Hypoxia-Inducible Protein 2 (<i>HIG2</i>), a Novel Diagnostic Marker for Renal Cell Carcinoma and Potential Target for Molecular Therapy

Togashi, Akira; Katagiri, Toyomasa; Ashida, Shingo; Fujioka, Tomoaki; Maruyama, Osamu; Wakumoto, Yoshiaki; Sakamoto, Yoshiro; Fujime, Μakoto; Kawachi, Yoshio; Shuin, Taro; Nakamura, Yusuke

doi:10.1158/0008-5472.can-05-0120

Cited by 93 publications

(83 citation statements)

References 20 publications

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“…HIG2 enhances the Wnt signaling when bound to the frizzled homologue 10 (Fzd10). This effect is reversed using antibodies or siRNA against HIG2 [99]. The Wnt signaling antagonist Dkk-1 [100] is also found to be overexpressed in 81% of hepatoblastomas and in 5 of 6 Wilms' tumor samples.…”

Section: Wnt Antagonists Failure: a Critical Step In Renal Cancer Devmentioning

confidence: 98%

Wnt Signaling in Renal Cancer

Guillen-Ahlers

2008

CDT

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About one fourth of people diagnosed with kidney cancer in 2007, are expected to die of this disease within 5 years from the date of diagnosis. Recent years have produced novel drugs, some with FDA approval, and many in clinical trials, all showing very discrete results. Failure in finding effective treatments to improve survival with drugs mainly targeting VEGF and its downstream effectors, urges to shift the drug development targets to other unexploited pathways shown to be also involved in renal cancer. Several studies show alterations in the Wnt signaling pathway, many of which differ from those implicated in other human cancers. Unlike colorectal or hepatocellular carcinomas, where APC and axin mutations, respectively, are the main Wnt signaling deregulating event, renal carcinomas seem to be affected by other factors. Recent studies have presented VHL, a tumor suppressor gene strongly associated with renal cell carcinoma, as a beta-catenin target. This confirms that Wnt signaling is likely playing a central role during renal carcinoma development, which needs to be considered and addressed to treat this disease. This review outlines briefly the molecular biology of the most common renal cancers and the drug treatments currently used to treat the disease. The canonical Wnt pathway is reviewed more carefully adding specific features in a renal carcinoma context, which present potential targets for drug development and biomarker use.

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Section: Wnt Antagonists Failure: a Critical Step In Renal Cancer Devmentioning

confidence: 98%

Wnt Signaling in Renal Cancer

Guillen-Ahlers

2008

CDT

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“…The link between Wnt pathway and kidney cancer can be established from the observation that the hypoxia-inducible protein-2 (HIG2) binds to the Wnt receptor Fz10 at its extracellular domain and induces transcription of Wnt signaling target genes [160]. HIG2 functions as a cell proliferation inducer and has been identified as a marker of RCC.…”

Section: Genetic Alterations Of Wnt Signaling In Cancermentioning

confidence: 99%

“…HIG2 functions as a cell proliferation inducer and has been identified as a marker of RCC. HIG2 is also a target gene of thecatenin/Tcf4 complex [160]. Similar to development of lung cancer the levels of the Wnt antagonist SFRP1 are reduced both at mRNA and protein levels in clear renal cell carcinoma (cRCC) and this may be due to the methylation of promoter of SFRP1 [161].…”

Section: Genetic Alterations Of Wnt Signaling In Cancermentioning

confidence: 99%

The Role of Wnt/Beta-Catenin Signaling in Renal Carcinogenesis: Lessons from Cadmium Toxicity Studies

