From the Departments of Cancer Biology and Pathology, Beckman Research Institute, City of Hope, Duarte, California 91010.
From the Departments of Cancer Biology and Pathology, Beckman Research Institute, City of Hope, Duarte, California 91010; the Department of Urology and Stanford University School of Medicine, Stanford, California 94305.
J Biol Chem. 2018 Dec 28;293(52):20123-20136. doi: 10.1074/jbc.RA118.005395. Epub 2018 Nov 6.
Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. Whereas up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional transgenic mouse strain, , to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred compound mice, in which transgenic expression and deletion of the tumor suppressor gene occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from compound mice compared with those from littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both transgene expression and deletion compared with null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors.
越来越多的证据表明，肝细胞生长因子（HGF）及其受体，原癌基因 MET 酪氨酸激酶（MET），可促进细胞增殖、运动、形态发生和血管生成。虽然在侵袭性和转移性前列腺癌中观察到 MET 表达上调，但 MET 在前列腺肿瘤发生中的功能仍不清楚。在这里，我们开发了一种条件性转基因小鼠品系 ，以模拟人前列腺癌细胞中在前列腺腔上皮细胞中高表达的 MET。我们发现这些小鼠在给予 HGF 后会发展为前列腺上皮内瘤变。为了进一步评估 MET 在前列腺癌进展中的生物学作用，我们繁殖了 复合小鼠，其中转基因 的表达和肿瘤抑制基因 的缺失仅同时发生在前列腺上皮细胞中。与 小鼠相比，这些复合小鼠表现出加速的前列腺肿瘤形成和侵袭以及增加的转移。此外，在复合小鼠的肿瘤病变中还出现了前列腺肉瘤样癌和类似于上皮-间质转化的病变。RNA-Seq 和 qRT-PCR 分析显示，与 同窝对照相比，从 复合小鼠中分离的样本中，已知的肿瘤进展和促进转移的基因明显富集。与 null MEFs 相比，在具有 转基因表达和 缺失的动物的小鼠胚胎成纤维细胞（MEFs）中，HGF 诱导的细胞增殖和迁移也增加。这些新开发的小鼠模型的结果表明，当与肿瘤抑制因子丢失结合时，MET 在加速肿瘤发生和转移中起作用。
