RNF43 Inhibits Cancer Cell Proliferation and Could be a Potential Prognostic Factor for Human Gastric Carcinoma

Niu, Lei; Qin, Hongzhen; Xi, Hongqing; Wei, Bo; Xia, Shaoyou; Chen, Lin

doi:10.1159/000430154

Cited by 34 publications

(49 citation statements)

References 31 publications

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“…Loss of RNF43 protein expression was observed in eight of 10 EGCs (80%) with Gly659fs mutations. This loss of RNF43 protein expression in tumours with frameshift mutation was consistent with the results of previous studies assessing advanced-stage GC [31,32].…”

Section: Somatic Genomic Alterationssupporting

confidence: 92%

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: Somatic Genomic Alterationssupporting

confidence: 92%

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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“…Whether its expression is transient and is degraded soon after functioning, or whether it is maintained within the cell for a period of time is unknown. RNF43 has been reportedly expressed in both the cytoplasm and nucleus of gastric cancer cells [14], the cytoplasm of gastric cancer and glioma cells [31, 32] as well as in the nuclear membrane and endoplasmic reticulum of cervical cancer cells [33]. A recent study described nuclear localization of RNF43 where it functioned to inhibit the Wnt pathway through its sequestering of TCF4, a transcription factor activated by beta-catenin target gene, to the nuclear membrane which prevented TCF4's mediated transcription of genes involved in downstream Wnt signalling [34].…”

Section: Discussionmentioning

confidence: 99%

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

et al. 2016

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Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC. We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia. RNF43 was mutated in 47/54(87%) BRAF mutant/MSI and 8/33(24%) BRAF mutant/microsatellite stable cancers compared to only 3/79(4%) BRAF wildtype cancers (p<0.0001). ZNRF3 was mutated in 16/54(30%) BRAF mutant/MSI and 5/33(15%) BRAF mutant/microsatellite stable compared to 0/27 BRAF wild type cancers (p=0.004). An RNF43 frameshift mutation (X659fs) occurred in 80% BRAF mutant/MSI cancers. This high rate was verified in a second series of 25/35(71%) BRAF mutant/MSI cancers. RNF43 and ZNRF3 had lower transcript expression in BRAF mutant compared to BRAF wildtype cancers and less cytoplasmic protein expression in BRAF mutant/MSI compared to other subtypes. Treatment with a porcupine inhibitor reduced RNF43/ZNRF3 mutant colony growth by 50% and synergised with a MEK inhibitor to dramatically reduce growth. This study suggests inactivation of RNF43 and ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for this cancer subtype.

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“…The disease is more prevalent in East Asia (including Korea, Japan, and China) than in other regions. However, effective targeted therapies and clinically available GC biomarkers have yet to be developed [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

WNT5A Correlates with Clinicopathological Characteristics in Gastric Cancer: a Meta-Analysis

Nam

Chung

Yang

2017

Cell Physiol Biochem

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Background/Aims: Gastric cancer (GC), the third-leading cause of cancer death in the world, is typically diagnosed only in its advanced stages. WNT signaling has been associated with clinicopathological characteristics in diverse cancer types. But the systematic analysis of WNT5A, a member in the signaling, has not been inspected. Thus, our study used a meta-analysis to statistically associate WNT5A expression with GC clinicopathological characteristics. Methods: For a systematic literature review of GC in combination with the WNT signaling molecule WNT5A, we searched for PubMed, Cochrane Library, and Web of Science. It led to the five cohorts, in four eligible studies, consisting of 1,034 patients (617 WNT5A-positive and 417 WNT5A-negative patients). These patients were inspected by the library “meta” in R software for our meta-analysis. Results: Our meta-analysis, revealed a statistically significant associations of WNT5A-positivity with lymph node metastasis (p=0.0047), some types of Lauren diffuse subtype GCs (p<0.0001), advanced tumor depth (p<0.0001), and advanced UICC stages (p=0.0461) with no observation of bias or confounding factors. Conclusions: These results support the feasibility of targeting this embryonic signaling pathway, both for therapy, and as a biomarker to “guide” various individual interventions (i.e., “personalized medicine”).

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RNF43 Inhibits Cancer Cell Proliferation and Could be a Potential Prognostic Factor for Human Gastric Carcinoma

Cited by 34 publications

References 31 publications

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

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

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

WNT5A Correlates with Clinicopathological Characteristics in Gastric Cancer: a Meta-Analysis

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