Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells.
Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells.
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发表时间：
1993-05
期刊：
影响因子：
8
通讯作者：
Z. Su;V. Austin;S. Zimmer;P. Fisher
中科院分区：
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作者：
Z. Su;V. Austin;S. Zimmer;P. Fisher
癌变需要一系列复杂的基因变化，通常涉及多个致癌基因和多个肿瘤抑制基因的失活。我们目前研究了Krev-1肿瘤抑制基因对ha -ras转化的克隆大鼠胚胎成纤维细胞（CREF）的致瘤性和转移潜力的影响。ha -ras转化的CREF细胞在形态上发生了转化，并且与锚定无关；与CREF细胞相比，nm23-H1（一种假定的转移抑制基因产物）和TIMP-1（金属蛋白酶1的组织抑制剂）转录物和mRNA的水平降低；与CREF细胞相比，产生更高水平的加密蛋白、94-kDa明胶酶/ IV型胶原酶（94-kDa GEL）、骨桥蛋白（OPN）、转蛋白/基质溶解素转录物和mRNA；在裸鼠和同基因大鼠中均具有致瘤性和转移性。共表达Krev-1基因的ha -ras转化的CREF细胞在细胞表型和基因表达方面与未转化的CREF细胞表现出逆转。然而，Ha-ras/Krev-1共表达的CREF细胞保留了致瘤和转移潜能，尽管潜伏期延长，但这与Ha-ras或Krev-1 mRNA或Ha-ras p21转化蛋白的最终水平没有直接关系。然而，转移潜能的发展与nm23-H1和TIMP-1转录和mRNA水平的降低以及cripto、94-kDa GEL、骨桥蛋白和transin的表达增强直接相关。相比之下，其他肿瘤抑制基因的表达，如RB基因和p53，或其他模型系统中与肿瘤发生相关的基因，如主要分泌糖蛋白（MEP）、72-kDa明胶酶/ IV型胶原酶（72-kDa GEL）、纤维连接蛋白（FIB）、tenascin和细胞内粘附分子1 (ICAM-1)，在体外转化抑制或逃避致瘤性和转移性抑制过程中，并没有以一致的方式改变。这些结果表明，Krev-1对ha -ras转化/致癌表型的抑制与特定的致癌抑制和致癌诱导基因的转录率和稳态mRNA水平的改变所表现的基因表达变化有关。这些数据支持ha -ras诱导的CREF细胞转移模型，该模型涉及在肿瘤进展过程中协调调节的致癌抑制基因和促进转移基因的特定组合的表达/抑制的直接调节。
Carcinogenesis requires a complex series of genetic changes often involving multiple oncogenes and the inactivation of multiple tumor-suppressor genes. We presently examined the effect of the Krev-1 tumor-suppressor gene on the tumorigenic and metastatic potential of Ha-ras-transformed cloned rat embryo fibroblast (CREF) cells. Ha-ras-transformed CREF cells are morphologically transformed and anchorage independent; produce reduced levels of nm23-H1 (a putative metastasis-suppressor gene product) and TIMP-1 (tissue inhibitor of metalloproteinase 1) transcripts and mRNA compared with CREF cells; produce increased levels of cripto, 94-kDa gelatinase/type IV collagenase (94-kDa GEL), osteopontin (OPN) and transin/stromelysin transcripts and mRNA compared with CREF cells; and are tumorigenic and metastatic in both nude mice and syngeneic rats. Ha-ras-transformed CREF cells coexpressing the Krev-1 gene display a reversion in cellular phenotype and gene expression to that of untransformed CREF cells. However, Ha-ras/Krev-1-coexpressing CREF cells retain, albeit with extended latency periods, both tumorigenic and metastatic potential that is not related directly to the final level of Ha-ras or Krev-1 mRNA or the Ha-ras p21 transforming protein. Development of metastatic potential is, however, directly correlated with a reduction in nm23-H1 and TIMP-1 transcription and mRNA levels and an enhanced expression of cripto, 94-kDa GEL, osteopontin and transin. In contrast, expression of additional tumor-suppressor genes, such as the RB gene and p53, or genes associated with tumorigenesis in other model systems, such as major excreted glycoprotein (MEP), 72-kDa gelatinase/type IV collagenase (72-kDa GEL), fibronectin (FIB), tenascin and intracellular adhesion molecule 1 (ICAM-1) is not altered in a consistent manner during in vitro transformation suppression or escape from tumorigenic and metastatic suppression. These results indicate that Krev-1 suppression of the Ha-ras-transformed/oncogenic phenotype is associated with a distinct program of gene expression changes manifested by altered rates of transcription and steady-state mRNA levels of specific oncogenic-suppressing and oncogenic-inducing genes. These data support a model of Ha-ras-induced metastasis in CREF cells that involves a direct modulation in the expression/suppression of specific combinations of oncogenic-suppressor genes and metastasis-promoting genes that are regulated coordinately in the process of tumor progression.