AKR1B10, a Transcriptional Target of p53, Is Downregulated in Colorectal Cancers Associated with Poor Prognosis

Abstract

p53 is one of the most important tumor suppressor genes, and it is frequently inactivated in various cancers. p53 modulates various cellular functions, such as apoptosis and cell-cycle arrest via transcriptional regulation. Recently, p53 has been reported to be involved in a wide range of cellular metabolic pathways, including glycolysis, oxidative phosphorylation, glutaminolysis, and the antioxidant response. To understand the functional mechanism of p53, it is important to find out the direct transcriptional targets of p53. In this study, aldo-keto reductase family 1, member B10 (AKR1B10) was identified as a direct target of the p53 family by cDNA microarray analysis after comparing the mRNA expression of control and H1299 cells that overexpressed with p53 family members. In addition, we found that the expression of AKR1B10 was significantly decreased in colorectal cancers and adenomas as compared with normal colon tissues. Knockdown of AKR1B10 significantly inhibited p53-induced apoptosis in colorectal cancer cells, whereas the overexpression of AKR1B10 enhanced p53-induced apoptosis and inhibited tumor proliferation in vivo. Furthermore, low expression of AKR1B10 in colon cancer patients was correlated with decreased survival and poor prognosis. These results suggest that decreased expression of AKR1B10 could disrupt the tumor suppressive function of p53, which result in decreased survival in colorectal cancer patients. In summary, AKR1B10 may be a novel prognostic predictor and a novel therapeutic target for colorectal cancer.

Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

“…The expression of AKR1B10 is known to be increased in many human cancers including breast cancer and lung cancer (48, 49), but is diminished in colorectal cancer (50). We found that AKR1B10 expression is also diminished in ulcerative colitis.…”

Expression of AKR1B10 as an independent marker for poor prognosis in human oral squamous cell carcinoma

“…AKR1B10 may exert disparate functions in tumorigenesis dependent upon the cellular context. Furthermore, it has been considered as a valuable prognostic marker for certain cancers . However, there have been no previous reports on AKR1B10 protein expression in OSCCs.…”

Down-regulation of aldo–keto reductase AKR1B10 gene expression by a phorbol ester via the ERK/c-Jun signaling pathway

“…Ohashi Abbreviations: AKR, aldo-keto reductase; TPA, 12-O-tetradecanoyl phorbol 13-acetate; PKC, protein kinase C; cPKC, conventional PKC; nPKC, novel PKC; aPKC, atypical PKC; ERK, extracellular signal regulate kinase; SPAK/JNK, stress-activated kinase/c-Jun N-terminal kinase. 78 inhibited tumor proliferation [12]. The expression of AKR1B10 was 79 significantly lower in gastric cancer than in paired, normal mucosa 80 [13].…”