Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer

Poursoltan, Pirooz; Currey, Nicola; Pangon, Laurent; Kralingen, Christa Van; Selinger, Christina; Mahar, Annabelle; Cooper, Wendy A.; Kennedy, Catherine; McCaughan, Brian C.; Trent, Ronald J.; Kohonen‐Corish, Maija

doi:10.1016/j.lungcan.2012.04.001

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…Furthermore, SNPs within the MCC gene and its expression levels are associated with responsiveness to chemotherapy treatment in acute myeloid leukaemia . Limited data are available for other cancer types, except for lung cancer where expression of MCC is also variable but promoter methylation is rare …”

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confidence: 99%

“…7 Limited data are available for other cancer types, except for lung cancer where expression of MCC is also variable but promoter methylation is rare. 8 A number of new biological functions have been identified for MCC, including repression of beta-catenin (b-cat) signaling. 4,[9][10][11] Hyperactivation of the b-cat pathway is widely accepted as a major event in colorectal carcinogenesis, largely due to APC mutation.…”

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MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

et al. 2014

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The mutated in colorectal cancer (MCC) is a multifunctional gene showing loss of expression in colorectal and liver cancers. MCC mutations can drive colon carcinogenesis in the mouse and in vitro experiments suggest that loss of MCC function promotes cancer through several important cellular pathways. In particular, the MCC protein is known to regulate beta-catenin (bcat) signaling, but the mechanism is poorly understood. Here we show that the b-cat repressor function of MCC is strongly impaired by the presence of a disease-associated mutation. We also identify deleted in breast cancer 1 (DBC1) as a new MCC interacting partner and regulator of b-cat signaling. RNA interference experiments show that DBC1 promotes b-cat transcriptional activity and that the presence of DBC1 is required for MCC-mediated b-cat repression. In contrast to all other DBC1 interacting partners, MCC does not interact through the DBC1 Leucine Zipper domain but with a glutamic-acid rich region located between the Nudix and EF-hand domains. Furthermore, MCC overexpression relocalizes DBC1 from the nucleus to the cytoplasm and reduces b-cat K49 acetylation. Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of b-cat K49. These data suggest that the cytoplasmic MCC-DBC1 interaction sequesters DBC1 away from the nucleus, thereby removing a brake on DBC1 nuclear targets, such as SIRT1. This study provides new mechanistic insights into the DBC1-MCC axis as a new APC independent b-cat inhibitory pathway.The mutated in colorectal cancer (MCC) gene was initially discovered because of its proximity to the APC gene on chromosome 5, 1 but its importance as a tumor suppressor gene has only recently been recognized. MCC mutations can drive colon carcinogenesis as shown through an unbiased genetic screen of a mouse model of colorectal cancer. 2 MCC mutations have been found in a wide range of different cancers but in colorectal cancer the MCC gene is most commonly altered through methylation (40-50%), which causes epigenetic silencing of gene expression. 3,4 In liver cancer, MCC expression is lost through LINE-1 retrotransposition events 5 or microRNA targeting. 6 Furthermore, SNPs within the MCC gene and its expression levels are associated with responsiveness to chemotherapy treatment in acute myeloid leukaemia. 7 Limited data are available for other cancer types, except for lung cancer where expression of MCC is also variable but promoter methylation is rare. 8 A number of new biological functions have been identified for MCC, including repression of beta-catenin (b-cat) signaling. 4,[9][10][11] Hyperactivation of the b-cat pathway is widely accepted as a major event in colorectal carcinogenesis, largely due to APC mutation. Mutated APC loses its ability to direct cytoplasmic b-cat for degradation, resulting in nuclear accumulation and inappropriate activation of b-cat-mediated transcription. MCC also inhibits b-cat dependent transcription in vitro, even in the absence of APC, through a mechanism independent and...

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MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

et al. 2014

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“…Despite its name, mutations of the MCC gene are found in only ~5% of colorectal cancers but MCC gene is silenced through promoter methylation in up to 50% of colorectal cancers (Kohonen-Corish et al, 2007;Fukuyama et al, 2008). For other cancers promoter methylation data are only available for lung cancer where MCC is not methylated (Poursoltan et al, 2012). MCC mutations have also been detected in 2-5% of other cancers, such as endometrial, melanoma, bladder urothelial, gastric, lung and prostate.…”

Section: Somaticmentioning

confidence: 99%

MCC (mutated in colorectal cancers)

Kohonen‐Corish¹,

Benthani²,

Pangon³

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…Moreover, it has also been found that the APC gene, as an cancer suppressor gene, is rarely mutated, and the mechanisms causing the loss of function of this gene include loss of heterozygosity and promoter methylation, in which the “silencing” of gene function caused by promoter methylation is the main cause of the down-regulated gene expression ( 31 , 32 ). Currently, APC gene promoter hypermethylation as well as gene transcription and expression deletion have been observed in colorectal ( 33 ), esophageal ( 34 ), gastric ( 35 ), pancreatic ( 36 ), hepatocellular ( 37 ), breast ( 38 ), endometrial ( 39 ), and lung ( 40 ) cancers.…”

Section: Introductionmentioning

confidence: 99%

Exosomal miR-125b-5p derived from cancer-associated fibroblasts promotes the growth, migration, and invasion of pancreatic cancer cells by decreasing adenomatous polyposis coli (APC) expression

Guo¹,

Li²,

Sun³

2023

J Gastrointest Oncol

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Background: A significant desmoplastic response, particularly in the fibroblasts, is a characteristic of pancreatic ductal adenocarcinoma (PDAC). Increasing evidence has shown that cancer-associated fibroblasts (CAFs) assist tumor development, invasion, and metastasis in PDAC. However, CAFs-derived molecular determinants that regulate the molecular mechanisms of PDAC have not been fully characterized. Methods:The expression of microRNA 125b-5p (miR-125b-5p) in Pancreas Cancer (PC) tissue and para-cancerous normal tissue was examined using Polymerase Chain Reaction (PCR). Cell counting kit-8 (CCK8), wound healing, and transwell experiments were utilized to assess the effect of miR-125b-5p. Using a cell luciferase activity test and bioinformatics, it was demonstrated that miR-125b-5p may bind to the 3'-untranslated region (3'-UTR) of the adenomatous polyposis coli (APC), thereby limiting the progression of pancreatic cancer.Results: PDAC cells are prompted to proliferate, undergo the epithelial-mesenchymal transition (EMT), and spread. Importantly, CAFs release exosomes into PDAC cells, which significantly increase the level of miR-125b-5p in those cells. Meanwhile, pancreatic cancer cell lines and PDAC tissues have considerably higher miR-125b-5p expression. MiR-125b-5p's elevated expression mechanically suppresses the expression of APC and accelerates the spread of pancreatic cancer.Conclusions: Exosomes released by CAFs promote PDAC growth, invasion, and metastasis. Exosomal miR-125b-5p inhibition offers an alternate strategy for combating the basic malady of PDAC.

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Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer

Cited by 5 publications

References 31 publications

MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

MCC (mutated in colorectal cancers)

Exosomal miR-125b-5p derived from cancer-associated fibroblasts promotes the growth, migration, and invasion of pancreatic cancer cells by decreasing adenomatous polyposis coli (APC) expression

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