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.

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

“…HIF-3a also contains long isoforms, such as HIF-3a1 and HIF-3a9, which can upregulate a distinct set of HIF-a target genes (18). HIF-3a1 is reported to promote colorectal cancer cell growth through noncanonical, transcription-independent activation of the JAK-STAT3 signaling pathway (27). Ectopic overexpression of a HIF-3a gene lacking the 3 0 untranslated region might disturb the regulatory circuit by altering HIF-1a transcriptional activity (28).…”

KIF20A Predicts Poor Survival of Patients and Promotes Colorectal Cancer Tumor Progression through the JAK/STAT3 Signaling Pathway

“…JAK/STAT3 signaling is a well-identified oncogenic pathway that plays a pivotal role in various cellular biological activities important for carcinogenesis, including cell survival, cell cycle, and angiogenesis in multiple cancers [39], and the activation of the JAK/STAT3 pathway in CRC has been largely indicated [32,40,41]. Activating the JAK/-STAT3 signaling pathway promotes the development of colon carcinoma cells [42]. Moreover, a previous report has illustrated that STAT3 targets MMP2 in cell migration and invasion of esophageal squamous carcinoma cells [43].…”

The miRNA-29b Is Downregulated in Placenta During Gestational Diabetes Mellitus and May Alter Placenta Development by Regulating Trophoblast Migration and Invasion Through a HIF3A-Dependent Mechanism

“…These data further confirm that HIF3A was the functional target of miR-29b. HIF3A promotes colorectal cancer cell growth through non-canonical transcription-independent mechanisms (18). Over-expression of miR-300 inhibited proliferation, invasion and migration of nonsmall cell lung cancer cells in vitro, and tumor growth in vivo by downregulating HIF3A expression (19).…”