- 學位論文
分泌型溶膠蛋白在前列腺癌可造成浸潤癌巢的淋巴球失能並引發細胞凋亡作用
Secreted gelsolin desensitizes infiltrating lymphocytes and induces their apoptosis in prostate cancer
摘要
研究目的：免疫監控系統的缺失是造成腫瘤細胞生長和擴展的主要原因之一。本研究的目的是在探討精液中的主要構成蛋白分子-溶膠蛋白在罹患前列腺癌病人之免疫監控系統的角色。 研究方法：溶膠蛋白在前列腺癌病理切片中的表現以抗體和免疫組織染色法染色。溶膠蛋白在前列腺癌病理切片中的表現程度和病理生理指數的關聯以統計方法分析。蛋白表現則以西方墨漬分析法與細胞流式儀確定。 研究結果：溶膠蛋白在前列腺癌細胞中高度表現，與腫瘤惡化、復發、轉移和預後較差有關。在試管內，分泌型溶膠蛋白能以結合CD37的方式去活化CD4陽性的淋巴球，以及經由Fas ligand在細胞接觸時，由第一型主要組織相容複體(major histocompatibility complex I)造成已活化CD8陽性淋巴球的凋亡。此外，分泌型溶膠蛋白能與分揀蛋白結合，活化細胞內的Wiskott-Aldrich syndrome protein family member 3 (WASF-3)，促進細胞的胞噬作用(endocytosis)與細胞內脂肪等物質的運輸促進癌細胞的生長和擴展。本研究結果發現，分泌型溶膠蛋白能促進前列腺癌巢中已經被活化之淋巴球凋亡 (apoptosis)。 結論與建議：正常生理情況下，溶膠蛋白是防止女性生殖器官對精子產生發炎的無害蛋白；在疾病狀態下，此蛋白能抑制免疫監控系統，提升腫瘤細胞的生長和擴展的能力。根據此研究，溶膠蛋白是將來發展免疫治療的高潛能標靶。
並列摘要
Objective：Loss of immunosurveillance is a major cause of cancer progression. The objective of this study is to examine the role of gelsolin, a constituent of ejaculate, in the immunosurveillance of patients with prostate cancer (PCa). Here, we demonstrate that gelsolin induces apoptosis of activated lymphocytes in prostate cancer. Methods and Materials：Pathology of PCa tissues was stained using antibodies to gelsolin and immunohistochemistry. The association between pathophysiological parameters and gelsolin staining was analyzed using statistical methods. Protein expression was further confirmed by using Western blotting analysis and flow cytometry. Results：Gelsolin was highly expressed in prostate cancer cells, and was associated with tumor progression, recurrence, metastasis, and poor prognosis. In vitro, secreted gelsolin inactivated CD4+ T cells by binding to CD37, and induced apoptosis of activated CD8+ T lymphocytes by binding to Fas ligand during cell contact dependent on major histocompatibility complex I. Moreover, secreted gelsolin bound to sortilin, which in turn bound to Wiskott-Aldrich syndrome protein family member 3(WASF-3), thereby enhancing the endocytosis and intracellular transport of essential lipids needed to facilitate tumor growth and expansion. Conclusion and Suggestion：Under normal conditions, gelsolin is a seemingly harmless protein that prevents immune responses in female recipients. In disease states, however, this protein can inhibit immunosurveillance and promote cancer progression. Gelsolin could be a potential target for immunotherapy of PCa.