Fizazi Karim, Martinez Luis A, Sikes Charles R, Johnston Dennis A, Stephens L Clifton, McDonnell Timothy J, Logothetis Christopher J, Trapman Jon, Pisters Louis L, Ordoñez Nelson G, Troncoso Patricia, Navone Nora M
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2002 Mar;8(3):775-81.
The molecular events leading to progression toward androgen-independent prostate cancer (AIPC) are not fully understood. The p21((WAF-1/CIP1)) (p21) gene has been identified as a key factor for the regulation of cell growth. The expression of p21 was examined by immunohistochemical studies in 105 prostate cancer samples: (a) 7 of 30 (23%) androgen-dependent tumors; and (b) 36 of 75 (48%) androgen-independent tumors stained positive for p21 (P < 0.02). No association was found between p21 expression and p53, bcl-2, and the androgen receptor protein expression in bone metastases of patients with AIPC, whereas there was a significant association with a high Ki-67 index (P < 0.05). In 4 of 43 (9%) cases, tumors displayed a p53-negative, bcl-2-negative, and p21-positive phenotype. A xenograft mouse model of prostate cancer using the androgen-responsive MDA PCa 2b prostate cancer cell line was used to study p21 expression after androgen deprivation and at relapse. Androgen deprivation reduced p21 expression to undetectable levels after 14 days. Tumor relapse, defining AIPC, was associated with increased expression of p21 to levels comparable with those found before castration. In this model, p21 expression at relapse was also correlated with a high Ki-67 index. In conclusion, p21 expression is associated with the progression to AIPC. A possible explanation involves a paracrine effect of p21 mediated by the release of mitogenic and antiapoptotic factors. Another explanation involves the regulation of p21 expression by the androgen receptor, which also suggests that p21 may have antiapoptotic function in prostate cancer.
导致前列腺癌向雄激素非依赖性前列腺癌（AIPC）进展的分子事件尚未完全明确。p21（WAF-1/CIP1）（p21）基因已被确定为细胞生长调控的关键因子。通过免疫组织化学研究检测了105例前列腺癌样本中p21的表达情况：（a）30例雄激素依赖性肿瘤中有7例（23%）；（b）75例雄激素非依赖性肿瘤中有36例（48%）p21染色呈阳性（P<0.02）。在AIPC患者的骨转移灶中，未发现p21表达与p53、bcl-2及雄激素受体蛋白表达之间存在关联，而与高Ki-67指数存在显著关联（P<0.05）。在43例（9%）病例中的4例中，肿瘤表现出p53阴性、bcl-2阴性和p21阳性的表型。利用雄激素反应性MDA PCa 2b前列腺癌细胞系建立前列腺癌异种移植小鼠模型，研究雄激素剥夺后及复发时p21的表达情况。雄激素剥夺14天后，p21表达降至无法检测的水平。定义为AIPC的肿瘤复发与p21表达增加至去势前相当的水平相关。在该模型中，复发时p21的表达也与高Ki-67指数相关。总之，p21表达与向AIPC的进展相关。一种可能的解释涉及由促有丝分裂和抗凋亡因子释放介导的p21旁分泌效应。另一种解释涉及雄激素受体对p21表达的调节，这也表明p21在前列腺癌中可能具有抗凋亡功能。
