探討α9-尼古丁接受器調控三陰性乳癌細胞表現癌幹細胞相關特性與癌症轉移的角色

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題名:	探討α9-尼古丁接受器調控三陰性乳癌細胞表現癌幹細胞相關特性與癌症轉移的角色 The Role of α9-nAChR in Nicotine-induced Cancer Stemness and Cell Metastasis in Triple Negative Breast Cancer Cells
作者:	李佳駺 Lee, Kha-Liang
貢獻者:	醫學科學研究所黃彥華
關鍵詞:	三陰性乳癌;腫瘤復發;類胰島素生長因子受體;alpha 9 乙酰;膽鹼接收器;OCT4;NANOG;上皮間質轉化 Triple negative breast cancer;Recurrence;Insulin-like growth factor-I receptor;alpha 9 nicotinic acetylcholine receptor;OCT4、NANOG;Epithelial-mesenchymal transition
日期:	2016
上傳時間:	2021-11-11 15:52:23 (UTC+8)
摘要:	乳癌的形成病因會因為不同分群間多樣且複雜的細胞訊息傳遞路徑而不同。其中，三陰性乳癌因缺乏有效的治療藥物選擇而導致治療成效不彰。在乳癌病人中，抽菸時所吸取的尼古丁一直被認為和癌症的惡化以及腫瘤的形成有很大的關聯。先前的研究顯示，在乳癌病人中 α9乙酰膽鹼接收器 (α9-nAChR) 是尼古丁增強癌症轉移的關鍵因子。癌幹細胞本身具有自我更新及自我分化的能力，因而在驅使腫瘤生長、癌症惡化，及癌症轉移中扮演重要的角色。另外，微環境對於惡性腫瘤的癌幹細胞特性扮演著舉足輕重的角色。在乳癌幹細胞的病理機制中，類胰島素生長因子（IGF-1）訊息傳遞能夠調控癌幹細胞。此外，在乳癌病患的血清中具有高濃度的IGF-1。在三陰性乳癌細胞株中，研究發現也存在IGF-1基因表現的活化。因此，我們希望藉由探討 α9-nAChR與IGF-1訊息傳遞之間的相互作用而調控癌幹細胞的作用機制，進而在治療癌症上提供一個嶄新的可能性。在人類乳癌的組織中，α9-nAChR或IGF-1R與OCT4/NANOG/CD44/CD24轉錄表現有高度正相關性，且 α9-nAChR與IGF-1R間也存在正相關性。而在三陰性乳癌細胞中，尼古丁及其代謝產物NNK刺激 α9-nAChR活化的實驗中發現磷酸化的 STAT3、α9-nAChR、IGF-1R及OCT4的表現量都上升的趨勢。另外，減弱 α9-nAChR的表現後，尼古丁所誘導的癌幹細胞標記ALDH活性與細胞爬行的效果有被抑制的現象。因此，我們證實在腫瘤微環境中，尼古丁的刺激能夠促進 α9-nAChR的活化，而增強癌幹細胞特性及癌症轉移的能力。藉由此篇論文，將更進一步證明 α9-nAChR在標靶治療的策略，可以透過調節癌幹細胞的微環境，進而有效的治療三陰性乳癌。 The molecular pathogenesis of breast cancer is diverse with numerous complex signals activation. In triple negative breast cancer (TNBC) patients, the lacking of effective therapeutic options dramatically entangles the disease prognosis. Smoking has been associated with cancer progression in breast cancer through the alpha9-nicotinic acetylcholine receptor (α9-nAChR) signaling in breast cancer cells. The mechanism is of interest as it could be a novel therapeutic perspective in inhibiting cancer progression. Cancer stem cells (CSCs) are proficient of driving tumor growth, progression and metastasis. The determination of CSC characteristics in malignancy dominantly relies on the tumor microenvironment. Insulin-like growth factor 1 (IGF-1) signaling regulates breast cancer stem/progenitors. High serum levels of IGF-I was found in breast cancer patients. What’s more, the activation of the IGF gene signature was found in triple-negative/basal-like breast cancer cell lines. We then suggest the possibility of interplay between α9-nAChR and IGF-1 signaling in cancer stemness pathology, understanding the mechanism provides a novel perspective in therapeutic potential. In this study, we hypothesized the role of α9-nAChR regulated the stemness properties and metastasis of triple negative breast cancer. In 67 frozen breast cancer patient tissues, we found a significant positive correlation between the gene levels of either α9-nAChR or IGF-1R with the cancer stem cell-related genes (OCT4/ NANOG/ CD44/ CD24). Besides, the gene levels of α9-nAChR are significantly correlated with that of IGF-1R. Evidence by treating the TNBC cells with tobacco-specific mitogen nicotine or its active metabolites, 4-(methynitrosamino)-2-(3-pyridyl)-1-butanone (NNK) showed α9-nAChR activations leads to increase α9-nAChR, IGF-1R and OCT4 expression. Further, knockdown of α9-nAChR protein expressions using shRNAs dramatically reduced the nicotine-induced ALDH activity and cell migration ability in MDA-MB-231 cells. Together with these results, we demonstrate that the nicotine impact in tumor microenvironment enhances the expressions of cancer stemness and metastasis of breast cancer cells through α9-nAChR-IGF-1R signal activation. Findings in this study will facilitate the potential strategy targeting on α9-nAChR for individualized adjuvant therapy against CSCs niches modification in TNBC.
描述:	碩士指導教授：黃彥華
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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