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

// Xiang Xue 1 , Kylie Jungles 1, 2 , Gunseli Onder 1 , Jalal Samhoun 1 , Balázs Győrffy 3 , Karin M. Hardiman 4 1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA 2 Saint Mary's College, Notre Dame, IN, USA 3 MTA TTK Lendület Cancer Biomarker Research Group, MTA-SE Pediatrics and Nephrology Research Group, Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary 4 Department of Surgery, University of Michigan, Ann Arbor, MI, USA Correspondence to: Xiang Xue, e-mail: xxue@umich.edu Keywords: hypoxia-inducible factor-3α, colorectal cancer, Janus kinase, signal transducer, activator of transcription 3 Received: August 15, 2015 Accepted: January 17, 2016 Published: February 09, 2016 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.