miR-31 ablates expression of the HIF regulatory factor FIH to activate the HIF pathway in head and neck carcinoma.
MicroRNAs (miRNA) are endogenously expressed noncoding RNAs with important biological and pathological functions that are yet to be fully defined. This study investigated alterations in miRNA expression in head and neck squamous cell carcinoma (HNSCC), the incidence of which is rising throughout the world. Initial screening and subsequent analysis identified a panel of aberrantly expressed miRNAs in HNSCC tissues, with miR-31 among the most markedly upregulated. Ectopic expression of miR-31 increased the oncogenic potential of HNSCC cells under normoxic conditions in cell culture or tumor xenografts. Conversely, blocking miR-31 expression reduced the growth of tumor xenografts. The in silico analysis suggested that miR-31 may target the 3' untranslated region (UTR) of factor-inhibiting hypoxia-inducible factor (FIH), a hypoxia-inducible factor (HIF) regulatory factor that inhibits the ability of HIF to act as a transcriptional regulator under normoxic conditions. In support of this likelihood, miR-31 expression repressed FIH expression and mutations within the predictive miR-31 target site in the FIH 3' UTR abrogated FIH repression. Furthermore, miR-31 expression increased HIF transactivation activity. We found that FIH suppressed oncogenic phenotypes under normoxic conditions and that this activity was abrogated by functional mutations. Lastly, increased miR-31 expression was correlated with decreased levels of FIH in tumor tissues. Our findings suggest that miR-31 contributes to the development of HNSCC by impeding FIH to activate HIF under normoxic conditions.
Institute of Oral Biology and Institute of Biochemistry, National Yang-Ming University, Taipei 112, Taiwan.
Chung-Ji
CJ
Liu
Meng-Miao
MM
Tsai
Pei-Shih
PS
Hung
Shou-Yen
SY
Kao
Tsung-Yun
TY
Liu
Kou-Juey
KJ
Wu
Shih-Hwa
SH
Chiou
Shu-Chun
SC
Lin
Kuo-Wei
KW
Chang
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D019073:HT29 Cells; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D006899:Mixed Function Oxygenases; D009361:Neoplasm Invasiveness; D010100:Oxygen / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D051793:Hypoxia-Inducible Factor 1; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D010100:Oxygen