Turley Ryan S, Finger Elizabeth C, Hempel Nadine, How Tam, Fields Timothy A, Blobe Gerard C
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Cancer Res. 2007 Feb 1;67(3):1090-8. doi: 10.1158/0008-5472.CAN-06-3117.
The transforming growth factor-beta (TGF-beta) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-beta. Although the loss of expression of either the type I (TbetaRI) or type II (TbetaRII) TGF-beta receptor has been documented in approximately 30% of prostate cancers, most prostate cancers become TGF-beta resistant without mutation or deletion of TbetaRI, TbetaRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-beta receptor (TbetaRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TbetaRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TbetaRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TbetaRIII promoter. Functionally, restoring TbetaRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TbetaRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity.
转化生长因子-β（TGF-β）信号通路在调节正常前列腺上皮、抑制增殖、分化以及雄激素剥夺诱导的和雄激素非依赖性凋亡中起重要作用。在前列腺癌形成过程中，大多数前列腺癌细胞对TGF-β的这些稳态效应产生抗性。尽管在大约30%的前列腺癌中已记录到I型（TβRI）或II型（TβRII）TGF-β受体表达缺失，但大多数前列腺癌在未发生TβRI、TβRII或Smad2、3和4的突变或缺失的情况下就对TGF-β产生抗性，因此，抗性机制仍有待确定。在这里，我们表明，与良性前列腺组织相比，在大多数人类前列腺癌中，III型TGF-β受体（TβRIII或β聚糖）在mRNA和蛋白质水平上的表达均降低或缺失。TβRIII表达缺失与肿瘤分期进展以及前列腺特异性抗原（PSA）复发的较高可能性相关，提示其在前列腺癌进展中起作用。TβRIII表达缺失是由TGFBR3基因组位点的杂合性缺失和TβRIII启动子的表观遗传调控介导的。在功能上，在前列腺癌细胞中恢复TβRIII表达可有效降低细胞运动性和通过基质胶的体外细胞侵袭能力以及体内前列腺肿瘤发生能力。综上所述，这些研究将TβRIII表达缺失定义为人类前列腺癌中的常见事件，并表明这种缺失通过对细胞运动性、侵袭性和肿瘤发生能力的影响对前列腺癌进展具有重要意义。
