title: HIF-inducible miR-191 promotes migration in breast cancer through complex regulation of TGFβ-signaling in hypoxic microenvironment.
abstract: The molecular mechanisms of hypoxia induced breast cell migration remain incompletely understood. Our results show that hypoxia through hypoxia-inducible factor (HIF) brings about a time-dependent increase in the level of an oncogenic microRNA, miR-191 in various breast cancer cell lines. miR-191 enhances breast cancer aggressiveness by promoting cell proliferation, migration and survival under hypoxia. We further established that miR-191 is a critical regulator of transforming growth factor beta (TGFβ)-signaling and promotes cell migration by inducing TGFβ2 expression under hypoxia through direct binding and indirectly by regulating levels of a RNA binding protein, human antigen R (HuR). The levels of several TGFβ pathway genes (like VEGFA, SMAD3, CTGF and BMP4) were found to be higher in miR-191 overexpressing cells. Lastly, anti-miR-191 treatment given to breast tumor spheroids led to drastic reduction in spheroid tumor volume. This stands as a first report of identification of a microRNA mediator that links hypoxia and the TGFβ signaling pathways, both of which are involved in regulation of breast cancer metastasis. Together, our results show a critical role of miR-191 in hypoxia-induced cancer progression and suggest that miR-191 inhibition may offer a novel therapy for hypoxic breast tumors.
authors: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, India-110016.
authors: Neha
authors: N
authors: Nagpal
authors: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India- 110067.
authors: Hafiz M
authors: HM
authors: Ahmad
authors: Department of Textile Technology, Indian Institute of Technology Delhi, India-110016.
authors: Shibu
authors: S
authors: Chameettachal
authors: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, India-110016.
authors: Durai
authors: D
authors: Sundar
authors: Department of Textile Technology, Indian Institute of Technology Delhi, India-110016.
authors: Sourabh
authors: S
authors: Ghosh
authors: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, India-110016.
authors: Ritu
authors: R
authors: Kulshreshtha
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D000067780:ELAV-Like Protein 1 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D000067780:ELAV-Like Protein 1; D051793:Hypoxia-Inducible Factor 1; C546177:MIRN191 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2