Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11.
A novel 1-cM (1.8 Mb) homozygous deletion (HD) on 13q12.11 was identified in a human hepatocellular carcinoma (HCC) cell line, SK-Hep-1, after high-density genetic marker scan and Southern blotting analysis. A loss of heterozygosity (LOH) analysis indicated that LOH frequency of the HD region in 48 pairs of HCC tissues was 52%. Interestingly, the occurrence of LOH in the 13q12.11 HD region is significantly associated with early-onset HCC, inferred from Fisher's exact test (P = 0.0047) and Mann-Whitney test (P = 0.023). Since the novel 1-cM (1.8 Mb) HD region is gene-rich with more than 37 predicted transcripts, we used a candidate gene approach by examining down-regulation of known tumor suppressor genes (TSGs), including LATS2, TG737, CRYL1, and GJB2, in HCC tissues. We detected only 14% down-regulation of the LAST2 gene that flanks the outside of the HD, in HCC tissues, by quantitative RT-PCR assays. However, we observed significant down-regulation of the TG737, CRYL1, and GJB2 genes located within the HD in 59, 64, and 71% of HCC tissues, respectively. Together, our results indicated that the identified 13q12.11 HD region contained at least three significant down-regulated TSGs, and preferential LOH in early-onset HCC patients is a putative tumor suppressor locus in HCC.
Chen
Chian-Feng
CF
Graduate Institute of Life Sciences, National Defense Medical Center, National Defense University Taipei, Taiwan.
Yeh
Shiou-Hwei
SH
Chen
Ding-Shinn
DS
Chen
Pei-Jer
PJ
Jou
Yuh-Shan
YS
D000368:Aged; D015139:Blotting, Southern; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002872:Chromosome Deletion; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D000072259:Connexin 26; D017630:Connexins; D016147:Genes, Tumor Suppressor; D006720:Homozygote; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26