J Dis Mod & Mechan：p53在前列腺癌发展中的重要作用

近日，来自加州大学戴维斯分校的研究者发现了一种遗传突变在前列腺癌的发展过程中扮演着重要角色，以前研究揭示在晚期疾病的发展中会出现p53的突变，但是现在p53绝对不会扮演起始因子的作用了，研究者的这项研究为诊断和治疗疾病开辟了一片新天地。

这项研究成果刊登在了国际著名杂志The Journal Disease Models & Mechanisms上，研究者Alexander表示，我们的研究小组发现了前列腺癌的分子途径，改变了当前对于疾病发展认识的常规想法。前列腺癌是美国男性主要诊断出的癌症之一，尽管局部患病的男性中有80%可以痊愈，但是如果癌症散布到了所有前列腺组织上时，治愈的比例就相当低了。

研究者构建了携带有p53突变的前列腺细胞的小鼠模型，这种小鼠相比p53未突变的小鼠而言更容易发展成前列腺癌，这首次揭示了p53的突变可以作为前列腺癌诊断的标准之一。研究者表示前列腺中p53的突变和p53缺失或者敲除不一样，这就表明这种分子机制并不仅仅是肿瘤抑制因子的缺失所导致的。

p53基因编码的蛋白可以抑制肿瘤的发生，可以组织DNA损伤的细胞进行分裂增殖。由于化学物质、辐射或者病毒引发的p53突变可以使得细胞分裂失控。因此p53的突变也涉及其它癌症如乳腺癌、肺癌等的早期诊断。其它研究结果涉及了前列腺癌p53的突变所引发的疾病恶化，但是研究者的这项研究首次揭示了p53在早起前列腺癌中所扮演的角色。

研究者目前正在试图去设计新的基于p53作为突变的标志物的新的诊断前列腺癌的方法，理解前列腺癌可以通过p53的突变来恶化对于研究者开发新的疗法可以提供一些线索。

编译自：Discovery alters traditional view of how prostate cancer develops

编译者：T.Shen

doi:10.1242/dmm.008995
PMC:
PMID:

Evidence for an alternate molecular progression in prostate cancer

Ruth L. Vinall, Jane Q. Chen, Neil E. Hubbard, Shola S. Sulaimon, Ralph W. DeVere White and Alexander D. Borowsky*

Tp53 mutations are common in prostate cancer (CaP), occurring with a frequency of ~30% and ~70% in localized and metastatic disease respectively. In vitro studies have determined several common mutations of Tp53 that have specific gain of function properties in addition to loss of function, including the ability to promote castrate resistant growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by p53 mutations in mediating CaP progression in vivo. Here we describe the effects of conditional expression of a mutant p53 that is equivalent to the human hotspot R273H into the prostate epithelium of mice. Heterozygous 'p53LSL.R270H/+' (129S4(Trp53tm3Tyj);Nkx3.1cre' (129S(Nkx3-1tm3CreMms) mice with prostate-specific expressionof the p53.R270H mutation (p53R270H/+ Nkx3.1cre mice) bred on to a FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53tm3Tyj/wt);FVB.129S(Nkx3-1tm3CreMms/wt) and littermate genotype negative control mice. These mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions that appeared earlier compared to the Nkx3.1 haploinsufficient (Nkx3.1cre het) littermate mice that did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression, and invasive adenocarcinoma that evolved into a high grade, sarcomatoid or epithelial-mesenchymal transition (EMT) phenotype. PIN lesions were similar to those seen in PTEN conditional knockout mice, with evidence of AKT activation concomitant with neoplastic proliferation. Meanwhile, the invasive tumor phenotype was unlike any previously described mouse model of prostatic neoplasia. These data indicate the p53R270H mutation plays a role in CaP initiation. This finding has not previously been reported. Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insights into the mechanisms by which the p53R270H mutation mediates CaP progression.