Labrecque Mark P, Takhar Mandeep K, Nason Rebecca, Santacruz Stephanie, Tam Kevin J, Massah Shabnam, Haegert Anne, Bell Robert H, Altamirano-Dimas Manuel, Collins Colin C, Lee Frank J S, Prefontaine Gratien G, Cox Michael E, Beischlag Timothy V
The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Oncotarget. 2016 Apr 26;7(17):24284-302. doi: 10.18632/oncotarget.8301.
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.
肿瘤抑制蛋白的缺失，如视网膜母细胞瘤蛋白（Rb），会导致肿瘤进展和转移。肿瘤内低氧环境可促进转移，这种低氧环境由缺氧诱导因子（HIFs）检测到。HIF1复合物，即HIF1α及其二聚化伴侣芳烃受体核转运蛋白（ARNT），是缺氧反应的主要调节因子。此前，我们证明Rb通过与HIF1结合来抑制对缺氧的转录反应。在本报告中，我们通过用逆转录病毒导入的短发夹RNA在LNCaP和22Rv1人前列腺癌细胞中稳定敲除Rb表达，进一步表征了Rb在介导缺氧调节的基因程序中所起的作用。DNA微阵列分析显示，Rb缺失与缺氧共同导致缺氧调节的基因程序异常表达，增加细胞侵袭并促进神经内分泌分化。我们首次在缺氧的肿瘤环境、Rb失活与晚期转移性神经内分泌前列腺癌进展之间建立了直接联系。了解导致良性前列腺肿瘤发展为转移性和致命性肿瘤的分子途径，将有助于开发更有效的前列腺癌治疗方法。
