Metastatic susceptibility locus, an 8p hot-spot for tumour progression disrupted in colorectal liver metastases: 13 candidate genes examined at the DNA, mRNA and protein level

Abstract

BackgroundMortality from colorectal cancer is mainly due to metastatic liver disease. Improved understanding of the molecular events underlying metastasis is crucial for the development of new methods for early detection and treatment of colorectal cancer. Loss of chromosome 8p is frequently seen in colorectal cancer and implicated in later stage disease and metastasis, although a single metastasis suppressor gene has yet to be identified. We therefore examined 8p for genes involved in colorectal cancer progression.MethodsLoss of heterozygosity analyses were used to map genetic loss in colorectal liver metastases. Candidate genes in the region of loss were investigated in clinical samples from 44 patients, including 6 with matched colon normal, colon tumour and liver metastasis. We investigated gene disruption at the level of DNA, mRNA and protein using a combination of mutation, semi-quantitative real-time PCR, western blotting and immunohistochemical analyses.ResultsWe mapped a 2 Mb region of 8p21-22 with loss of heterozygosity in 73% of samples; 8/11 liver metastasis samples had loss which was not present in the corresponding matched primary colon tumour. 13 candidate genes were identified for further analysis. Both up and down-regulation of 8p21-22 gene expression was associated with metastasis. ADAMDEC1 mRNA and protein expression decreased during both tumourigenesis and tumour progression. Increased STC1 and LOXL2 mRNA expression occurred during tumourigenesis. Liver metastases with low DcR1/TNFRSF10C mRNA expression were more likely to present with extrahepatic metastases (p = 0.005). A novel germline truncating mutation of DR5/TNFRSF10B was identified, and DR4/TNFRSF10A SNP rs4872077 was associated with the development of liver metastases (p = 0.02).ConclusionOur data confirm that genes on 8p21-22 are dysregulated during colorectal cancer progression. Interestingly, however, instead of harbouring a single candidate colorectal metastasis suppressor 8p21-22 appears to be a hot-spot for tumour progression, encoding at least 13 genes with a putative role in carcinoma development. Thus, we propose that this region of 8p comprises a metastatic susceptibility locus involved in tumour progression whose disruption increases metastatic potential.

microRNA-320a inhibits tumor invasion by targeting neuropilin�1 and is associated with liver metastasis in colorectal cancer

“…The region of chromosome 8p21-22 has been identified as a liver metastatic susceptibility locus whose disruption increases metastatic potential (44). Chromosome 8p is also frequently lost in late stage and metastatic CRC (45,46). Given this, it is likely that a reduction in miR-320a expression may also be associated with clinicopathological parameters in primary CRC.…”

ADAMDEC1 Is a Metzincin Metalloprotease with Dampened Proteolytic Activity

“…It is expressed during differentiation of dendritic cells and is constitutively expressed in macrophages (1,12). Until now, ADAMDEC1 has primarily been studied on a transcriptional level, where it has been found differently regulated in a number of pathologies (13)(14)(15)(16)(17)(18).…”

“…Moreover, expression is strongly induced by spontaneous as well as by CD40-or LPS-stimulated maturation of immature dendritic cells (1,12). ADAMDEC1 expression was found to be up-regulated in atherosclerotic plaques (13), pulmonary sarcoidosis (14), intestinal inflammation (15), intracranial tumor (craniopharyngioma) (16), and infection of lymphoblastoid cells by Epstein-Barr virus (17), whereas it is down-regulated in colorectal cancer (18). In addition, ADAMDEC1 is up-regulated during pregnancy (19).…”

Gene Dysregulations Driven by Somatic Copy Number Aberrations-Biological and Clinical Implications in Colon Tumors

“…As stated above, MTUS1 is most likely a tumor suppressor gene. 74,75,85 The down-regulation of ADAMDEC1 and EPHX2 were recently associated with colon cancer metastasis, 86 and PPP2CB codes for the catalytic component of tumor suppressor protein phosphatase 2A. 87 We now hypothesize that the poor CRC prognostication of 8p loss may be explained by the fact that it harbors a number of genes with tumor suppressive properties and which play crucial roles in later stages of carcinogenesis.…”