林培正劉哲育David Pei-Cheng LinJer-Yuh Liu陳伯易Bo-Yie生化暨生物科技研究所2026-10-289999-12-312007https://handle.ncl.edu.tw/11296/x542sqhttps://scholars.csmu.edu.tw/handle/123456789/35590非荷爾蒙依賴性前列腺癌的起源和發展所知有限，並且至今尚無有效的治療方式。最近，腫瘤幹細胞(Cancer Stem Cell)的學說提出此前列腺癌的發生可能源自於前列腺基礎細胞的不正常分化。Hedgehog(Hh)訊息活化於成體組織幹細胞的自我更新複製或分化，扮演調控組織再生分化的功能；同時，活化腫瘤幹細胞參與腫瘤的發生調控。最近的報告指出Hedgehog訊息高度活化表現於惡性或轉移的前列腺癌。然而，至今依然不清楚Hedgehog訊息之分子機制是否參與前列腺癌的早期發展。在本論文的研究，我們在小鼠的前列腺注射Hedgehog表現載體，以電擊轉植的方式使Hedgehog蛋白過度表現，誘發小鼠前列腺腫瘤形成。指出Hedgehog訊息的活化表現，造成前列腺基礎細胞異常快速分化，在小鼠前列腺腫瘤產生Prostatic Intraepithelial Neoplasia (PIN)和Invasive Prostate Adenocarcinoma (Invasive CaP)的病理特徵。我們進一步分析，指出Hedgehog訊息的活化參與並促進基礎細胞後裔子代族群的分化、不表現AR之前列腺癌形成、腫瘤幹細胞活化、癌細胞增生和轉移。另外，在人類前列腺組織，我們指出Hedgehog訊息高度表現在基礎細胞贅生(Basal Cell Hyperplasia；BCH）和前列腺癌腺體組織。本實驗結果指出Hedgehog 訊息的過度活化會促進前列腺基礎幹細胞的惡化和前列腺腫瘤幹細胞的分化，起始前列腺癌的發展。小鼠前列腺癌模式的建立，有助於了解Hedgehog 訊息在前列腺癌發生過程的角色；同時，提供了實驗的動物平台有助於未來抗癌藥物的開發。With little knowledge about the origin and development of androgen-independent prostate cancer, no effective therapy has been available so far. Recently, a cancer stem/progenitor cell hypothesis has been proposed, in which abnormal prostatic basal cells or their progeny cells are regarded as the cause of malignant androgen- independent tumorigenesis. Hedgehog (Hh) gene is thought to be reactivated during self-renewal and differentiation of adult stem cells, leading to tissue regeneration or cancer stem cells activation. Recent studies have implicated hyperactive Hh signaling in advanced and metastatic prostate cancers, but the molecular mechanism of Hh involved in prostate tumorigenesis remains unclear. In this study, we addressed the effects of Hh overexpression by intraprostate injection of an Hh-expressing vector. The manipulation, with confirmed Hh signaling pathway activation, caused lesions originated from prostatic basal cells showing characteristic PIN or invasive CaP phenotypes. Further analyses demonstrated Hh involvement in heterogeneous basal cell lineage differentiation, AR-negative cancer formation, cancer stem cell activation, cell proliferation, and metastasis. Furthermore, we indicated Hedgehog involvement in forming BCH and its progressing towards CaP in human prostate cancer, presumably by transforming the normal basal stem cells into the cancer stem cells where persistent Hedgehog activation might be mandatory for tumorigenesis. To conclude, a mouse prostate cancer model induced by Hh-overexpression was established and may be used for testing novel therapeutical approaches targeting at Hh signaling pathway.thesis