferation-promoting effect of miR-146a-5p, silencing of endogenous miR-146a-5p significantly reduced proliferation of SCC-9. Together, these results suggest that miR-146a-5p affects proliferation and apoptosis in a cellular context-dependent manner and selectively disarms the TRAF6-mediated branch of the TGF-β signaling in OSCC cell lines by sparing Smad4 involvement.

Tagging Functional Polymorphism in 3’ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke

“…For example, the rs2910164 polymorphism harboring the sequence for miR-146a was shown to influence susceptibility to gastric cancer in a Chinese population, while rs4143815 and rs4819388 SNPs in the 3'-UTRs of B7-H1 and B7-H2 genes, respectively, were also associated with the development of gastric cancer [25]. The function of SNPs localized at miRNA-binding sites, also defined as 3′ UTRs, could affect the binding of miRNAs to their targets and thereby suppress or activate the expression of the target genes and alter the susceptibility to cancer [20, 26].…”

miR-146a-5p Plays an Oncogenic Role in NSCLC via Suppression of TRAF6

“…Via down-regulation of TRAF6, miR-146a-5p suppressed hepatocellular carcinoma (HCC) cell proliferation and invasion in vitro and inhibited tumor formation in vivo and in vitro (Zu et al, 2016). miR-146a was not only overexpressed in cervical cancer and promoted cancer cell proliferation by targeting TRAF6 through NF-κB signaling (Li et al, 2019), but also in oral carcinoma by targeting IRAK1, TRAF6, and NUMB (Hung et al, 2013;Min et al, 2017). miR-146a-5p/TRAF6/NF-κB-p65 axis regulated cell growth and gemcitabine (GEM) chemotherapy sensitivity in pancreatic ductal adenocarcinoma (PDAC; Meng et al, 2020).…”

miR-146a Overexpression in Oral Squamous Cell Carcinoma Potentiates Cancer Cell Migration and Invasion Possibly via Targeting HTT

“…The role of miR-146a in various cancer etiology, including blood, breast, cervical, kidney, liver, and lung cancer, had been extensively studied (18). Only pieces of literature are available regarding the role of miR-146a in OSCC, and the results are controversial (17,19,20). Hung and colleagues reported the upregulation of miR-146a in OSCC tissues and blood circulation of OSCC patients, and the involvement in OSCC oncogenicity (17).…”

“…Hung and colleagues reported the upregulation of miR-146a in OSCC tissues and blood circulation of OSCC patients, and the involvement in OSCC oncogenicity (17). Similarly, Min and colleagues reported a higher expression of miR-146a in OSCC (19). In contrast, Shi and colleagues reported the loss of miR-146a expression in high-grade oral cancer tumors and reexpression of miR-146a reduced oncogenic phenotypes and metastasis (20).…”