HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells

Department of Biochemistry, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
Cancer Research (Impact Factor: 9.33). 06/2011; 71(13):4640-52. DOI: 10.1158/0008-5472.CAN-10-3320
Source: PubMed


Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions.

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    • "Hypoxia-regulated genes are mediated by the HIF-1 complex composed of a heterodimeric pair of HIF-1α and -1β (28,29), and HIF-1α is an important transcription factor in prostate carcinogenesis, which suggests that HIF-1α may be a potential prognostic biomarker in the proteomic assessments of prostate cancers (55,56). Additionally, HIF-1α induces human ES cell markers, such as NANOG (14,30,31), OCT4 (14,30,31) and CD133 (32), in cancer cells. The findings of the current study showing the coexpression of NANOG, OCT4 and HIF-1α support these studies. "
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    ABSTRACT: Cancer stem cells (CSCs) have been identified in a variety of cancer types, including prostate cancer. The aim of the present study was to evaluate the immunohistochemical expression of NANOG, octamer 4 (OCT4), cluster of differentiation 133 (CD133) and NESTIN, which are all CSC markers, and assess their function in prostate carcinogenesis. A total of 114 patients were referred to the Kanazawa Medical University Hospital (Uchinada, Japan) having presented with elevated serum prostate-specific antigen levels and/or abnormal digital rectal examinations, and underwent transrectal ultrasound sonography guided eight core biopsies. The prostate pathological specimens were re-evaluated for selection in this study. When specimens were diagnosed as prostate cancer, immunohistochemical analysis of the four different stem cell markers (NANOG, OCT4, CD133 and NESTIN) and hypoxia-inducible factor (HIF)-1α was performed. Prostate cancer was found in 38 cases (33.3%), while the other patients had benign prostate hyperplasia with prostatitis. All prostate cancers were histopathologically identified as adenocarcinomas of various grades, and cancer cells and intraepithelial neoplasia (high grade) were immunohistochemically shown to express NANOG and OCT4, but not CD133 and NESTIN. The intensity of NANOG expression was much greater than that of OCT4, and the positivity and intensity of the four stem cell markers, including NANOG, were elevated with high Gleason scores. A significant correlation was observed between the NANOG- and HIF-1α-positive regions. The CSC markers, in particular OCT4 and NANOG, were immunohistochemically expressed in prostate cancers. Furthermore, HIF-1α expression may affect NANOG and/or OCT4 expression. The findings of the current study suggested that NANOG expression may be a biomarker for the diagnosis of prostate cancer, and the coexpression of NANOG and HIF-1α may be involved in prostate carcinogenesis.
    Full-text · Article · Sep 2014 · Oncology letters
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    • "In addition to the identification of CSCs, we need to investigate how CSCs and differentiated bulk tumor cells dynamically respond to microenvironmental changes [44]. For example, hypoxia (HIF1α) [45, 46], epithelial-mesenchymal transition [47], inflammatory cytokines (e.g., IL-6 and TGFβ) [48, 49], and embryonic microenvironments [50] can all promote the reprogramming of CCs and increase the overall stemness of the tumor. It is worth restating that understanding what controls the maintenance of the stem-like and differentiation states may give insights into the cellular signals involved in cancer and may ultimately lead to the development of more efficient anticancer therapies. "
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    ABSTRACT: Enrichment of cancer stem cells (CSCs) is thought to be responsible for glioblastoma multiforme (GBM) recurrence after radiation therapy. Simulation results from our agent-based cellular automata model reveal that the enrichment of CSCs may result either from an increased symmetric self-renewal division rate of CSCs or a reprogramming of non-stem cancer cells (CCs) to a stem cell state. Based on plateau-to-peak ratio of the CSC fraction in the tumor following radiation, a downward trend from peak to subsequent plateau (i.e., a plateau-to-peak ratio exceeding 1.0) was found to be inconsistent with increased symmetric division alone and favors instead a strong reprogramming component. The two contributions together are seen to be the product of a dynamic equilibrium between CSCs and CCs that is highly regulated by the kinetics of single cells, including the potential for CCs to reacquire a stem cell state and confer phenotypic plasticity to the population as a whole. We conclude that tumor malignancy can be gauged by a degree of cancer cell plasticity.
    Full-text · Article · May 2014 · Stem cell International
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    • "Lastly, the functional importance of HIF-1 to the letrozole-resistant cell phenotype was explored. In cancer cells, hypoxia and HIF-1 are known to be involved in increased cell survival, chemoresistance [56,57], resistance to apoptosis [58] and maintenance of cancer stem cell characteristics [59,60]. Previous findings from our laboratory [52] have already demonstrated that letrozole resistance and cancer stem cell characteristics of LTLTCa cells are reduced by inhibition of HER2 and/or BCRP. "
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    ABSTRACT: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERalpha, HER2, and HIF-1alpha (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERalpha to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1alpha to determine its importance. Basal HIF-1alpha protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1alpha expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1alpha affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.
    Full-text · Article · Jan 2014 · Breast cancer research: BCR
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