The role of HIF1α in renal cell carcinoma tumorigenesis

Gudas, Lorraine J.; Fu, Leiping; Minton, Denise R.; Mongan, Nigel P.; Nanus, David M.

doi:10.1007/s00109-014-1180-z

Cited by 89 publications

(84 citation statements)

References 98 publications

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“…4,39 To determine whether this growth factor is involved in MARCKS signaling, we evaluated VEGFA-stained cells in the xenograft tumors and found parallel reduction of VEGFA and MARCKS expression in tumors derived from MARCKS-silenced 786-O cells (Figure 4a). To validate this finding in human RCC, samples from the GSE53757 data set ( n = 144) were grouped into high- and low-MARCKS expression using the median as a cutoff and subjected to Wilcoxon–Mann– Whitney test on the VEGFA expression levels of the two groups; these data showed a significantly higher level of VEGFA in the high-MARCKS subset (Figure 4b; W = 4902, P -value <0.01).…”

Section: Resultsmentioning

confidence: 99%

“…1,2 Under normoxic conditions, the VHL protein contributes to the degradation of the α -subunit of hypoxia-induced factors (HIFs). Because of Q3 the inactivation of the VHL gene, which is common in clear-cell RCC, the HIF-α proteins accumulate and induce expression of their target genes, such as vascular endothelial growth factor (VEGF) and others, 3,4 which are involved in angiogenesis; therefore, anti-angiogenic therapies have played a pivotal role in RCC treatment. 5 For metastatic RCC in particular, the two standard targets are the VEGF receptor and mammalian target of rapamycin (mTOR), a downstream component in the phosphoinositide 3-kinase (PI3K)/AKT pathway known to upregulate HIF-1α activity.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Chen

Fong

et al. 2017

Oncogene

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Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Chen

Fong

et al. 2017

Oncogene

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“…A recent survey of malignant and normal tissues found that the expression of both HIF-1 and HIF-2 is commonly increased in a variety of human tumors, including bladder, breast, colon, glial, hepatocellular, ovarian, pancreatic, prostate, and renal tumors [102]. A variety of clinical and mechanistic data supports that HIF-1α has an important role in promoting tumorigenesis in a clinically important and large subset of human renal carcinoma (see review [103] by Gudas et al).…”

Section: Renal Tumorigenesismentioning

confidence: 99%

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

Luo

Shi

et al. 2016

Cell Physiol Biochem

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Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis. However, the underlying signaling mechanisms, whereby hypoxia alters cellular behaviors, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are key signal-transducing enzymes activated by a wide range of extracellular stimuli, including hypoxia/ischemia. There are four major family members of MAPKs: the extracellular signal-regulated kinases-1 and -2 (ERK1/2), the c-Jun N-terminal kinases (JNK), p38 MAPKs, and extracellular signal-regulated kinase-5 (ERK5/BMK1). Recent studies, including ours, suggest that these MAPKs are differentially involved in renal responses to hypoxic/ischemic stress. This review will discuss their changes in hypoxic/ischemic pathophysiology with acute kidney injury, chronic kidney diseases and renal carcinoma.

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“…These studies argue that whereas HIF2a activity is tumor promoting, there is a selection against HIF1a expression or activity during the progression of some cases of ccRCC. On the other hand, because HIF1a is strongly expressed in single and multicellular clusters of VHL-null cells and in cystic lesions in VHL patients (4), and because transgenic overexpression of HIF1a in mouse proximal tubular epithelial cells causes a clear cell appearance, increased proliferation, and a disorganized tubular morphology (25), and because many human ccRCCs express HIF1a and HIF1a target genes (26), it may also be argued that HIF1a plays an important role in promoting ccRCC development. These studies have largely focused on fully transformed, genetically complex ccRCC cell lines derived from advanced tumors, and it remains unclear if and how HIF1a and HIF2a contribute to the earliest stages of initiation of ccRCC.…”

Section: Introductionmentioning

confidence: 99%

Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α

et al. 2016

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The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1a has been implicated as a renal tumor suppressor, whereas HIF2a is considered an oncoprotein. In this study, we investigated the contributions of HIF1a and HIF2a to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1a and HIF2a differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhldeficient renal epithelial cells. HIF1a, but not HIF2a, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1a and HIF2a exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025-36. Ó2016 AACR.

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The role of HIF1α in renal cell carcinoma tumorigenesis

Cited by 89 publications

References 98 publications

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α

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