The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells.
The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells.
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DOI：
10.18632/oncotarget.8301
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Beischlag TV
中科院分区：
文献类型：
--
作者：
Labrecque MP;Takhar MK;Nason R;Santacruz S;Tam KJ;Massah S;Haegert A;Bell RH;Altamirano-Dimas M;Collins CC;Lee FJ;Prefontaine GG;Cox ME;Beischlag TV
肿瘤抑制蛋白（如视网膜母细胞瘤蛋白（Rb））的缺失导致肿瘤进展和转移。通过缺氧诱导因子（HIF）检测到的肿瘤内的低氧可用性促进了转移。HIF 1 α和二聚化配偶体芳烃受体核转运蛋白（ARNT）的复合物HIF 1是低氧反应的主要调节剂。以前，我们证明，Rb抑制缺氧的转录反应凭借其与HIF 1。在这份报告中，我们进一步的特点Rb在介导缺氧调节的遗传程序中发挥的作用，通过稳定消融Rb表达与逆转录病毒引入短发夹RNA在LNCaP和22Rv1人前列腺癌细胞。DNA微阵列分析表明，Rb基因的缺失与缺氧导致缺氧调节的基因程序的异常表达，增加细胞侵袭和促进神经内分泌分化。这是第一次，我们已经建立了一个直接联系之间的缺氧肿瘤环境，Rb失活和进展到晚期转移性神经内分泌前列腺癌。了解良性前列腺肿瘤进展为转移和致命形式的分子途径将有助于开发更有效的前列腺癌治疗方法。
Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.
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DOI：
10.1073/pnas.94.17.9040
发表时间：
1997-08-19
影响因子：
11.1
作者：
Chang, KH;Chen, YM;Lee, WH
通讯作者：
Lee, WH
影响因子：
2.8
作者：
Ghafar, MA;Anastasiadis, AG;Buttyan, R
通讯作者：
Buttyan, R
DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
影响因子：
4.8
作者：
Gilkes, Daniele M.;Bajpai, Saumendra;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
2.9
作者：
Cangul H
通讯作者：
Cangul H