結腸癌細胞表現黏液素MUC2抑制腫瘤生成及誘發先天性免疫之分子機制

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Title:	結腸癌細胞表現黏液素MUC2抑制腫瘤生成及誘發先天性免疫之分子機制 Molecular Mechanism of Mucin MUC2 Expression of Colon Cancer Cells Inhibits Tumorigenesis and Induces Innate Immunity
Authors:	陳怡伶
Contributors:	嘉南藥理大學老人服務事業管理系
Keywords:	結腸癌黏液素細胞激素標靶治療 Colorectal cancer mucin interleukin ,target therapy
Date:	2014
Issue Date:	2015-11-06 16:10:21 (UTC+8)
Abstract:	在台灣，大腸癌是常見的癌症，第二期和第三期大腸癌患者的治療策略是非常重要。過去研究針對第三期大腸癌患者，標準治療方法，術後結合輔助性化療。然而，部分第二期患者可以手術治癒；有部分的第二期大腸癌患者，化療的使用有所爭議，最主要問題是如何選擇患者進行化療，並得到最大助益。 MUC2 是大腸最主要分泌型黏液素，腺癌和黏液性癌都會表現。細胞癌化MUC2 表現量會下降，MUC2 表現量缺失可能和疾病復發以及存活率較差有關。因此，推測 MUC2 的表現和免疫反應及預後相關。在大腸癌病人血液中高量細胞激素 IL-6和腫瘤生長、轉移及預後差具有相關性。在免疫反應過程中 MUC2 和 IL-6之間連結如何調控免疫機制。本計劃的研究目的之一：證實在大腸癌表現 MUC2 和 IL-6交互作用之分子機制；之二探討大腸癌細胞異常過度表現 MUC2 對致癌性及腫瘤浸潤免疫細胞之分化。本計劃的研究方式?用原位癌的結腸癌模式，使用的結腸癌細胞株-CT26細胞和HT-29能在小鼠的盲腸生長，且癌細胞會表現黏液素MUC2。之前的研究，我們?用分生技術(siRNA)，降低結腸癌細胞株的內生性MUC2的表現，這些穩定的細胞株，其MUC2的表現量較低：(1)分析穩定的細胞株，其細胞培養液中IL-6分泌量。(2)當這些細胞株種植到免疫完整或免疫缺失的小鼠的盲腸部位，其癌細胞的生長。(3)動物其體內腫瘤部位、腹水、腸系膜淋巴結等免疫細胞浸潤。(4)腫瘤免疫浸潤細胞分化。(5) MUC2和IL-6之間訊息傳遞調控機制。(6)我們使用阿斯匹靈治療原位結腸癌，測試癌細胞其MUC2表現量高低是否會影響治療效果。本研究計畫的重要性有?部分：(1)證明在結腸癌的治療，MUC2 和 IL-6是否是有?的免疫標的分子；(2)提供MUC2 和 IL-6之間交互作用的免疫調控機制。我們預計應用此動物模式，研究癌細胞所減少MUC2 表現量，可作為新穎預測癌細胞轉移的標誌，也是具有潛力發展藥物干擾的標靶。 Colon cancer is the most common cancer in Taiwan. It is critically important to therapy strategies between stage II and stage III colon cancer. In previous studies, postoperative adjuvant chemotherapy has been recommended as the standard therapy for stage III colon cancer. In contrast, some stage II colon cancer patients can be cured with surgery. In some patients with stage II colon cancer, the use of chemotherapy has been controversial. The main question is that how to select patients most to benefit from chemotherapy. MUC2 is the major secreted mucin in the large intestine and expressed by adenomas and mucinous carcinomas. The down-regulation of MUC2 observed in carcinomas. The loss of MUC2 expression may be associated with disease recurrence and worse survival in colon cancer. Therefore, the expression of MUC2 in colon cancer may be a key factor in amplifying the immune responses and preventing colonic carcinogenesis. In previous studies, high serum concentrations of IL-6 in colorectal carcinoma patients are associated with tumor progression, metastasis and poor survival. Most importantly, the regulation mechanism of immunologic responses established a link between MUC2 and IL-6 pathway. The aims of this research project are: (a) to determine the effects of MUC2 on IL-6 expression in colonic cancer cells and the molecular mechanisms involved; (b) to determine the immunogenic effect of MUC2 in colonic carcinomas and differentiation of tumor-associated immune cells involved. The research will be performed on a unique orthotropic colon cancer animal model. The colon adenocarcinoma cell line-CT26 cells and HT-29 cells are able to grow orthotropically in mouse cecum; furthermore, MUC2 was expressed in this cell line. In previous studies, we use siRNA targeting MUC2 to downregulate the endogenous expression in CT26 cells and HT-29 cells. CT26 cells and HT-29 cells were stably transfected with vector control or MUC2 siRNA (MUC2 RNAi). The stable clones with low expression of MUC2 will be compared with vector control and parental cell lines on the following properties: (a) the secretion of IL-6 in conditioned medium (b) growth when implanted into cecum of immune competent mice or immune-deficient mice, (c) the infiltration of immune cells in tumor, ascetic fluid and mesenteric lymph nodes, (d) the differentiation by the tumor-associated immune cells, (e) to explore signal transduction mechanism between the MUC2 and IL-6 complete the connections, (f) we used aspirin treatment and tested their antitumor effects in the MUC2 high or low expression tumor cells. The significance of this research proposal is two-fold: (1) demonstrate whether MUC2 and IL-6 is useful immunological target for colonic cancer therapy; (2) provide immune-regulation mechanism of interaction between MUC2 and IL-6. We anticipate that the animal model, decrease expression of MUC2 is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention.
Relation:	計畫編號：NSC102-2410-H041-006 計畫年度：103；起迄日期：2013-08-01~2014-07-53
Appears in Collections:	[Dept. of Senior Service and Health Management] MOST Project

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