Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

Yang, Guang; Shi, Rachel; Zhang, Qing

doi:10.3390/ijms21218162

Cited by 61 publications

(51 citation statements)

References 191 publications

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“…Transient hypoxia has also been found to cause an increase in dihydrofolate reductase and P-glycoprotein, which contributes to the resistance of drugs targeting topoisomerase II ( Kovacic and Osuna, 2000 ; Gray et al, 2005 ). Interestingly, oxygen concentration may affect the efficacy of the anti-cancer drugs doxorubicin and mitomycin C, by delivering electrons to the oxygen ( Brown and Wilson, 2004 ; Trédan et al, 2007 ; Yang G. et al, 2020 ).…”

Section: Tme-driven Adaptive Mechanisms Of Therapy Resistancementioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

114

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Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.

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Section: Tme-driven Adaptive Mechanisms Of Therapy Resistancementioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

114

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“…UCA1 has been shown to be overexpressed in several breast cancer cells, including MCF-7 [ 48 , 54 , 55 ], LM2-4 [ 56 ], and MDA-MB-231 [ 57 , 58 ]. UCA1 was also reported to be upregulated in breast cancer compared to matched normal tissues [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

UCA1 Overexpression Promotes Hypoxic Breast Cancer Cell Proliferation and Inhibits Apoptosis via HIF-1α Activation

Choudhry

2021

Journal of Oncology

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The noncoding RNA termed urothelial carcinoma-associated 1 (UCA1) is an oncogenic lncRNA involved in promoting the growth of several tumors through various pathways. The aim of this study was to explore the expression of UCA1 in hypoxic breast cancer and its impact on tumorigenesis in low levels of oxygen. Here, we show that UCA1 is upregulated in a number of hypoxic (1% O2) breast cancer cells. In addition, UCA1 expression is significantly overexpressed in breast cancer tissues compared to matched normal cells. UCA1 knockdown in hypoxia inhibits breast cancer proliferation and induces apoptosis. The knockdown of hypoxia-inducible transcription factor 1α (HIF-1α) but not HIF-2α significantly decreases the expression of UCA1 in hypoxia. Overall, these findings indicate that UCA1 is a hallmark of hypoxic breast cancer and its expression is positively regulated by HIF-1α.

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“…Heterozygous germline EP300 mutations were first described in Rubinstein–Taybi syndrome (RBTS), a congenital neurodevelopmental disorder associated with renal development abnormalities and an increased risk of chronic kidney diseases [ 96 ]. The histone acetyltransferase encoded by EP300 is known to initiate hypoxic responses by coupling with the HIF alpha subunit [ 97 ], thus enabling the induction of a range of hypoxia-responsive genes critical for tumor angiogenesis, invasion, and immune escape [ 98 , 99 ]. Detailed investigations of the role of the hypoxic tumor microenvironment in melanoma are warranted.…”

Section: Discussionmentioning

confidence: 99%

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

Hubert

Suybeng

Vallée

et al. 2021

Cancers

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Background: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. Results: We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in MITF (p.E318K locus, N = 9 cases), BAP1 (N = 3), CDKN2A (N = 2), FLCN (N = 2), and PTEN (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including PIK3CD, NFRKB, EP300, MTOR, and related epigenetic modifier SETD2. The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Conclusions: Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management.

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Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

Cited by 61 publications

References 191 publications

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

UCA1 Overexpression Promotes Hypoxic Breast Cancer Cell Proliferation and Inhibits Apoptosis via HIF-1α Activation

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

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