title: HIF-2α mediates a marked increase in migration and stemness characteristics in a subset of glioma cells under hypoxia by activating an Oct-4/Sox-2-Mena (INV) axis.
abstract: Hypoxia is a salient feature of most solid tumors and plays a central role in tumor progression owing to its multiple contributions to therapeutic resistance, metastasis, angiogenesis and stemness properties. Reports exist in literature about hypoxia increasing stemness characteristics and invasiveness potential of malignant cells. In order to delineate molecular crosstalk among factors driving glioma progression, we used knockdown and overexpression strategies. We have demonstrated that U87MG and A172 glioma cells inherently have a subset of cells with high migratory potential due to migration-inducing Mena transcripts. These cells also have elevated stemness markers (Sox-2 and Oct-4). There was a significant increase of number in this subset of migratory cells on exposure to hypoxia with corresponding elevation (over 1000 fold) in migration-inducing Mena transcripts. We were able to demonstrate that a HIF-2α-Sox-2/Oct-4-Mena (INV) axis that is strongly activated in hypoxia and markedly increases the migratory potential of the cells. Such cells also formed tumor spheres with greater efficiency. We have correlated our in-vitro results with human glioblastoma samples and found that hypoxia, invasiveness and stemness markers correlated well in native tumor samples. This study identifies a novel signaling mechanism mediated by HIF-2α in regulating invasiveness and stemness characteristics, suggesting that under hypoxic conditions, some tumor cells acquire more migratory potential by increased Pan Mena and Mena INV expression as a consequence of this HIF-2α mediated increase in Oct-4 and Sox-2. These properties would help the cells to form a new nidus after local invasion or metastasis.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: mohita444@gmail.com.
authors.forename: Mohita
authors.initials: M
authors.lastname: Bhagat
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: jayanth.aiims@gmail.com.
authors.forename: Jayanth Kumar
authors.initials: JK
authors.lastname: Palanichamy
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Ave, New York, NY 10065, USA. Electronic address: pradeep_vpr@yahoo.co.in.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Ramalingam
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: madeehamudassir@gmail.com.
authors.forename: Madeeha
authors.initials: M
authors.lastname: Mudassir
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: khushbooirshad@gmail.com.
authors.forename: Khushboo
authors.initials: K
authors.lastname: Irshad
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: kunzangchosdol@yahoo.com.
authors.forename: Kunzang
authors.initials: K
authors.lastname: Chosdol
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: sarkar.chitra@gmail.com.
authors.forename: Chitra
authors.initials: C
authors.lastname: Sarkar
authors.affiliation: National Brain Research Centre (NBRC), NH-8, Nainwal Road, Manesar, Haryana 122051, India. Electronic address: pseth@nbrc.ac.in.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York 10461, USA. Electronic address: sumanta.goswami@einstein.yu.edu.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Goswami
authors.affiliation: National Brain Research Centre (NBRC), NH-8, Nainwal Road, Manesar, Haryana 122051, India. Electronic address: subrata.sinha@nbrc.ac.in.
authors.forename: Subrata
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: parthoaiims@hotmail.com.
authors.forename: Parthaprasad
authors.initials: P
authors.lastname: Chattopadhyay
mesh_terms: D000328:Adult; D000368:Aged; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000503:physiopathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors
keywords: Glioma; HIF-2α; Hypoxia; Mena; Metastasis; Stemness