Molecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling

Tsukiyama, Tadasuke; Fukui, Akimasa; Terai, Sayuri; Fujioka, Yoichiro; Shinada, Keisuke; Takahashi, Hidehisa; Yamaguchi, Terry P.; Ohba, Yusuke; Hatakeyama, Susumi

doi:10.1128/mcb.00159-15

Cited by 75 publications

(141 citation statements)

References 49 publications

(74 reference statements)

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“…Notably, two missense RNF43 mutations (M1I and C119Y) in either the extracellular protease‐associated domain or the signal peptide region were found in MSS EGCs. RNF43 missense mutations change protein localization from the endosome to the endoplasmic reticulum, resulting in the failure of frizzled‐dependent suppression of Wnt–β‐catenin signalling, but the protein retains the ability to suppress non‐canonical Wnt signalling . In general, these RNF43 mutations and the APC mutations were mutually exclusive, which is consistent with their ability to activate Wnt–β‐catenin signalling .…”

Section: Resultsmentioning

confidence: 62%

Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Min

Hwang

Kim

et al. 2016

The Journal of Pathology

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Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 62%

Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Min

Hwang

Kim

et al. 2016

The Journal of Pathology

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“…A potential limitation of this study was that the N‐terminal domains (exons 2–8) of RNF43 but not the intracytoplasmic region (exons 9–10) were sequenced. The N‐terminal domains of RNF43, including the extracellular protease‐associated domain and the intracellular ring finger domain, play a critical role in the suppression of canonical Wnt signalling, whereas the intracytoplasmic region relates more to the suppression of the non‐canonical Wnt pathway but not canonical Wnt activity . Deleterious mutations in the intracytoplasmic region were not common in intraductal papillary mucinous neoplasm of the pancreas and mucinous tumours of the ovary .…”

Section: Discussionmentioning

confidence: 99%

“…The N-terminal domains of RNF43, including the extracellular protease-associated domain and the intracellular ring finger domain, play a critical role in the suppression of canonical Wnt signalling, whereas the intracytoplasmic region relates more to the suppression of the non-canonical Wnt pathway but not canonical Wnt activity. 21,22 Deleterious mutations in the intracytoplasmic region were not common in intraductal papillary mucinous neoplasm of the pancreas and mucinous tumours of the ovary. 14,19 Because the intracytoplasmic region was not sequenced in this study, the RNF43 mutation rate in IPNB could be higher than the 12% reported in this study.…”

Section: Discussionmentioning

confidence: 99%

“…RNF43 encodes a transmembrane ubiquitin E3 ligase, and has been postulated to function as a tumour suppressor gene . The N‐terminal domains of RNF43, including the extracellular protease‐associated domain and the intracellular ring finger domain, induce Frizzled ubiquitination and suppress the Wnt signalling pathway . RNF43 also functions as a potent negative feedback regulator of the Wnt signal transduction cascade .…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] The N-terminal domains of RNF43, including the extracellular protease-associated domain and the intracellular ring finger domain, induce Frizzled ubiquitination and suppress the Wnt signalling pathway. 21,22 RNF43 also functions as a potent negative feedback regulator of the Wnt signal transduction cascade. 23,24 Loss-offunction mutations in RNF43 promote Wnt signalling activity, reinforce cell proliferation, and result in neoplastic transformation.…”

Section: Introductionmentioning

confidence: 99%

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