Altered Expression of Multiple Genes Involved in Retinoic Acid Biosynthesis in Human Colorectal Cancer

Abstract

All-trans-retinoic acid (atRA), the oxidized form of vitamin A (retinol), regulates a wide variety of biological processes, such as cell proliferation and differentiation. Multiple alcohol, retinol and retinaldehyde dehydrogenases (ADHs, RDHs, RALDHs) as well as aldo-keto reductases (AKRs) catalyze atRA production. The reduced atRA biosynthesis has been observed in several human tumors, including colorectal cancer. However, subsets of atRA-synthesizing enzymes have not been determined in colorectal tumors. We investigated the expression patterns of genes involved in atRA biosynthesis in normal human colorectal tissues, primary carcinomas and cancer cell lines by RT-PCR. These genes were identified using transcriptomic data analysis (expressed sequence tags, RNA-sequencing, microarrays). Our results indicate that each step of the atRA biosynthesis pathway is dysregulated in colorectal cancer. Frequent and significant decreases in the mRNA levels of the ADH1B, ADH1C, RDHL, RDH5 and AKR1B10 genes were observed in a majority of colorectal carcinomas. The expression levels of the RALDH1 gene were reduced, and the expression levels of the cytochrome CYP26A1 gene increased. The human colon cancer cell lines showed a similar pattern of changes in the mRNA levels of these genes. A dramatic reduction in the expression of genes encoding the predominant retinol-oxidizing enzymes could impair atRA production. The most abundant of these genes, ADH1B and ADH1C, display decreased expression during progression from adenoma to early and more advanced stage of colorectal carcinomas. The diminished atRA biosynthesis may lead to alteration of cell growth and differentiation in the colon and rectum, thus contributing to the progression of colorectal cancer.

Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8 + T Cell-Mediated Immunity in Colorectal Cancer

“…Nevertheless, when compared with normal colonic mucosa, colitis, dysplasia and colon carcinoma are all characterized by a decrease in ALDH1A1 and a concomitant increase in the CYP26A1, indicative of reduced colonic levels of atRA. These findings are in accord with recent investigations of sporadic CRC (Kropotova et al, 2014), including a study demonstrating that CYP26B1 expression directly correlates with disease prognosis (Brown et al, 2014). In the present study, we found a significant correlation between CYP26A1 transcript expression and both overall survival and disease-free survival in a multi-center cohort of CRC patients (Marisa et al, 2013).…”

Aldo-keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds

“…AKR1B10 is primarily expressed in intestinal epithelial cells , but downregulated in colorectal cancer . The downregulation of AKR1B10 may inhibit p53‐induced apoptosis and disrupt homeostasis of retinoic acid, promoting progression of colorectal carcinoma . This study further found that AKR1B10 expression disappeared in precancerous lesions of the colon, including ulcerative colitis, Crown's disease, and adenomatous polyps.…”

Transcriptional landscape of human cancers

“…Among the 11 genes, SCARA5 expression has been shown to be frequently downregulated in various cancers [59], and has been proposed as a novel tumor suppressor gene [60]. ADH1B was shown to be downregulated in colorectal cancer [61] and lung cancer [62]. SYNE1 has been shown to be downregulated in various human cancers [63].…”