Daneshmand Siamak, Quek Marcus L, Lin Ed, Lee Charlotte, Cote Richard J, Hawes Debra, Cai Jie, Groshen Susan, Lieskovsky Gary, Skinner Donald G, Lee Amy S, Pinski Jacek
Section of Urologic Oncology, Division of Urology, Oregon Health & Science University, Portland, OR 97239, USA.
Hum Pathol. 2007 Oct;38(10):1547-52. doi: 10.1016/j.humpath.2007.03.014. Epub 2007 Jul 19.
Chemotherapy resistance is a significant contributor to treatment failure and death in men with hormone-refractory prostate cancer. One unexplored mechanism for drug resistance is the induction of stress response proteins referred to as the glucose-regulated proteins (GRPs). We sought to determine the level of expression of GRP78, the best characterized GRP in lymph node-positive prostate cancer. Archived, paraffin-embedded, radical prostatectomy specimens were obtained from 153 patients with lymph node-positive prostate cancer (stage D1). The level of GRP78 expression was determined by immunohistochemistry. We assessed the expression and specificity of GRP78 immunoreactivity in benign prostatic tissue, prostate cancer, and lymph node metastasis. We correlated the intensity of immunopositivity with prostate cancer recurrence and survival. Whereas immunohistochemical staining demonstrated that all prostate tissue was immunoreactive for GRP78, the intensity of expression was markedly higher in the primary tumor compared with areas of benign epithelium. GRP78 expression was also evident in lymph node metastases although less intensely than in the primary tumor. Patients with strong GRP78 immunoreactivity in the primary tumor are at higher risk for clinical recurrence (relative risk = 2.0, P = .019) and death (relative risk = 1.8, P = .024) than patients with weak GRP78 expression. This finding confirms that GRP78 protein expression is significantly higher in prostate cancer than in benign prostatic tissue. The intensity of expression is significantly associated with survival and clinical recurrence. GRP78 has considerable potential not only as a prognostic indicator but also as a potential therapeutic target.
化疗耐药是激素难治性前列腺癌男性患者治疗失败和死亡的一个重要原因。耐药的一种未被探索的机制是诱导应激反应蛋白，即葡萄糖调节蛋白（GRP）。我们试图确定GRP78在淋巴结阳性前列腺癌中最具特征的GRP的表达水平。从153例淋巴结阳性前列腺癌（D1期）患者中获取存档的石蜡包埋根治性前列腺切除术标本。通过免疫组织化学确定GRP78的表达水平。我们评估了GRP78免疫反应性在良性前列腺组织、前列腺癌和淋巴结转移中的表达及特异性。我们将免疫阳性强度与前列腺癌复发和生存情况进行关联分析。免疫组织化学染色显示所有前列腺组织对GRP78均有免疫反应性，但与良性上皮区域相比，原发性肿瘤中的表达强度明显更高。GRP78在淋巴结转移中也有表达，尽管强度低于原发性肿瘤。原发性肿瘤中GRP78免疫反应性强的患者比GRP78表达弱的患者临床复发风险更高（相对风险=2.0，P=0.019），死亡风险更高（相对风险=1.8，P=0.024）。这一发现证实前列腺癌中GRP78蛋白表达明显高于良性前列腺组织。表达强度与生存和临床复发显著相关。GRP78不仅作为一种预后指标具有相当大的潜力，而且作为一种潜在的治疗靶点也具有相当大的潜力。
