Zhao X, Li J, He Y, Lan F, Fu L, Guo J, Zhao R, Ye Y, He M, Chong W, Chen J, Zhang L, Yang N, Xu B, Wu M, Wan D, Gu J
National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai 200032, China.
Cancer Res. 2001 Oct 15;61(20):7383-7.
Previous studies have shown that there is a high frequency of loss of heterozygosity (LOH) on chromosome 17p13.3 in hepatocellular carcinoma [HCC (M. Fujimori et al., Cancer Res., 51: 89-93, 1991; H. Nagai et al., Oncogene, 14: 2927-2933, 1997; V. Boige et al., Cancer Res., 57: 1986-1990, 1997; Z. Piao et al., Int. J. Cancer, 75: 29-33, 1998; and B. Charroux et al., J. Cell Biol., 148: 1177-1186, 2000)]. The minimum region of LOH on chromosome 17p13.3 in HCC has been defined within the region between D17S643 and D17S1574. Moreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 of 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human HCC with densely clustered genes identified, submitted for publication). Here we describe the cloning and characterization of one of these novel genes, designated HCC suppressor 1 (HCCS1), located at this region. HCCS1 had 18 exons, and its full-length cDNA was 2.0 kb. The protein expression product of HCCS1 was located in mitochondria. HCCS1 had a high frequency of mutations in HCC samples, whereas no alteration has been found in matched noncancerous liver tissues. Immunohistochemistry revealed a significantly higher expression of HCCS1 in the noncancerous liver tissues (33 of 35 samples) than in the HCC samples (2 of 35 samples). Transfection of HCCS1 cDNA into the HCC cell line remarkably reduced the efficiency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a HCC putative suppressor gene.
先前的研究表明，在肝细胞癌中，17号染色体p13.3区域杂合性缺失（LOH）的频率很高[肝细胞癌（M. Fujimori等人，《癌症研究》，51: 89 - 93，1991；H. Nagai等人，《癌基因》，14: 2927 - 2933，1997；V. Boige等人，《癌症研究》，57: 1986 - 1990，1997；Z. Piao等人，《国际癌症杂志》，75: 29 - 33，1998；以及B. Charroux等人，《细胞生物学杂志》，148: 1177 - 1186，2000）]。肝细胞癌中17号染色体p13.3区域LOH的最小区域已被界定在D17S643和D17S1574之间的区域内。此外，LOH最小区域内的D17S926具有最高的LOH频率，并且已经完成了其测序分析。在该区域，13个新基因中的6个已被鉴定（X. Zhao、D. Wan、M. He、Yu. Ye、Yi. He、L. Han、M. Guo、Y. Huang、W. Qin、M - W. Wang、W. Chong、J. Chen、L. Zhang、N. Yang、B. Xu、M. Wu、L. Zuo和J. Gu。人类肝细胞癌17号染色体p13.3上高频LOH区域，有密集簇集基因被鉴定，已提交发表）。在此，我们描述了位于该区域的这些新基因之一、命名为肝癌抑制因子1（HCCS1）的克隆和鉴定。HCCS1有18个外显子，其全长cDNA为2.0 kb。HCCS1的蛋白质表达产物定位于线粒体。HCCS1在肝癌样本中具有较高的突变频率，而在匹配的非癌肝组织中未发现改变。免疫组织化学显示，HCCS1在非癌肝组织（35个样本中的33个）中的表达明显高于肝癌样本（35个样本中的2个）。将HCCS1 cDNA转染到肝癌细胞系中显著降低了其集落形成效率，并抑制了裸鼠体内的肿瘤生长。综上所述，这些发现强烈提示HCCS1作为一种潜在的肝癌抑制基因发挥作用。
