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.
Highlights
Hypoxia-inducible factors (HIFs) are transcription factors that mediate hypoxia signaling, which is crucial in many cellular process including cancer development and progression
We have reported that intestine-specific disruption of Vhl (Vhl∆IE) activates HIF signaling, and when these mice are crossed to the Apcmin/+ intestinal tumor model (Vhl∆IE/Apcmin/+), colorectal tumorigenesis is robustly increased compared with littermate control mice (VhlF/F/Apcmin/+) [14]
Tumors isolated from VhlF/F/Apcmin/+ mice demonstrate an increase in HIF-3α expression compared to their adjacent normal tissue
Summary
Hypoxia-inducible factors (HIFs) are transcription factors that mediate hypoxia signaling, which is crucial in many cellular process including cancer development and progression. HIF is a heterodimer consisting of a hypoxia-inducible alpha subunit (HIF-α) and a constitutively expressed beta subunit (HIF-1β, or aryl hydrocarbon receptor nuclear translocator [Arnt]) [1]. HIF-α is hydroxylated by the oxygen-sensitive prolyl hydroxylase domain protein (PHD) and recognized by the von Hippel-Lindau tumor suppressor protein (VHL) coupled to the E3 ubiquitin ligase complex to initiate its degradation [2, 3]. In a hypoxic environment, the binding of VHL to HIF-α is decreased, which results in an accumulation of HIF-α and activation of its target gene expression [4]. While numerous studies have shown that HIF-1α and HIF-2α are activated in both physiologic and pathologic conditions [5], very little is known about HIF-3α
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