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

Hypoxic environment is critical in colorectal cancer (CRC) development. Most studies have mainly focused on hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha as the major hypoxic transcription factors in CRC development and progression. However, the role of HIF-3 alpha in CRC is not clear. Here we found that HIF-3 alpha protein was increased in colorectal tumors from both mouse models and human patients. Moreover, increased HIF-3 alpha expression was correlated with decreased survival. Overexpression of a long isoform of HIF-3 alpha, HIF-3 alpha 1, increased cell growth in two CRC cell lines. Surprisingly, overexpressed HIF-3 alpha 1 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-3 alpha 1. The activation of p-STAT3 was independent of the transcriptional activity of HIF-3 alpha 1. However, the inhibition of the upstream regulator Janus kinase (JAK) abolished HIF-3 alpha 1-induced p-STAT3 and cell growth. Together, these results demonstrated that HIF-3 alpha 1 promotes CRC cell growth by activation of the JAK-STAT3 signaling pathway through non-canonical transcription-independent mechanisms.