VHL and Hypoxia Signaling: Beyond HIF in Cancer

Zhang, Jing; Zhang, Qing

doi:10.3390/biomedicines6010035

Cited by 96 publications

(70 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In consequence, the stabilized HIFs activate transcription of several target genes (e.g., VEGF, PDGF) that support cell's adaptation to hypoxia. Mutations that inactivate VHL, lead to persistent HIF upregulation and activation of hypoxia-induced genes, regardless of the oxygen status [153].…”

Section: Relevance Of Ciliary Genes In Renal Cancermentioning

confidence: 99%

Ciliary Genes in Renal Cystic Diseases

Adamiok‐Ostrowska

Piekiełko-Witkowska

2020

Cells

View full text Add to dashboard Cite

Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.

show abstract

Section: Relevance Of Ciliary Genes In Renal Cancermentioning

confidence: 99%

Ciliary Genes in Renal Cystic Diseases

Adamiok‐Ostrowska

Piekiełko-Witkowska

2020

Cells

View full text Add to dashboard Cite

show abstract

“…In sum, our data put forward a relevant role for the GRK2/HuR/HIF1α module in cancer cells and in response to the adrenergic overdrive, regardless of the oxygen status. Enhanced GRK2 expression and S670 phosphorylation status in the given tumor contexts would lead to enhanced HuR functionality, thus, counteracting the canonical HIF protein degradation driven by prolyl hydroxylases [7,9] and recapitulating a pseudo-hypoxic state in normoxia, as a consequence. Besides inducing the angiogenic remodeling of tumoral stroma, GRK2-induced pseudo-hypoxia might favor cancer cell de-differentiation and emergence of cancer stem-like cells.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in cancerous cells, the HIF signaling pathway can also be regulated by other environmental and intracellular signaling factors in an oxygen-independent manner, via modulation of protein stability, gene transcription, or mRNA binding proteins such as YB-1 and HuR (Human antigen R), which are often up-regulated in tumor contexts thereby leading to enhanced translation of HIF-1α mRNA in normoxic and hypoxic conditions [7][8][9]. HIF-1α is often downstream of the activation of different plasma membrane receptors-triggered signaling pathways, thus linking HIF-1α status to the growth needs of cells [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress

Reglero

Lafarga

Rivas

et al. 2020

Cancers

View full text Add to dashboard Cite

Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses.

show abstract

“…Prognostic biomarkers are important for treating clinicians to help mitigate the risk of postoperative recurrence. In the clinic, von Hippel-Lindau (VHL) mutational status is often used as both a prognostic and predictive biomarker for RCC [153], given its role in hypoxia signaling [154]. VHL mutations were found to be significantly associated with well-defined tumor margins (p = 0.013), nodular tumor enhancement (p = 0.021), and gross appearance of intratumoral vascularity (p = 0.018) [155].…”

Section: Kidneysmentioning

confidence: 99%

Radiogenomics: bridging imaging and genomics

et al. 2019

View full text Add to dashboard Cite

From diagnostics to prognosis to response prediction, new applications for radiomics are rapidly being developed. One of the fastest evolving branches involves linking imaging phenotypes to the tumor genetic profile, a field commonly referred to as "radiogenomics." In this review, a general outline of radiogenomic literature concerning prominent mutations across different tumor sites will be provided. The field of radiogenomics originates from image processing techniques developed decades ago; however, many technical and clinical challenges still need to be addressed. Nevertheless, increasingly accurate and robust radiogenomic models are being presented and the future appears to be bright.

show abstract

VHL and Hypoxia Signaling: Beyond HIF in Cancer

Cited by 96 publications

References 111 publications

Ciliary Genes in Renal Cystic Diseases

Ciliary Genes in Renal Cystic Diseases

GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress

Radiogenomics: bridging imaging and genomics

Contact Info

Product

Resources

About