Down-regulation of tyrosine aminotransferase at a frequently deleted region 16q22 contributes to the pathogenesis of hepatocellular carcinoma

Abstract

Loss of 16q is one of the most frequent alterations in many malignancies including hepatocellular carcinomas (HCC), suggesting the existence of a tumor suppressor gene (TSG) within the frequently deleted region. In this report we describe the identification and characterization of one candidate TSG, tyrosine aminotransferase gene (TAT), at 16q22.1. Loss of one TAT allele was detected in 27/50 (54%) of primary HCCs by quantitative real-time polymerase chain reaction. In addition, homo-deletion of TAT alleles was detected in two cases. Down-regulation of TAT was detected in 28/50 (56%) of HCCs, which was significantly associated with the loss of TAT allele and hypermethylation of TAT 5 0 CpG island (CGI) region (P < 0.001). Functional studies found that TAT has a strong tumor suppressive ability. Introduction of the TAT gene into HCC cell lines could effectively inhibit colony formation in soft agar, foci formation, and tumor formation in nude mice. Further study found that the tumor suppressive mechanism of TAT was associated with its proapoptotic role in a mitochondrial-dependent manner by promoting cytochrome-c release and activating caspase-9 and PARP. Conclusion: Taken together, our findings suggest that TAT plays an important suppressive role in the development and progression of HCC.

Aneuploidy as a mechanism for stress-induced liver adaptation

“…On the one hand, hepatic aneuploidy could have pathological consequences. Aneuploidy has been extensively described in hepatocellular carcinoma (28)(29)(30), but it is unknown whether tumors arose from preexisting aneuploid hepatocytes or simply became aneuploid during tumorigenesis. It is intriguing that whole chromosome gains/losses were reported in dozens of lesions (28).…”

Small nucleolar RNA 113–1 suppresses tumorigenesis in hepatocellular carcinoma

“…In addition, other genes, including secreted phosphoprotein 1 (SPP1, osteopontin), fatty acid desaturase 2 (FADS2) and serine peptidase inhibitor kazal type 1(SPINK1), also have been reported to be associated with HCC progression [15–17]. Among the downregulated genes, TAT, JDP2, HSD17B13, CYP2B6 and PCK1 showed more than 30-fold decreased expression in HCC tumors, and all of these genes have been reported to be associated with HCC progression previously, except HSD17B13 [18–21]. The identification of these well-known HCC biomarkers suggested that the results of the array were reliable.…”

TATN-1 Mutations Reveal a Novel Role for Tyrosine as a Metabolic Signal That Influences Developmental Decisions and Longevity in Caenorhabditis elegans

“…Tyrosine aminotransferase has also been found to be a tumor suppressor gene in human hepatocellular carcinoma (HCC) [7]. The human tyrosine aminotransferase gene is located on 16q, which is frequently deleted in HCC, and analysis of tumors reveals that gene deletion or silencing via hypermethylation is common [7].…”

“…Specifically, in people elevated serum tyrosine levels occur with obesity and represent a risk factor for the development of diabetes [1]–[6]. Additionally, the enzyme tyrosine aminotransferase (TAT), which acts to normally convert tyrosine to energy, has been identified as a tumor suppressor gene which acts to promote apoptosis and prevent the development of hepatocellular carcinoma [7]. How changes in tyrosine metabolism could contribute to these disease processes is currently unknown, but it is possible that levels of this amino acid could play a direct regulatory role for the behavior of specific cells and tissues.…”