Jia Lin, Ren Jian-Min, Wang Yi-Ying, Zheng Yu, Zhang Hui, Zhang Qing, Kong Bei-Hua, Zheng Wen-Xin
Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University Jinan, Shandong, 250012, China ; Department of Pathology, University of Arizona College of Medicine Tucson, AZ, 85724, USA.
Department of Endocrinology, Qilu Hospital, Shandong University Jinan, Shandong, 250012, China.
Int J Clin Exp Pathol. 2014 Apr 15;7(5):2247-55. eCollection 2014.
To characterize the exact individual roles of gonadotropins on ovarian epithelial carcinogenesis, an earlier study showed that prohibitin was significantly up-regulated by luteinizing hormone (LH). To further clarify the role of prohibitin in ovarian carcinogenesis and its association with LH, herein we studied the expression of prohibitin in various ovarian tissues including different developmental stages of ovarian epithelial tumors.
A total of 135 samples were studied by immunohistochemistry. These included benign ovarian cases with follicles, ovarian surface epithelia and ovarian epithelial inclusions (OEI) (n=30), serous cystadenoma (n=14), serous borderline tumor (n=12), serous carcinoma (n=20), mucinous cystadenoma (n=10), mucinous borderline tumor (n=10), mucinous carcinomas (n=10), endometrioid carcinomas (n=12), poorly/undifferentiated carcinomas (n=5), and fallopian tube (n=12).
Strong and diffuse staining of prohibitin was detected in luteinized ovarian stromal cells, follicular cells, fallopian tube, and OEI with serous differentiation. A significantly higher prohibitin expression in luteinized stromal cells than in non-luteinized stromal cells was observed (P<.01). Within the ovarian epithelium, the level of prohibitin expression was basically negative in ovarian surface epithelia, but highly expressed in OEI. However, compared to the level of prohibitin expression in OEI, it showed a trend of gradual loss from benign ovarian tumors, to borderline tumors and to carcinomas (P<.0001). Compared to the serous tumors, epithelial tumors with mucinous differentiation showed a significant lower level of prohibitin (P<.0001). An inverse correlation was noted between prohibitin expression and cancer grade. It is interesting to note that a high prohibitin expression level was seen in the fallopian tube, which is similar to OEI.
These data further suggest that prohibitin plays a tumor suppressing role, which is probably associated with LH mediated protection role against ovarian epithelial carcinoma. In addition to the tumor suppressive role of prohibitin, it also plays a role in cellular differentiation, which may be helpful to differentiate ovarian mucinous tumors from the tumors with serous differentiation in clinical settings. More importantly, our findings are supportive that the ovarian epithelial cancers, particularly the serous cancers including those precursors with serous differentiation are likely to be derived from fallopian tube instead of ovarian surface epithelia.
为了明确促性腺激素在卵巢上皮癌发生过程中的确切个体作用，一项早期研究表明，黄体生成素（LH）可使抗增殖蛋白显著上调。为了进一步阐明抗增殖蛋白在卵巢癌发生中的作用及其与LH的关系，我们在此研究了抗增殖蛋白在包括卵巢上皮肿瘤不同发育阶段的各种卵巢组织中的表达。
通过免疫组织化学研究了总共135个样本。这些样本包括有卵泡的良性卵巢病例、卵巢表面上皮和卵巢上皮包涵体（OEI）（n = 30）、浆液性囊腺瘤（n = 14）、浆液性交界性肿瘤（n = 12）、浆液性癌（n = 20）、黏液性囊腺瘤（n = 10）、黏液性交界性肿瘤（n = 10）、黏液性癌（n = 10）、子宫内膜样癌（n = 12）、低分化/未分化癌（n = 5）以及输卵管（n = 12）。
在黄体化的卵巢基质细胞、卵泡细胞、输卵管以及具有浆液性分化的OEI中检测到抗增殖蛋白的强而弥漫性染色。观察到黄体化基质细胞中的抗增殖蛋白表达明显高于未黄体化基质细胞（P <.01）。在卵巢上皮内，抗增殖蛋白表达水平在卵巢表面上皮基本为阴性，但在OEI中高表达。然而，与OEI中的抗增殖蛋白表达水平相比，从良性卵巢肿瘤到交界性肿瘤再到癌，其呈现逐渐降低的趋势（P <.0001）。与浆液性肿瘤相比，具有黏液性分化的上皮性肿瘤的抗增殖蛋白水平显著更低（P <.0001）。抗增殖蛋白表达与癌症分级呈负相关。有趣的是，在输卵管中观察到高抗增殖蛋白表达水平，这与OEI相似。
这些数据进一步表明抗增殖蛋白发挥肿瘤抑制作用，这可能与LH介导的对卵巢上皮癌的保护作用相关。除了抗增殖蛋白的肿瘤抑制作用外，它还在细胞分化中起作用，这可能有助于在临床环境中将卵巢黏液性肿瘤与具有浆液性分化的肿瘤区分开来。更重要的是，我们的研究结果支持卵巢上皮癌，特别是包括那些具有浆液性分化的前体的浆液性癌，可能起源于输卵管而非卵巢表面上皮。