Thévenod¹,

Chakraborty

2010

CMM

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Wnt/beta-catenin signaling plays a crucial role during embryogenesis. However, this signaling pathway also plays a role in normal adult tissues and in carcinogenesis, including cadmium (Cd2+) induced nephrocarcinogenesis, which is the topic of this review. Wnt/beta-catenin signaling is tightly regulated in mature epithelia to balance cell proliferation, differentiation and death. This is accomplished by modulating phosphorylation of the multifunctional protein beta-catenin which in turn determines its preference for a particular fate, i.e. cell-cell adhesion by binding to E-cadherin, proteasomal degradation, or co-activation of the transcription factor Tcf/Lef. The pivotal role of beta-catenin is not limited to Wnt signaling, but can be challenged by other transcription factors under stress conditions (e.g. FOXO, HIF-1alpha, NF-kappaB, c-jun), where beta-catenin acts as a molecular switch in response to the cellular redox status. Aberrant Wnt/beta-catenin signaling can contribute to carcinogenesis of intestinal, lung or kidney epithelia, either by mutations of its signaling components and/or disruption of linked signaling networks. The nephrotoxic metal Cd2+ causes renal cancer in humans. Because it is not genotoxic Cd2+ is thought to induce mutations and carcinomas indirectly: Possible mechanisms include oxidative stress, inhibition of DNA repair, aberrant gene expression, deregulation of cell proliferation, resistance to apoptosis, and/or disruption of cell adhesion. Wnt signaling may contribute to Cd2+ carcinogenesis because Cd2+ disrupts the junctional E-cadherin/beta-catenin complex, resulting in excessive nuclear translocation of beta-catenin and activation of Tcf4. Up-regulation of target genes of the beta-catenin/Tcf4 complex, such as c-myc, cyclin D1 and the multidrug transporter P-glycoprotein (MDR1/ABCB1), leads to increased proliferation, evasion of apoptosis, adaptation to Cd2+ toxicity and thereby promotes the selection of mutated and pre-neoplastic cells.

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“…Molecules indirectly associated with Wnt signaling: RCC exhibits increased expression of FZD5 and FZD8 (Janssens et al, 2004) and hypoxia-inducible protein 2 (HIG2) which binds to FZD10 leading to induction of certain genes typically associated with Wnt signaling (Togashi et al, 2005). Humanized anti-HIG2 antibody may provide a potential therapy for RCC via a modulation of Wnt signaling.…”

Section: Strategies For Inhibiting Wnt/β-catenin In Renal Fibrosismentioning

confidence: 99%

Wnt/β-catenin signaling: A novel target for therapeutic intervention of fibrotic kidney disease

Hwang¹,

Seo²,

2009

Arch. Pharm. Res.

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Fibrosis of epithelial parenchymal organs and end-stage organ failure, the final common pathway of many progressive chronic diseases including chronic kidney disease, continue to increase worldwide and are a major determinant of morbidity and mortality. Fibrosis is an active biosynthetic healing response initiated to protect the tissue from injury through the timed release of proteins but leads to serious tissue damage when it becomes independent from the initiating stimulus. Massive deposition of extracellular matrix by accumulation of myofibroblasts and disruption of the normal tissue architecture are characteristic of tissue fibrosis. The highly conserved Wnt/beta-catenin signaling pathway is essential to embryonic development in general and kidney morphogenesis in particular by regulating the expression of target genes, most often through the transcription factor T cell factor (TCF) and/or lymphoid enhancer factor (LEF). Emerging evidence from studies of renal fibrosis suggests that altered Wnt/beta-catenin signaling is linked to the pathogenesis of renal fibrosis. The renoprotective properties of some currently available drugs might be attributable in part to inhibition of Wnt signaling. The development of orally active Wnt modulators will provide a potentially important pharmacological tool for further investigating the role of Wnt/beta-catenin signaling and might offer a novel therapeutic strategy in renal fibrosis.

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Hypoxia-Inducible Protein 2 (HIG2), a Novel Diagnostic Marker for Renal Cell Carcinoma and Potential Target for Molecular Therapy

Cited by 93 publications

References 20 publications

Wnt Signaling in Renal Cancer

Wnt Signaling in Renal Cancer

The Role of Wnt/Beta-Catenin Signaling in Renal Carcinogenesis: Lessons from Cadmium Toxicity Studies

Wnt/β-catenin signaling: A novel target for therapeutic intervention of fibrotic kidney disease

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