EGF Up-Regulates miR-31 through the C/EBPβ Signal Cascade in Oral Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPβ expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPβ expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPβ, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPβ and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPβ and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPβ expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.

MicroRNA expression patterns in oral squamous cell carcinoma: hsa‐mir‐99b‐3p and hsa‐mir‐100‐5p as novel prognostic markers for oral cancer

“…Upregulation of hsa-mir-31-5p is found in HNSCC and OSCC tissue, oral swirls, plasma of patients with OSCC, and HNSCC and OSCC cell lines. 66 In addition to this, several studies highlight the potential role of hsa-mir-31-5p as a diagnostic and prognostic marker: Severino et al and Siow et al found a higher hsa-mir-31-5p expression level in N0 OSCC cases, thus indicating hsa-mir-31-5p may be a favorable prognostic factor. 14,33, 34 Lu et al found that the upregulation of hsa-mir-31-5p in OSCC is inter alia caused through stimulation of epithelial growth factor I.…”

“…Samples were tested for 16 HPV subtypes (HPV 6,11,16,18,31,33,35,39,45,51,52,56,58,59,66, and 68) using multiplexbased fluorescence PCR (F-HPV typing™, Genomed Diagnostics AG, Paisley, United Kingdom). Samples were tested for 16 HPV subtypes (HPV 6,11,16,18,31,33,35,39,45,51,52,56,58,59,66, and 68) using multiplexbased fluorescence PCR (F-HPV typing™, Genomed Diagnostics AG, Paisley, United Kingdom).…”

Targeting of miR‐31/96/182 to the Numb gene during head and neck oncogenesis

“…MicroRNAs (miRNAs) are noncoding RNAs that downregulate the expression of targeted genes by binding to the specific sequences in the 3′untranslated region (UTR) of the transcript via seed sequences . Many miRNAs are involved in the neoplastic process associated with HNSCC . Our previous studies have shown that there is drastic upregulation of miR‐31 in HNSCC .…”

Systematical analyses of variants in DNase I hypersensitive sites to identify hepatocellular carcinoma susceptibility loci in a Chinese population

“…Among them, only CEBPB retained after bonferroni adjustment. As an important regulator, CEBPB is implicated in various biological activities, including adiposeness, inflammatory responses, cell differentiation and proliferation, and cancer progression, such as breast cancer, oral carcinomas, and esophageal squamous cell carcinomas . Fang et al .…”