c-Myc-mediated repression of miR-15-16 in hypoxia is induced by increased HIF-2α and promotes tumor angiogenesis and metastasis by upregulating FGF2.
Previous studies have established the link between aberrant microRNA (miRNA) expression and hypoxia in various neoplasms. However, how these hypoxia-related miRNAs modulate tumor progression is still unclear. Therefore, the patterns of miRNA in colorectal carcinoma cell lines in response to hypoxia or not were first screened and the hypoxia-induced repression of the miR-15-16 cluster was confirmed. Then, this repression was found to be associated with high tumor stage and poor prognosis in colorectal carcinoma and is shown to promote tumor angiogenesis and metastasis by the loss of restriction of its target gene, fibroblast growth factor-2 (FGF2). Moreover, the general and alterative promoters of the miR-15-16 host (deleted in lymphocytic leukemia 2, DLEU2) were mapped, and three c-Myc/Max binding sites in response to the hypoxia-induced repression of miR-15-16 were further identified. Finally, an enhanced stability of c-Myc/Max heterodimer promoted by increased hypoxia-inducible factor-2α (HIF-2α) was validated, and we also verified that the enhancement contributed to the hypoxia-induced repression of miR-15-16. In brief, the c-Myc-mediated transcriptional repression of miR-15-16 in hypoxia is induced by increased HIF-2α and promoted tumor angiogenesis and hematogenous metastasis by the further loss of post-transcriptional inhibition of FGF2. Our study provides a better understanding of the coping mechanisms in response to tumor hypoxia and may be helpful in developing an effective prognostic marker or treatment target against solid tumors.
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
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G
Xue
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
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HL
Yan
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
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Y
Zhang
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
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LQ
Hao
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
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XT
Zhu
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
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Q
Mei
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
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SH
Sun
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic / Q000235:genetics; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D016222:Fibroblast Growth Factor 2; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; C489427:MYC protein, human