近日,，來自加州大學(xué)戴維斯分校的研究者發(fā)現(xiàn)了一種遺傳突變在前列腺癌的發(fā)展過程中扮演著重要角色,，以前研究揭示在晚期疾病的發(fā)展中會出現(xiàn)p53的突變，但是現(xiàn)在p53絕對不會扮演起始因子的作用了,，研究者的這項研究為診斷和治療疾病開辟了一片新天地,。
這項研究成果刊登在了國際著名雜志The Journal Disease Models & Mechanisms上，研究者Alexander表示,，我們的研究小組發(fā)現(xiàn)了前列腺癌的分子途徑,，改變了當(dāng)前對于疾病發(fā)展認(rèn)識的常規(guī)想法,。前列腺癌是美國男性主要診斷出的癌癥之一,，盡管局部患病的男性中有80%可以痊愈,，但是如果癌癥散布到了所有前列腺組織上時，治愈的比例就相當(dāng)?shù)土恕?/p>
研究者構(gòu)建了攜帶有p53突變的前列腺細(xì)胞的小鼠模型,，這種小鼠相比p53未突變的小鼠而言更容易發(fā)展成前列腺癌,，這首次揭示了p53的突變可以作為前列腺癌診斷的標(biāo)準(zhǔn)之一,。研究者表示前列腺中p53的突變和p53缺失或者敲除不一樣,，這就表明這種分子機(jī)制并不僅僅是腫瘤抑制因子的缺失所導(dǎo)致的。
p53基因編碼的蛋白可以抑制腫瘤的發(fā)生,，可以組織DNA損傷的細(xì)胞進(jìn)行分裂增殖,。由于化學(xué)物質(zhì),、輻射或者病毒引發(fā)的p53突變可以使得細(xì)胞分裂失控。因此p53的突變也涉及其它癌癥如乳腺癌,、肺癌等的早期診斷,。其它研究結(jié)果涉及了前列腺癌p53的突變所引發(fā)的疾病惡化，但是研究者的這項研究首次揭示了p53在早起前列腺癌中所扮演的角色,。
研究者目前正在試圖去設(shè)計新的基于p53作為突變的標(biāo)志物的新的診斷前列腺癌的方法,，理解前列腺癌可以通過p53的突變來惡化對于研究者開發(fā)新的療法可以提供一些線索。（生物谷Bioon.com）
編譯自：Discovery alters traditional view of how prostate cancer develops
編譯者：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.
