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標題: | 細胞激素受體 IL-17RB 與乳腺脂肪細胞在乳癌癌化過程中所扮演之角色 The roles of IL-17RB and mammary gland adipocytes in breast cancer tumorigenesis |
作者: | Chun-Kai Huang 黃俊凱 |
指導教授: | 李文華 |
關鍵字: | 乳癌,細胞激素,脂肪細胞, breast cancer,tumorigenesis,IL-17RB,adipocytes, |
出版年 : | 2015 |
學位: | 博士 |
摘要: | 癌症發展過程中,癌細胞除了自身細胞內調控影響外,也受周遭細胞影響。以癌細胞本身而言,癌細胞常常利用大量表現表面受體方式來增加自己生長與存活優勢。乳癌病人中大約有 20~25% 病人會大量表現第二型人類表皮生長因子受體 (HER2),這類病人可利用針對此受體之單株抗體-trastuzumab進行有效治療。然而目前除了 HER2 外,少有其他可應用於乳癌治療之專一標的被證實。在本論文中,我們證實細胞激素受體 IL-17RB 及其配體 IL-17B 對於乳癌癌化過程是重要的,此路徑活化亦可干擾正常乳腺上皮細胞乳腺發育過程,進而促進乳癌發展。 藉由受體 IL-17RB 及其配體 IL-17B結合,可活化下游轉錄因子 NF-κB,並進一步促進抑制細胞凋亡分子 Bcl-2表現,使癌細胞對於 Etoposide 細胞毒殺耐受性增加。另一方面,在乳癌病人臨床檢體中我們也觀察到 IL-17RB 與 HER2 表現量呈現正相關,同時大量表現 IL-17RB 與 HER2 的乳癌病人具有較差預後。在具trastuzumab 抗性之乳癌細胞中,抑制 IL-17RB 的表現亦可有效抑制其致癌性,顯示 IL-17RB 與 HER2 在乳癌細胞中可能扮演不同角色。當我們以 IL-17RB 與 IL-17B 中和性抗體對乳癌細胞進行處理後發現,無論是中和 IL-17RB 或 IL-17B 皆可有效抑制乳癌細胞致癌性,顯示 IL-17RB 與 IL-17B 在乳癌癌化過程中扮演重要角色,並具有可用來發展相對應治療方式之潛力。 另一方面,癌細胞與其微環境之交互作用對於癌症產生與發展過程亦扮演重要角色。乳腺組織中,脂肪細胞是間質細胞中比例最高的,臨床研究上也指出較大乳房女性具有較高乳癌危險因子。然而,目前對於脂肪細胞是如何影響乳癌發展則是未有定論。因此在本論文中,我們首先證實從乳癌病人乳房組織分離之脂肪細胞可促進某類乳癌細胞生長,此類細胞與雌激素受體之表現並無顯著相關性,暗示有其他重要路徑存在。透過cDNA微陣列與RNA干擾實驗結果交叉分析,我們發現 monocarboxylate transporter 2 (MCT2) 分子在對於脂肪細胞促進乳癌細胞生長過程中扮演重要角色。MCT2已知功能主要參與在酮體之一 β-hydroxybutyrate 由外而內之運輸。β-hydroxybutyrate 在細胞中可被做為內生性 HDAC 抑制劑,當我們以 β-hydroxybutyrate 處理具有 MCT2 表現之細胞時,可有效增加組蛋白 H3K9 位置的乙醯化,此位置目前被認為與基因表現呈現正相關。細胞經 β-hydroxybutyrate 處理後,可被誘導產生許多與促進癌細胞生長相關之因子表現,例如細胞激素 IL1β 與脂肪素 LCN2,進而促進乳癌細胞致癌性。同時,我們也觀察到在乳癌臨床檢體中,MCT2表現量與 IL1β 及 LCN2表現量具有高度正相關,並顯示較差預後。總結來說,在本研究中我們闡述了乳癌微環境中脂肪細胞如何與 MCT2 表現之乳癌細胞進行交互作用,進而促進乳癌發展。 Cancer cells are not only regulated by autonomous signals, but also influenced by the surrounding cells. In the aspect of cancer cell-autonomous regulation, gain of function of membrane receptor is a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been served as a target for developing trastuzumab to treat 20~25% of breast cancer. However, little or none of other membrane receptor is found to be useful as potential target for breast cancer treatment since then. Here, we found that amplified signal of Interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated NF-κB to up-regulate anti-apoptotic factor Bcl-2 and induce etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 play an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signal pathway may serve as a therapeutic target for developing treatment to manage IL-17RB associated breast cancer. The crosstalk between cancer cells and their microenvironments also contributes to cancer initiation and progression. Adipocyte is the most abundant cell type in mammary glands, and larger breast size is associated with an increased risk for breast cancer. However, how adipocytes in mammary gland affect breast cancer formation is not completely understood. Here, we showed that primary adipocytes derived from mammary glands promote malignant growth of distinct type of tumor cells independent of its status of estrogen receptor α (ER-α). Through differential microarray analyses and RNAi knockdown screening, monocarboxylate transporter 2 (MCT2), responsible for transporting β-hydroxybutyrate, a ketone body, was identified as a critical factor that mediated the promotion of tumorigenicity associated with the adipocytes. Treating MCT2-expressing breast cancer cells with β-hydroxybutyrate, a physiological HDAC inhibitor, increased histone H3K9 acetylation, a gene activation mark, up-regulated tumor-promoting genes including cytokine IL1β as well as adipokine lipocalin 2 (LCN2), and enhanced tumorigenic activity. Consistently, elevated expressions of MCT2 as well as IL1β and LCN2, were significantly correlated with poor prognosis in breast cancer patients. These results suggest a novel mechanism of a specific crosstalk between MCT-2-expressing cancer cells and β-hydroxybutyrate secreting adipocytes in mammary gland microenvironment for promoting breast cancer malignancy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4673 |
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顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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