Authors' Affiliations: Departments of Cancer Biology, Medical Oncology, and Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Cancer Res. 2014 Jan 15;74(2):508-19. doi: 10.1158/0008-5472.CAN-13-1313. Epub 2013 Nov 26.
Improved clinical management of prostate cancer has been impeded by an inadequate understanding of molecular genetic elements governing tumor progression. Gene signatures have provided improved prognostic indicators of human prostate cancer. The TGF-β/BMP-SMAD4 signaling pathway, which induces epithelial-mesenchymal transition (EMT), is known to constrain prostate cancer progression induced by Pten deletion. Herein, cyclin D1 inactivation reduced cellular proliferation in the murine prostate in vivo and in isogenic oncogene-transformed prostate cancer cell lines. The in vivo cyclin D1-mediated molecular signature predicted poor outcome of recurrence-free survival for patients with prostate cancer (K-means HR, 3.75, P = 0.02) and demonstrated that endogenous cyclin D1 restrains TGF-β, Snail, Twist, and Goosecoid signaling. Endogenous cyclin D1 enhanced Wnt and ES cell gene expression and expanded a prostate stem cell population. In chromatin immunoprecipitation sequencing, cyclin D1 occupied genes governing stem cell expansion and induced their transcription. The coordination of EMT restraining and stem cell expanding gene expression by cyclin D1 in the prostate may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer.
对控制肿瘤进展的分子遗传因素缺乏充分了解，阻碍了前列腺癌的临床治疗。基因特征为人类前列腺癌提供了更好的预后指标。TGF-β/BMP-SMAD4 信号通路可诱导上皮-间充质转化（EMT），已知其可抑制 Pten 缺失诱导的前列腺癌进展。本文中，细胞周期蛋白 D1 的失活减少了体内小鼠前列腺和同种致癌基因转化的前列腺癌细胞系中的细胞增殖。体内的细胞周期蛋白 D1 介导的分子特征预测了前列腺癌患者无复发生存率的不良预后（K-means HR，3.75，P=0.02），并表明内源性细胞周期蛋白 D1 抑制 TGF-β、Snail、Twist 和 Goosecoid 信号。内源性细胞周期蛋白 D1 增强了 Wnt 和胚胎干细胞基因的表达，并扩大了前列腺干细胞群体。在染色质免疫沉淀测序中，细胞周期蛋白 D1 占据了控制干细胞扩增的基因，并诱导其转录。细胞周期蛋白 D1 在前列腺中对 EMT 抑制和干细胞扩增基因表达的协调可能有助于其对人类前列腺癌生化无复发生存不良预后的强预后价值。
