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


CONCLUSIONS
Taken together, our findings suggest that TAT plays an important suppressive role in the development and progression of HCC.
Fu
Li
L
State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
Dong
Sui-Sui
SS
Xie
Yi-Wu
YW
Tai
Lai-Shan
LS
Chen
Leilei
L
Kong
Kar Lok
KL
Man
Kwan
K
Xie
Dan
D
Li
Yan
Y
Cheng
Yingduan
Y
Tao
Qian
Q
Guan
Xin-Yuan
XY
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D053453:Caspase 9 / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D018899:CpG Islands; D045304:Cytochromes c / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D004789:Enzyme Activation; D017353:Gene Deletion; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000494:pharmacology; D014444:Tyrosine Transaminase / Q000235:genetics*
D034741:RNA, Small Interfering; D045304:Cytochromes c; D014444:Tyrosine Transaminase; D053453:Caspase 9