Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.
Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.
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Klf5 缺失通过多种致癌信号通路促进 Pten 缺失引发的管腔型小鼠前列腺肿瘤。
DOI：
10.1016/j.neo.2014.09.006
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发表时间：
2014-11
期刊：
影响因子：
4.8
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
--
作者：
Xing, Changsheng;Ci, Xinpei;Sun, Xiaodong;Fu, Xiaoying;Zhang, Zhiqian;Dong, Eric N.;Hao, Zhao-Zhe;Dong, Jin-Tang
Krüppel样因子5（KLF 5）调节多种生物学过程。然而，它在肿瘤发生中的功能似乎是矛盾的，既表现出抑癌活性，又表现出促癌活性。在这项研究中，我们研究了Klf 5是否以及如何在前列腺肿瘤发生中发挥作用，使用前列腺特异性缺失Klf 5和磷酸酶和张力蛋白同源物（Pten）的小鼠，这两者在人类前列腺癌中经常失活。组织学分析表明，当一个Pten等位基因缺失时，其导致小鼠前列腺上皮内瘤变（mPIN），Klf 5缺失加速mPIN的出现和进展。当两个Pten等位基因都缺失时，这会导致前列腺癌，Klf 5缺失会促进肿瘤生长，增加细胞增殖，并导致更严重的形态和分子改变。Klf 5基因纯合性缺失比半合性缺失更有效。出乎意料的是，虽然如所报道的那样，单独的Pten缺失扩增了肿瘤中的基底细胞群体，但Pten无效背景中的Klf 5缺失明显降低了基底细胞群体，同时扩增了管腔细胞群体。全球基因表达谱分析、通路分析和实验验证表明，多种机制可以介导Klf 5缺失的促肿瘤效应，包括表皮生长因子及其下游信号分子AKT和ERK的上调以及p15细胞周期抑制剂的失活。KLF 5还与CREB 1、Sp1、Myc、ER和AR等多种转录因子协同调控基因表达。这些发现证实了KLF 5的肿瘤抑制功能。他们还产生了一个小鼠模型，该模型与人类前列腺癌有两个共同的遗传改变-Pten突变/缺失和Klf 5缺失。
Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer—mutation/deletion of Pten and deletion of Klf5.
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DOI：
10.3109/10799893.2012.695798
发表时间：
2012-08
期刊：
Journal of receptor and signal transduction research
影响因子：
--
作者：
Chetram MA;Hinton CV
通讯作者：
Hinton CV
影响因子：
6.4
作者：
Chen, Ceshi;Zhou, Zhongmei;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
--
作者：
Byrne, Jennifer A;Chen, Yuyan;Peters, Gregory B
通讯作者：
Peters, Gregory B
影响因子：
4
作者：
Culig, Zoran;Bartsch, Georg
通讯作者：
Bartsch, Georg
影响因子：
50.3
作者：
Choi N;Zhang B;Zhang L;Ittmann M;Xin L
通讯作者：
Xin L