Roles of estrogen receptors and estrogen-responsive genes in the development of benign prostatic hyperplasia and prostate cancer

雌激素受体和雌激素反应基因在良性前列腺增生和前列腺癌发展中的作用

• 批准号: 14571485
• 负责人: TAKAHASHI Satoru
• 金额: $ 2.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571485/
• 关键词: estrogen receptors; estrogen-responsive genes; prostate canner; benign prostatis hypserplasia; EBAG9; RCAS1; ERBex; efp

We investigated expression of ERα, wild-type ERβ(wtERβ) and a C-terminal truncated splice variant of ERβ(ER,βex) in 50 benign and 100 malignant human prostatic tissue samples by immunohistochemistry. While strong immunostaining of ERα was consistently identitied in stioinal cmpartment, wtERβ was expressed in epithelial cells in both the benign and malignant foci. However, wtERβ expression was significantly lower in the cancers than in the benign epithellum, and inversely correlated with Gleason tumor gradle (p<0.0001 and p=0.0099, respectively). In contrast, ERβcx was significantly more expressed in the high grade cancers(83%), compared with the low grade tumors (22%) and the benign sites (11%)(p<0.0001,both). Cancer-specific survival of patients with lower wtERβ expression was significantly worse than those with higher expression of wtERβ(p=0.0018). Conversely, higher ER β expression significantly correlated with poor cancer-specific survival(p=0.0058). These results suggest that diff … More erential expression of wtERβ and ERI8 ex may be prognostic predictorss for prostatic cancer.Estrogen Receptor-binding Fragmentassocoiated Gene 9 (EBAG 9) has been identified as a primary estrogen-responsive gene from MCF-7 human breast cancer cells (Watanabe T, et al., Mol Cell Biol,1998; 18: 442-449). EBAGO is identical with RCAS1(Receptor-inding cancer antigen expressed on SiSo cells), Which has been reported as a cancer cell surface antigen implicated in immune escape (Nithashima M, et al., Nat Med, 1999; 5 938-942). In the present study, we examined EBAG9 expression in human prostatic tissues, and investigated its prognostic significance in patients with prostatic cancer. EBAG9 expression in normal prostatic epithelial cells and PC-3, DU145, LNCaP cancer cells was determined by Western blot analysis. Immunohistochemical analysis was performed in 21 benign and 81 malignant prostatic spocimens, and patients' charts were reviewed for clinical, pathological, and survival data. EBAG9 was abundantly expressed in the prostate cancer cells, compared with the normal epithelird cells. Strong mmdl (liffuse immunostaining in the cytoplasmn of EBAG9 was found in 44 of 81(54%) cancerous tissue samples, EBAG9 expression significantly correlated with advancedl 1)flthological stages and high Gleason score (p=0.030 and l < 0.0001, respectively). EBAG9 was more frequently expressed at sites of capsular penetration (79%) audI lymnph nodle metastasis (100%), coml)ared with intracapsular primary tumors (54%) (p0.02G4 and 0.0018, respectively). Positive EBAG9 immnunoreactivity significantly correlated with poor PSA failurefree survival (p=0.0059). EBAG9/RCAS1 may play a significant role in the cancer rogression via an immune escape system. Immunodletection of EBAG9/RCAS1 expression can be a negative progflostic indlicator for patients with prostatic cancer. Less

