Aberrant Methylation of the Netrin‐1 Receptor Genes <i>UNC5C</i> and <i>DCC</i> Detected in Advanced Colorectal Cancer

Hibi, Kenji; Mizukami, Hajime; Shirahata, Atsushi; Goto, Tetsuhiro; Sakata, Makiko; Yukitoshi, Sanada

doi:10.1007/s00268-008-9909-x

Cited by 68 publications

(77 citation statements)

References 15 publications

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“…8 We included TNFAIP3 (A20) and HACE1 in the candidate gene list because they have been described as tumor-suppressor genes in many previous studies. [31][32][33]35,36 Although these were not located on the most frequently deleted MCR, 29% and 31% of cases showed deletion of these genes. The expression levels of POPDC3 and AIM1 did not differ between neoplastic samples and normal NK cells.…”

Section: Discussionmentioning

confidence: 95%

Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses

Karube

Nakagawa

Tsuzuki

et al. 2011

Blood

150

148

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Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligoarray CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumorsuppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Reexpression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10.

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Section: Discussionmentioning

confidence: 95%

Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses

Karube

Nakagawa

Tsuzuki

et al. 2011

Blood

150

148

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“…P-cadherin is classified as an oncogene due to its ability to increase crypt cell proliferation in the context of inflammation (14). In addition, two reports have suggested that CDH3 upregulation in cancer tissue is associated with gene promoter demethylation (14,15). However, using a quantitative approach, increased promoter hypomethylation was identified in only 77% of carcinomas (15), which does not account for the universal upregulation of the expression of this gene in AD and cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression changes of cell-cell adhesion-related genes in colorectal tumors

et al. 2015

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Abstract. Epithelial tissues achieve a highly organized structure due to cell-cell junction complexes. Carcinogenesis is accompanied by changes in cell interactions and tissue morphology, which appear in the early stages of benign tumors and progress along with invasive potential. The aim of the present study was to analyze the changes in expression levels of genes encoding intercellular junction proteins that have been previously identified to be differentially expressed in colorectal tumors compared with normal mucosa samples (fold change, >2.5) in genome-wide expression profiling. The expression of 20 selected genes was assessed using quantitative reverse transcription polymerase chain reaction in 26 colorectal cancer, 42 adenoma and 24 normal mucosa samples. Between these tissue types, differences were observed in the mRNA levels of genes encoding adherens junction proteins (upregulation of CDH3 and CDH11, and downregulation of CDH19 and PTPRF), tight junction proteins (upregulation of CLDN1 and CLDN2, and downregulation of CLDN5, CLDN8, CLDN23, CLDN15, JAM2 and CGN) and desmosomes (upregulation of DSC3 and DSG3, and downregulation of DSC2), in addition to a decrease in the expression of certain other genes involved in intercellular connections: PCDHB14, PCDH7, MUPCDH and NEO1. The differences between tissue types were statistically significant, and separate clustering of normal adenoma and carcinoma samples was observed in a hierarchical clustering analysis. These results indicate that the morphological changes in neoplastic colon tissue that occur during the 'adenoma-carcinoma sequence' are accompanied by specific changes in the expression of multiple genes encoding the majority of cell-cell junction complexes. The particular differential expression patterns appear to be consistent among patients with cancer and adenoma, in addition to normal mucosa samples.

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“…Another group of Netrin-1 receptors referred to as UNC5H (1-3/A-C) are also downregulated in a number of tumors. Overexpression of these receptors inhibits tumor cell anchorage-independent growth and invasion (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

The Tumor-Suppressive Function ofUNC5Dand Its Repressed Expression in Renal Cell Carcinoma

Lü

Dong

Zhou

et al. 2013

Clinical Cancer Research

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Purpose: As a newly added member of the UNC5H receptors, the function of UNC5D/H4 in tumorigenesis remains poorly defined. The aim of this study was to examine the expression of UNC5D in primary renal cell carcinomas (RCC), analyze the mechanisms responsible for its downregulation in RCC, and assess its functional relevance to tumor growth and migration.Experimental Design: Forty-four paired primary RCCs and corresponding adjacent noncancerous tissues were collected. The mRNA and protein expression level of UNC5D was assessed by reverse transcriptase-PCR, real-time PCR, or immunohistochemistry. Epigenetic alterations in UNC5D promoter and LOH in the UNC5D locus were also analyzed. Ectopic expression of UNC5D in renal cancer cells with silenced expression of UNC5D was used for analysis of the biologic functions of UNC5D.Results: UNC5D expression was attenuated in multiple carcinoma cell lines including renal cancer cells. Similar reduction was also observed in primary RCC tissues as compared with paired adjacent noncancerous tissues. Methylation-specific PCR showed hypermethylation in UNC5D promoter in a significant proportion (18 of 44) of tumor tissue (40.9%). LOH of UNC5D was observed in 13 of 44 patients with RCCs (29.5%). Restoration of UNC5D expression in renal cancer cells significantly inhibited cell proliferation, anchorage-dependent and -independent growth, as well as migration and invasion, whereas knockdown of UNC5D promoted cell growth. Furthermore, ectopic expression of UNC5D induced G 2 -M cell-cycle arrest.Conclusions: UNC5D is a functional tumor suppressor that is frequently downregulated in RCCs due to promoter hypermethylation and LOH.

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Aberrant Methylation of the Netrin‐1 Receptor Genes UNC5C and DCC Detected in Advanced Colorectal Cancer

Abstract: A significant difference was observed in the Dukes stage (p = 0.0438). Netrin-1 receptors might act as a tumor suppressor in colorectal cancers, and thus methylation might present a malignant potential in colorectal cancer.

Cited by 68 publications

References 15 publications

Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses

Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses

Expression changes of cell-cell adhesion-related genes in colorectal tumors

The Tumor-Suppressive Function ofUNC5Dand Its Repressed Expression in Renal Cell Carcinoma

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