Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer.

Circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer.

Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer.

The Eph receptors, members of a large family of transmembrane receptor tyrosine kinases, play important roles in a variety of biological functions. Recent studies have suggested that EphA4 and EphB2 participate in the growth and development of various carcinomas. This study examined the relationship of EphA4 and EphB2 gene expression to clinicopathological factors, especially metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal cancer. The relative expression levels of EphA4 and EphB2 mRNA in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of EphA4 mRNA was higher in the presence than in the absence of liver metastasis, whereas the relative expression levels of EphB2 mRNA were similar. Analysis of the relationship between clinicopathological features and gene expression showed that high expression of the EphA4 gene and low expression of the EphB2 gene correlated with liver metastasis. There was no correlation between EphA4 and EphB2 gene expression. Our results suggest that overexpression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer. Overexpression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer.

Clinicopathological significance of the gene expression of matrix metalloproteinase-7, insulin-like growth factor-1, insulin-like growth factor-2 and insulin-like growth factor-1 receptor in patients with colorectal cancer: insulin-like growth factor-1 receptor gene expression is a useful predictor of liver metastasis from colorectal cancer.

Matrix metalloproteinase-7 (MMP-7), secreted by cancer cells, has been implicated classically in the basement membrane destruction associated with tumor cell invasion and metastasis. Epidemiological studies have established a correlation between high levels of circulating insulin-like growth factor-1 (IGF-1) and the relative risk of colorectal cancer, which is known to produce MMP-7. We examined the clinicopathological significance of the relative expression of MMP-7, IGF-1, IGF-2 and IGF-1 receptor genes in patients with colorectal cancer, especially with regard to metastasis. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal carcinoma. MMP-7, IGF-1, IGF-2, IGF-1R and beta-actin mRNA in cancer tissue and adjacent normal mucosa were measured by quantitative real-time reverse-transcriptase polymerase chain reaction. MMP-7 and IGF-1R gene expression levels were higher in cancer tissue than in adjacent normal mucosa. In contrast, IGF-1 gene expression was lower in cancer tissue than in adjacent normal mucosa. As for the relationship of gene expression to clinicopathological factors, IGF-1R expression correlated with venous invasion and liver metastasis. IGF-1R gene expression is thus considered a useful predictor of liver metastasis from colorectal cancer.

Clinicopathological significance of the gene expression of matrix metalloproteinases and reversion-inducing cysteine-rich protein with Kazal motifs in patients with colorectal cancer: MMP-2 gene expression is a useful predictor of liver metastasis from colorectal cancer.

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and membrane-type matrix metalloproteinase 1 (MT1-MMP) are involved in colorectal cancer invasion and metastasis. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) inhibits MMP-2, MMP-9 and MT1-MMP. We examined the clinicopathological significance of the relative expression of these genes in patients with colorectal cancer, especially with regard to metastasis. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal carcinoma. MMP-2, MMP-9, MT1-MMP, RECK and beta-actin mRNA of cancer tissue and adjacent normal mucosa were measured by quantitative real-time reverse-transcriptase polymerase chain reaction. MT1-MMP gene expression was higher in cancer tissue than in adjacent normal mucosa. In contrast, MMP-2, MMP-9 and RECK gene expression levels were lower in cancer tissue than in adjacent normal mucosa. As for the relationship between the gene expression and clinicopathological factors, MMP-2 expression correlated with the depth of invasion, venous invasion and liver metastasis; MMP-9 and RECK expression correlated with venous invasion. There were positive correlations among the gene expression levels of MMP-2, MMP-9 and RECK. MMP-2 gene expression was considered a useful predictor of liver metastasis from colorectal cancer.

Reduced expression of the claudin-7 gene correlates with venous invasion and liver metastasis in colorectal cancer.

Claudins, members of a large family of adherent junction proteins, regulate the integrity and function of tight junctions and influence tumorigenesis. Studies have suggested that altered levels of different claudins are related to carcinoma-cell invasion and disease progression. This study examined the relationship between the relative expression of claudin genes and clinicopathological factors, especially invasion and metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa from 205 patients with untreated colorectal carcinoma. The relative expression levels of claudin-1, -3, -4 and -7 mRNA in cancer and in normal adjacent mucosa were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression levels of the claudin-1, -3 and -4 genes were higher in cancer than in normal adjacent mucosa, whereas the relative expression of the claudin-7 gene was similar. An analysis of the relationship between the clinicopathological features and gene expression showed that reduced expression of claudin-7 correlated with venous invasion and liver metastasis. There was also a correlation between claudin-3 and -4 gene expression. Our results suggested that a reduced expression of the claudin-7 gene might lead to venous invasion and liver metastasis in colorectal cancer. Reduced expression of the claudin-7 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer.