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MiR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes.

ABSTRACT: MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial to tumorigenesis. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. Up-regulation of miR-146 has been identified in OSCC tissues. However, the roles of miR-146 in carcinogenesis are controversial as it is suppressive in many other malignancies. The present study investigated the pathogenic implications of miR-146a in oral carcinogenesis. Microdissected OSCC exhibits higher levels of miR-146a expression than matched adjacent mucosal cells. The plasma miR-146a levels of patients are significantly higher than those of control subjects; these levels decrease drastically after tumor resection. miR-146a levels in tumors and in patients' plasma can be used to classify OSCC and non-disease status (sensitivity: >0.72). Exogenous miR-146a expression is significantly increased in vitro oncogenic phenotypes as well as during xenograft tumorigenesis and OSCC metastasis. The plasma miR-146a levels of these mice parallel the xenograft tumor burdens of the mice. A miR-146a blocker abrogates the growth of xenograft tumors. miR-146a oncogenic activity is associated with down-regulation of IRAK1, TRAF6 and NUMB expression. Furthermore, miR-146a directly targets the 3'UTR of NUMB and a region within the NUMB coding sequence when suppressing NUMB expression. Exogenous NUMB expression attenuates OSCC oncogenicity. Double knockdown of IRAK1 and TRAF6, and of TRAF6 and NUMB, enhance the oncogenic phenotypes of OSCC cells. Oncogenic enhancement modulated by miR-146a expression is attenuated by exogenous IRAK1 or NUMB expression. This study shows that miR-146a expression contributes to oral carcinogenesis by targeting the IRAK1, TRAF6 and NUMB genes.

SUBMITTER: Hung PS

PROVIDER: S-EPMC3841223 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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miR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes.

Hung Pei-Shi PS Liu Chung-Ji CJ Chou Chung-Shan CS Kao Shou-Yen SY Yang Cheng-Chieh CC Chang Kuo-Wei KW Chiu Ting-Hui TH Lin Shu-Chun SC

PloS one 20131126 11

MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial to tumorigenesis. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. Up-regulation of miR-146 has been identified in OSCC tissues. However, the roles of miR-146 in carcinogenesis are controversial as it is suppressive in many other malignancies. The present study investigated the pathogenic implications of miR-146a in oral carcinogenesis. Microdissected OSCC exhibits higher levels of miR-146a ...[more]

PMID: 24302991

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Project description:BackgroundSarcopenia during aging is closely linked to sterile, low-grade, chronic inflammation. However, considering the increasingly aging global population, the effectiveness of existing treatments for sarcopenia is not exact, and acupuncture, as an effective anti-inflammatory therapy, has the potential to treat it.MethodsFifty Sprague-Dawley rats were randomly allocated into five groups, including Control group, D-galactose (D-gal) group, D-gal + acupuncture (DA) group, D-gal + non-acupoint (DN) group and D-gal amino acid mixture (DAA) group. An aging rat was model constructed using D-gal for 12 weeks. Rats in the control group received 0.9% physiological saline daily. Treatment groups were acupunctured or given amino acid mixture interventions daily, and lasted for last 4 consecutive weeks. The effects of acupuncture were evaluated by the hematoxylin and eosin staining (H&E), transmission electron microscopic (TEM) examination and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The anti-inflammatory mechanism of acupuncture was studied by using the expressions of microRNA-146a (miR-146a) mediated nuclear factor-kappa B (NF-κB) signaling pathway-related proteins were detected by immunofluorescence, western blotting, quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).ResultsRats injected by D-galactose (D-gal) revealed apparent skeletal muscle atrophy with significantly reduced cross-sectional area and fiber diameter. In contrast, acupuncture treatment alleviated these hallmarks of skeletal muscle atrophy and mitigated the mitochondrial aberrations and skeletal muscle apoptosis in D-gal rats. In addition, acupuncture also downgraded the overexpression of inflammatory factors in skeletal muscle, influenced miR-146a and the target genes level, and inhibited NF-κB nuclear translation in D-gal rats.ConclusionsAcupuncture may ameliorate skeletal muscle atrophy, and its effects may be associated with the control of mitochondrial function regulation and the suppression of inflammation.

Project description:BACKGROUND:microRNA-146a-5p (miRNA-146a-5p) is a key molecule in the negative regulation pathway of TLRs and IL-1 receptor (TIR) signaling. Our recent study demonstrated that MyD88-dependent signaling pathway of TIR in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) plays a role in peripheral nerve injury-induced neuropathic pain. However, it was not clear whether and how miRNA-146a-5p regulates the TIR pathway of DRG and SDH in the development of neuropathic pain. METHODS:The sciatic nerve chronic constriction injury (CCI) model of rat was used to induce chronic neuropathic pain. The levels and cellular distribution of miRNA-146a-5p were detected with quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). The RNA level, protein level, and cellular distribution of IRAK1 and TRAF6 that is targeted by miRNA-146a-5p were detected with qPCR, western blot, and immunofluorescent. The pain-related behavioral effect of miRNA-146a-5p was accessed after intrathecal administration. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. RESULTS:We found that the level of miRNA-146a-5p significantly increased in L4-L6 DRGs and SDH after CCI surgery; meanwhile, the protein level of IRAK1 and TRAF6 in DRGs was significantly increased after CCI. Intrathecal injection of miR146a-5p agomir or miRNA-146a-5p antagomir regulates miRNA-146a-5p level of L4-L6 DRGs and SDH. We found that intrathecal injection of miR146a-5p agomir can alleviate mechanical and thermal hyperalgesia in CCI rats and reverse the upregulation of IRAK1 and TRAF6 of L4-L6 DRGs and SDH induced by CCI. We furthermore found that intrathecal injection of miRNA-146a-5p antagomir can exacerbate the mechanical and thermal pain-related behavior of CCI rats and meanwhile increase IRAK1 and TRAF6 of L4-L6 DRGs and SDH expression even further. CONCLUSIONS:miRNA-146a-5p of DRG and SDH can modulate the development of CCI-induced neuropathic pain through inhibition of IRAK1 and TRAF6 in the TIR signaling pathway. Hence, miRNA-146a-5p may serve as a potential therapeutic target for neuropathic pain.

Dataset Information

MiR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes.

Publications

miR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes.

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