应用免疫组织化学方法检测了50例良性前列腺组织和100例恶性前列腺组织中ERα、野生型ERβ（wtERβ）和ER β C端截短剪接变异体（ER，βex）的表达。ERα在原发性乳腺癌中表达较强，而wtERβ在良性和恶性病灶的上皮细胞中均有表达。而wtERβ在乳腺癌中的表达明显低于乳腺良性上皮，并与Gleason分级呈负相关（分别为p<0.0001和p=0.0099）。ERβcx在高度恶性肿瘤中的表达率（83%）明显高于低度恶性肿瘤（22%）和良性肿瘤（11%）（P<0.0001）。wtERβ表达较低的患者的癌症特异性生存率显著低于wtERβ表达较高的患者（p=0.0018）。相反，ER β的高表达与癌症特异性生存率低显著相关（p=0.0058）。这些结果表明，差异 ...更多信息 雌激素受体结合片段相关基因9（EBAG 9）已被鉴定为来自MCF-7人乳腺癌细胞的主要雌激素应答基因（Watanabe T，et al.，分子细胞生物学，1998; 18：442-449）。EBAGO与RCAS 1（在SiSo细胞上表达的受体结合癌抗原）相同，RCAS 1已被报道为涉及免疫逃逸的癌细胞表面抗原（Nithashima M，et al.，Nat Med，1999; 5 938-942）。在本研究中，我们检测了EBAG 9在人前列腺组织中的表达，并探讨了其在前列腺癌患者中的预后意义。Western blot分析EBAG 9在正常前列腺上皮细胞和PC-3、DU 145、LNCaP癌细胞中的表达。对21例良性和81例恶性前列腺病灶进行免疫组织化学分析，并对患者的临床、病理和生存数据进行回顾。EBAG 9在前列腺癌细胞中的表达高于正常前列腺上皮细胞。在81例癌组织中，44例（54%）发现EBAG 9的胞质中存在强烈的mmdl免疫染色，EBAG 9的表达与晚期组织学分期和高Gleason评分显著相关（分别为p=0.030和p < 0.0001）。EBAG 9在包膜穿透部位（79%）和淋巴结转移部位（100%）表达更频繁，而在包膜内原发性肿瘤部位（54%）表达更频繁（分别为p <0.02G4和0.0018）。EBAG 9阳性免疫反应性与PSA无失败生存率显著相关（p=0.0059）。EBAG 9/RCAS 1可能通过免疫逃逸系统在癌症进展中发挥重要作用。EBAG 9/RCAS 1表达的免疫检测可作为前列腺癌患者的阴性化疗指标。少

项目成果

Takahashi S, Urano T, Tsuchiya F, Fujimura T, Kitamura T, Ouchi Y, Muramatsu M, Inoue.: "EBAG9/RCAS1 expression and its prognostic significance in prostatic cancer."Int.J.Cancer. 106. 310-315 (2003)

Takahashi S、Urano T、Tsuchiya F、Fujimura T、Kitamura T、Ouchi Y、Muramatsu M、Inoue.：“EBAG9/RCAS1 在前列腺癌中的表达及其预后意义。”Int.J.Cancer。

Satoru Takahashi, et al.: "EBAG9/RCAS1 expression and its prognostic significance in prostatic cancer"Int.J.Cancer. (in press). (2003)

Satoru Takahashi 等人：“EBAG9/RCAS1 在前列腺癌中的表达及其预后意义”Int.J.Cancer。

Takahashi S.Urano T, Tsuchiya F, Fujimura T, Kitamura T, Ouchi Y, Murarnatsu M, Inoue.: "EBAG9/RCAS1 expression and its prognostic significance in prostatic cancer."Int.J. Cancer. 106. 310-315 (2003)

Takahashi S.Urano T、Tsuchiya F、Fujimura T、Kitamura T、Ouchi Y、Murarnatsu M、Inoue.：“EBAG9/RCAS1 表达及其在前列腺癌中的预后意义。”Int.J.

Fujimura T, Takahashi S, Urano T, Ogawa, Ouchi Y, Kitamura T, Muramatsu M, Inoue S.: "Differential expression of estrogen receptorβ (ERβ) and its C-terminal truncated splice variant ERβcx as prognostic predictors in human prostatic cancer."Biochem.Biophys

Fujimura T、Takahashi S、Urano T、Okawa、Ouchi Y、Kitamura T、Muramatsu M、Inoue S.：“雌激素受体 β (ERβ) 及其 C 端截短剪接变体 ERβcx 的差异表达作为人类前列腺癌的预后预测因子。 ” “生物化学。

Fujimura T, Takahashi S.Urano T, Ogawa, Ouchi Y, IKliarnura T, Muramatsu M, Inoue S.: "Differential expression of estrogen receptorβ (ERβ) and its C-terminal truncated splice variant ER βex as prognostic predictors in human prostatic cancer."Biochem. Biop

Fujimura T、Takahashi S.Urano T、Okawa、Ouchi Y、IKliarnura T、Muramatsu M、Inoue S.：“雌激素受体 β (ERβ) 及其 C 端截短剪接变体 ERβex 的差异表达作为人类前列腺癌的预后预测因子。 “生物化学。Biop