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A Novel Growth Suppressor Gene on Chromosome 17p13.3 with a High Frequency of Mutation in Human Hepatocellular Carcinoma¹

National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai 200032 [X. Z., J. L., Y. H., F. L., L. F., J. G., R. Z., D. W., J. G.]; Shanghai GeneCore Bio Technologies Co., Ltd., Shanghai 200233 [Y. Y., M. H.]; Shanghai Research Center of Life Sciences, Shanghai 200031 [X. Z.]; Eastern Hepatobiliary Surgery Hospital, Shanghai 200433 [W. C., M. W.]; Qidong Liver Cancer Institute, Qidong 226200 [J. C., B. X.]; and Guangxi Cancer Institute, Guangxi 530021 [L. Z., N. Y.], China

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.

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