Lehman T A, Reddel R, Peiifer A M, Spillare E, Kaighn M E, Weston A, Gerwin B I, Harris C C
Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892.
Environ Health Perspect. 1991 Jun;93:133-44. doi: 10.1289/ehp.9193133.
The functional role of oncogenes in human lung carcinogenesis has been investigated by transfer of activated oncogenes into normal cells or an immortalized bronchial epithelial cell line, BEAS-2B. Transfection of v-Ha-ras, Ki-ras, or the combination of myc and raf into BEAS-2B cells produced tumorigenic cell lines, while transfection of raf or myc alone produced nontumorigenic cell lines. In addition to studying the pathogenic role of oncogenes, we are attempting to define negative growth-regulating genes that have tumor-suppressive effects for human lung carcinomas. Our strategy to identify tumor-suppressor genes involves loss of heterozygosity studies, monochromosome-cell fusion, and cell-cell fusion studies. Loss of heterozygosity studies have revealed consistent allelic DNA sequence deletions on chromosome 17p in squamous cell carcinomas, while large cell carcinomas and adenocarcinomas retained this locus. Mutations in p53, a tumor-suppressor gene located on chromosome 17p, have been observed. Cell-cell hybrid clones produced from fusion of nontumorigenic BEAS-2B cells with tumorigenic HuT292DM cells generally are nontumorigenic. The mechanistic role of the known tumor-suppressor genes Rb-1 and p53 in the development of human lung carcinomas is being investigated in this epithelial cell model of human bronchogenic carcinogenesis.
通过将活化的癌基因导入正常细胞或永生化支气管上皮细胞系BEAS-2B，研究了癌基因在人类肺癌发生中的功能作用。将v-Ha-ras、Ki-ras或myc与raf的组合转染到BEAS-2B细胞中可产生致瘤细胞系，而单独转染raf或myc则产生非致瘤细胞系。除了研究癌基因的致病作用外，我们还试图确定对人类肺癌具有肿瘤抑制作用的负性生长调节基因。我们鉴定肿瘤抑制基因的策略包括杂合性缺失研究、单染色体细胞融合和细胞-细胞融合研究。杂合性缺失研究显示，鳞状细胞癌中17号染色体短臂存在一致的等位基因DNA序列缺失，而大细胞癌和腺癌保留了该位点。已观察到位于17号染色体短臂上的肿瘤抑制基因p53发生突变。由非致瘤性BEAS-2B细胞与致瘤性HuT292DM细胞融合产生的细胞-细胞杂交克隆通常是非致瘤性的。在这种人类支气管源性癌发生的上皮细胞模型中，正在研究已知的肿瘤抑制基因Rb-1和p53在人类肺癌发生中的机制作用。
