The Hypoxic Tumor Microenvironment: Driving the Tumorigenesis of Non-Small-Cell Lung Cancer

Foster, John G.; Wong, Sybil C K; Sharp, Tyson V.

doi:10.2217/fon.14.201

Cited by 42 publications

(43 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given this evidence, we argue that hypoxic microenvironment promotes tumor growth in specific lung sites, a conclusion supported by the data that a high-rate intermittent hypoxia mimicking the one experienced by OSAS patients induces melanoma lung metastasis [1]. Other evidence also suggests that hypoxic tumor microenvironment contribute to the tumorigenesis of non-small-cell lung cancer [28]. It should be noted that, no animal or cell models have encompassed the major components of OSAS such as intermittent hypoxia and fragment sleep, and swinging shifts in intrathoracic pressure and episodic hypercapnia [26].…”

Section: Discussionmentioning

confidence: 59%

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Lü

Xue

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Based on our hospital database, the incidence of lung cancer diagnoses was similar in obstructive sleep apnea Syndrome (OSAS) and hospital general population; among individual with a diagnosis of lung cancer, the presence of OSAS was associated with an increased risk for mortality. In the gene expression and network-level information, we revealed significant alterations of molecules related to HIF1 and metabolic pathways in the hypoxic-conditioned lung cancer cells. We also observed that GBE1 and HK2 are downstream of HIF1 pathway important in hypoxia-conditioned lung cancer cell. Furthermore, we used publicly available datasets to validate that the late-stage lung adenocarcinoma patients showed higher expression HK2 and GBE1 than early-stage ones. In terms of prognostic features, a survival analysis revealed that the high GBE1 and HK2 expression group exhibited poorer survival in lung adenocarcinoma patients. By analyzing and integrating multiple datasets, we identify molecular convergence between hypoxia and lung cancer that reflects their clinical profiles and reveals molecular pathways involved in hypoxic-induced lung cancer progression. In conclusion, we show that OSAS severity appears to increase the risk of lung cancer mortality.

show abstract

Section: Discussionmentioning

confidence: 59%

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Lü

Xue

et al. 2017

Oncotarget

View full text Add to dashboard Cite

show abstract

“…12 PHDs require oxygen for catalytic activity; thus, prolyl hydroxylation of HIF-1α is reduced in low oxygen tension, allowing HIF-1α to escape pVHL-mediated degradation and then accumulate in the nucleus. 12,13 Elevated levels of HIF-1α drive the expression of common target genes, characterized by a consensus hypoxia-responsive element, which is involved in cell growth, proliferation, migration and cancer vascularization. 7,14 Increase of HIF-1α and hypoxia-related proteins are associated with poor outcome in lung cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1

et al. 2017

View full text Add to dashboard Cite

Hypoxia plays a critical role during the evolution of malignant cells and tumour microenvironment (TME).Tumour-derived exosomes contain informative microRNAs involved in the interaction of cancer and stromal cells, thus contributing to tissue remodelling of tumour microenvironment. This study aims to clarify how hypoxia affects tumour angiogenesis through exosomes shed from lung cancer cells. Lung cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. miR-23a was significantly upregulated in exosomes from lung cancer under hypoxic conditions. Exosomal miR-23a directly suppressed its target prolyl hydroxylase 1 and 2 (PHD1 and 2), leading to the accumulation of hypoxia-inducible factor-1 α (HIF-1 α) in endothelial cells. Consequently, hypoxic lung cancer cells enhanced angiogenesis by exosomes derived from hypoxic cancer under both normoxic and hypoxic conditions. In addition, exosomal miR-23a also inhibits tight junction protein ZO-1, thereby increasing vascular permeability and cancer transendothelial migration. Inhibition of miR-23a by inhibitor administration decreased angiogenesis and tumour growth in a mouse model. Furthermore, elevated levels of circulating miR-23a are found in the sera of lung cancer patients, and miR-23a levels are positively correlated with proangiogenic activities. Taken together, our study reveals the clinical relevance and prognostic value of cancer-derived exosomal miR-23a under hypoxic conditions, and investigates a unique intercellular communication, mediated by cancer-derived exosomes, which modulates tumour vasculature.

show abstract

“…The physiological response to hypoxia is initiated by the stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription factor targeting genes containing a hypoxia response element (HRE) (Wenger et al 2005;Lokmic et al 2012;Hong et al 2014;Semenza 2014b). HIF-1α is also important for promoting cancer cell survival through interactions with Myc and Jun, and it is well documented that hypoxia drives tumor angiogenesis (Harris 2002;Laderoute et al 2002;Nelson et al 2004;Dang et al 2008;Rankin and Giaccia 2008;Li et al 2009;Foster et al 2014). HIF-1α directly stimulates the transcription of vascular endothelial growth factor (VEGF).…”

Section: Introductionmentioning

confidence: 99%

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs

Fry

Law

Ilkayeva

et al. 2017

RNA

View full text Add to dashboard Cite

Post-transcriptional regulation of mRNA during oxygen deprivation, or hypoxia, can affect the survivability of cells. Hypoxia has been shown to increase stability of a subset of ischemia-related mRNAs, including VEGF. RNA binding proteins and miRNAs have been identified as important for post-transcriptional regulation of individual mRNAs, but corresponding mechanisms that regulate global stability are not well understood. Recently, mRNA modification by N 6 -methyladenosine (m 6 A) has been shown to be involved in post-transcriptional regulation processes including mRNA stability and promotion of translation, but the role of m 6 A in the hypoxia response is unknown. In this study, we investigate the effect of hypoxia on RNA modifications including m 6 A. Our results show hypoxia increases m 6 A content of poly(A) + messenger RNA (mRNA), but not in total or ribosomal RNA in HEK293T cells. Using m 6 A mRNA immunoprecipitation, we identify specific hypoxia-modified mRNAs, including glucose transporter 1 (Glut1) and c-Myc, which show increased m 6 A levels under hypoxic conditions. Many of these mRNAs also exhibit increased stability, which was blocked by knockdown of m 6 A-specific methyltransferases METTL3/14. However, the increase in mRNA stability did not correlate with a change in translational efficiency or the steady-state amount of their proteins. Knockdown of METTL3/14 did reveal that m 6 A is involved in recovery of translational efficiency after hypoxic stress. Therefore, our results suggest that an increase in m 6 A mRNA during hypoxic exposure leads to post-transcriptional stabilization of specific mRNAs and contributes to the recovery of translational efficiency after hypoxic stress.

show abstract

The Hypoxic Tumor Microenvironment: Driving the Tumorigenesis of Non-Small-Cell Lung Cancer

Cited by 42 publications

References 114 publications

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs

Contact Info

Product

Resources

About

The Hypoxic Tumor Microenvironment: Driving the Tumorigenesis of Non-Small-Cell Lung Cancer

Cited by 42 publications

References 114 publications

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1

N6-methyladenosine is required for the hypoxic stabilization of specific mRNAs

Contact Info

Product

Resources

About

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs