HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling

Xiang Xue, Kylie Jungles, Gunseli Onder, Jalal Samhoun, B. Györffy, Karin M. Hardiman

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11567-11579
Number of pages13
JournalOncotarget
Volume7
Issue number10
DOIs
Publication statusPublished - 2016

Fingerprint

Janus Kinases
Colorectal Neoplasms
Growth
STAT3 Transcription Factor
Hypoxia
Hypoxia-Inducible Factor 1
Cytosol
Protein Isoforms
Transcription Factors

Keywords

  • Activator of transcription 3
  • Colorectal cancer
  • Hypoxia-inducible factor-3α
  • Janus kinase
  • Signal transducer

ASJC Scopus subject areas

  • Oncology

Cite this

HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling. / Xue, Xiang; Jungles, Kylie; Onder, Gunseli; Samhoun, Jalal; Györffy, B.; Hardiman, Karin M.

In: Oncotarget, Vol. 7, No. 10, 2016, p. 11567-11579.

Research output: Contribution to journalArticle

Xue, X, Jungles, K, Onder, G, Samhoun, J, Györffy, B & Hardiman, KM 2016, 'HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling', Oncotarget, vol. 7, no. 10, pp. 11567-11579. https://doi.org/10.18632/oncotarget.7272
Xue, Xiang ; Jungles, Kylie ; Onder, Gunseli ; Samhoun, Jalal ; Györffy, B. ; Hardiman, Karin M. / HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling. In: Oncotarget. 2016 ; Vol. 7, No. 10. pp. 11567-11579.
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