The role of hypoxia-inducible factor-2 in digestive system cancers

Zhao, Jun; Du, Feiya; Shen, Guoshuang; Zheng, Fangchao; Xu, Binghe

doi:10.1038/cddis.2014.565

Cited by 103 publications

(73 citation statements)

References 106 publications

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“…This distinct activation profile fits with a model based on our findings whereby gradual deterioration of lung function over a long period of CS exposure results in chronic and mild systemic and tissue hypoxia, resulting in selective activation of HIF-2α. HIF-1α and HIF-2α also appear to regulate overlapping and distinct gene networks, and our observation that VEGF (but not other known HIF-1α targets such as CD73 and gravin) is induced in the colons of CS-exposed mice fits with prior observations that HIF-2α is the dominant isoform in the regulation of VEGF (54). Selective activation of HIF-2α observed in the colons of CS-exposed mice also provides a potential mechanistic explanation for the link between smoking and colorectal cancer (55), as HIF-2α may have roles in promoting tumorigenesis (54).…”

Section: Discussionsupporting

confidence: 76%

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Fricker¹,

Goggins²,

Mateer³

et al. 2018

JCI Insight

106

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Section: Discussionsupporting

confidence: 76%

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Fricker¹,

Goggins²,

Mateer³

et al. 2018

JCI Insight

106

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“…Human HIFα, also known as endothelial PAS domain protein 1 (EPAS1), consists of 870 aa residues [44][45][46][47][48] and exhibits great similarity to HIF-1α with respect to its protein structure, O 2 lability, and potential for dimerization with HIF-1β [49]. The C-terminal NLS, constituted by homologous amino acids to HIF-1α, is also present in HIF-2α [19].…”

Section: Hif-mediated Adaptive Responses To Hypoxiamentioning

confidence: 99%

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

2015

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In order to pass through the nuclear pore complex, proteins larger than ∼40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ∼100-120 kDa proteins, consisting of one out of three different O2-labile α subunits (primarily HIF-1α) and a more constitutive 1β subunit. In the presence of O2, the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1α and HIF-1β is mainly mediated by importins α and β (α/β). HIF-1α can shuttle between nucleus and cytoplasm, while HIF-1β is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin α/β receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1α occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin α/β receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases.

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“…Our study showed LINC01436 acts as a ceRNA to regulate EPAS1 by sponging miR-30a-3p in lung cancer. EPAS1, also named HIF-2a, was associated with therapy resistance, metastasis and poor clinical prognosis in various cancers, including lung cancer Zhao et al, 2015). High EPAS1 protein levels were detected in~50% of cases and were strongly correlated with poor OS in NSCLC (Giatromanolaki et al, 2001;Wu et al, 2011), suggesting that EPAS1 may directly contribute to NSCLC progression.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐sensitive LINC01436 is regulated by E2F6 and acts as an oncogene by targeting miR‐30a‐3p in non‐small cell lung cancer

et al. 2019

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Dysregulation of long noncoding RNA (lncRNA) is known to be involved in numerous human diseases, including lung cancer. However, the precise biological functions of most lnc RNA remain to be elucidated. Here, we identified a novel up‐regulated lnc RNA , LINC 01436 (RefSeq: NR _110419.1), in non‐small cell lung cancer ( NSCLC ). High expression of LINC 01436 was significantly associated with poor overall survival. Notably, LINC 01436 expression was transcriptionally repressed by E2F6 under normoxia, and the inhibitory effect was relieved in a hypoxic microenvironment. Gain‐ and loss‐of‐function studies revealed that LINC 01436 acted as a proto‐oncogene by promoting lung cancer cell growth, migration and invasion in vitro . Xenograft tumor assays in nude mice confirmed that LINC 01436 promoted tumor growth and metastasis in vivo . Mechanistically, LINC 01436 exerted biological functions by acting as a microRNA (miR)‐30a‐3p sponge to regulate the expression of its target gene EPAS 1 . Our findings characterize LINC 01436 as a new hypoxia‐sensitive lnc RNA with oncogenic function in NSCLC , suggesting that LINC 01436 may be a potential biomarker for prognosis and a potential target for treatment.

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The role of hypoxia-inducible factor-2 in digestive system cancers

Cited by 103 publications

References 106 publications

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

Hypoxia‐sensitive LINC01436 is regulated by E2F6 and acts as an oncogene by targeting miR‐30a‐3p in non‐small cell lung cancer

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