title: HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling.
abstract: Hypoxic environment is critical in colorectal cancer (CRC) development. Most studies have mainly focused on hypoxia-inducible factor (HIF)-1α and HIF-2α as the major hypoxic transcription factors in CRC development and progression. However, the role of HIF-3α in CRC is not clear. Here we found that HIF-3α protein was increased in colorectal tumors from both mouse models and human patients. Moreover, increased HIF-3α expression was correlated with decreased survival. Overexpression of a long isoform of HIF-3α, HIF-3α1, increased cell growth in two CRC cell lines. Surprisingly, overexpressed HIF-3α1 was localized to the cytosol and increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3). STAT3 inhibition effectively reduced p-STAT3 levels and cell growth induced by HIF-3α1. The activation of p-STAT3 was independent of the transcriptional activity of HIF-3α1. However, the inhibition of the upstream regulator Janus kinase (JAK) abolished HIF-3α1-induced p-STAT3 and cell growth. Together, these results demonstrated that HIF-3α1 promotes CRC cell growth by activation of the JAK-STAT3 signaling pathway through non-canonical transcription-independent mechanisms.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.|Saint Mary's College, Notre Dame, IN, USA.
authors.forename: Kylie
authors.initials: K
authors.lastname: Jungles
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Gunseli
authors.initials: G
authors.lastname: Onder
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jalal
authors.initials: J
authors.lastname: Samhoun
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, MTA-SE Pediatrics and Nephrology Research Group, Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hardiman
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D051379:Mice; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D053612:Janus Kinases; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C116973:HIF3A protein, human; C444643:Hif3a protein, mouse; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse
keywords: Janus kinase; activator of transcription 3; colorectal cancer; hypoxia-inducible factor-3α; signal transducer