A novel growth suppressor gene on chromosome 17p13.3 with a high frequencyof mutation in human hepatocellular carcinoma

Previous studies have shown that there is a high frequency of loss of heter ozygosity (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. Pia o et al, Int. J. Cancer, 75: 29-33, 1998; and B. Charroux et al, J. Cell Bi ol., 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. M oreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 o f 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Y i. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Z hang, 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 characteriza tion of one of these novel genes, designated HCC suppressor 1 (HCCS1), loca ted 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. HCCS 1 had a high frequency of mutations in HCC samples, whereas no alteration h as been found in matched noncancerous liver tissues. Immunohistochemistry r evealed a significantly higher expression of HCCS1 in the noncancerous live r tissues 33 of 35 samples) than in the HCC samples (2 of 35 samples). Tran sfection of HCCS1 cDNA into the HCC cell line remarkably reduced the effici ency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a H CC putative suppressor gene.