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

SUBMITTER: Xue X

PROVIDER: S-EPMC4905494 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Xue Xiang X Jungles Kylie K Onder Gunseli G Samhoun Jalal J Győrffy Balázs B Hardiman Karin M KM

Oncotarget 20160301 10

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 isof ...[more]

PMID: 26871465

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Project description:Introduction:The broccoli isothiocyanate sulforaphane was shown to inhibit inflammation and tumor progression, also in pancreatic cancer, while its effect on tumor immunity is poorly understood. We investigated the immunoregulatory effect of sulforaphane on human dendritic cells alone and in presence of pancreatic tumor antigens, as well as underlying molecular mechanisms. Methods:Sulforaphane-treated human dendritic cells were matured in vitro with a cytokine cocktail, and the expression of regulatory molecules was examined by flow cytometry. The subsequent T-cell response was analyzed by T-cell proliferation assay and CD25 expression. To confirm the findings, dendritic cells pulsed with pancreatic cancer-derived tumor antigens were used. To identify the involved pathway- and microRNA-signaling in sulforaphane-treated dendritic cells, inhibitors of various signaling pathways, western blot analysis, microRNA array, and bioinformatic analysis were applied. Results:Sulforaphane modulated the expression of the costimulatory CD80, CD83 and the suppressive B7-H1 molecules on dendritic cells and thereby promoted activation of T cells. The effect was verified in presence of pancreatic tumor antigens. Phosphorylation of STAT3 in dendritic cells was diminished by sulforaphane, and the inhibition of JAK/STAT3 led to downregulation of B7-H1 expression. Among the identified top 100 significant microRNA candidates, the inhibition of miR-155-5p, important for the expression of costimulatory molecules, and the induction of miR-194-5p, targeting the B7-H1 gene, were induced by sulforaphane. Conclusion:Our findings demonstrate that sulforaphane promotes T-cell activation by dendritic cells through the modulation of regulatory molecules, JAK/STAT3- and microRNA-signaling in healthy conditions and in context of pancreatic cancer-derived antigens. They explore the immunoregulatory properties of sulforaphane and justify further research on nutritional strategies in the co-treatment of cancer.

Dataset Information

HIF-3?1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling.

Publications

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

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