Ko Jesang, Lee Young Han, Hwang Seung Yong, Lee Youn Soo, Shin Seung Min, Hwang Jae Hoon, Kim Jin, Kim Yong Wook, Jang Sung-Wuk, Ryoo Zae Young, Kim In-Kyung, Namkoong Sung Eun, Kim Jin Woo
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
Oncogene. 2003 Jul 24;22(30):4679-89. doi: 10.1038/sj.onc.1206624.
Basic studies of oncogenesis have demonstrated that either the elevated production of particular oncogene proteins or the occurrence of qualitative abnormalities in oncogenes can contribute to neoplastic cellular transformation. The purpose of this study was to identify unique oncogenes that are differentially expressed in human cancers and characterize their functions in tumorigenesis. To discover new putative oncogenes, the differential display RT-PCR method was applied using normal cervical tissues, cervical cancer cell lines, cervical cancer tissues, and metastatic tissues. We identified a new human cervical cancer oncogene HCCR-2 that was overexpressed in various human tumors including leukemia, lymphoma, and carcinomas of the breast, kidney, ovary, stomach, colon, and uterine cervix. Ectopic expression of HCCR-2 resulted in direct tumorigenic conversions of NIH/3T3 and Rat1 fibroblasts. Nude mice injected with NIH/3T3 cells stably transfected with HCCR-2 formed tumors in 4 weeks. The resultant tumors display characteristics of an epithelial carcinoma. In HCCR-2 transfected NCI-H460 cells and RKO cells, stabilization of the p53 tumor suppressor occurred without genetic mutation and correlated with functional impairment, as indicated by the defective induction of p53-induced p21(WAF1), MDM2, and bax. These results indicate that HCCR-2 probably represents a new oncogene that is related to tumorigenesis, functioning as a negative regulator of the p53 tumor suppressor.
肿瘤发生的基础研究表明，特定癌基因蛋白产量的升高或癌基因中定性异常的出现都可能导致肿瘤细胞转化。本研究的目的是鉴定在人类癌症中差异表达的独特癌基因，并表征它们在肿瘤发生中的功能。为了发现新的潜在癌基因，我们应用差异显示逆转录聚合酶链反应（RT-PCR）方法，使用正常宫颈组织、宫颈癌细胞系、宫颈癌组织和转移组织。我们鉴定出一种新的人类宫颈癌癌基因HCCR-2，它在包括白血病、淋巴瘤以及乳腺癌、肾癌、卵巢癌、胃癌、结肠癌和宫颈癌在内的多种人类肿瘤中过表达。HCCR-2的异位表达导致NIH/3T3和Rat1成纤维细胞直接发生致瘤转化。注射了稳定转染HCCR-2的NIH/3T3细胞的裸鼠在4周内形成肿瘤。所形成的肿瘤表现出上皮癌的特征。在转染了HCCR-2的NCI-H460细胞和RKO细胞中，p53肿瘤抑制因子发生稳定化，但没有基因突变，并且与功能受损相关，这表现为p53诱导的p21（WAF1）、MDM2和bax的诱导缺陷。这些结果表明，HCCR-2可能代表一种与肿瘤发生相关的新癌基因，作为p53肿瘤抑制因子的负调节因子发挥作用。
