利用太平洋紫杉醇治療胃癌轉移與胃癌轉移相關基因之研究

Studies of Gastric Tumor Metastasis-Associated Genes and Paclitaxel Treatment on Gastric Tumor Metastasis

段宗帆(Tsung-Fan Tuan)

指導教授 ： 黃玲玲

共同指導教授 ： 陳炯東(Chiung-Tong Chen)

臺北醫學大學/醫學院/醫學科學研究所/博士(2013年)

https://doi.org/10.6831/TMU.2013.00050

摘要

胃癌是造成癌症死亡的疾病之一，臨床上證實擴散型(diffuse type)胃癌細胞會轉移至腹腔及肝臟，是造成胃癌死亡的主要原因。在這篇研究中，探討靜脈注射太平洋紫杉醇(paclitaxel)在擴散型胃癌細胞轉移上的治療效果，並利用該細胞找出可能與胃癌轉移有關的基因。藉由動物及Transwell®篩選系統，本研究利用持續有綠色螢光(GFP)表現的MKN45擴散型胃癌細胞建立具有高轉移能力的細胞亞株，分別為MKN45-GFP-ip4、MKN45-GFP-4、MKN45-GFP-10及MKN45-GFP-12。其中MKN45-GFP-ip4及MKN45-GFP-12相較於其他細胞亞株有很高的轉移能力。MKN45-GFP-ip4細胞亞株被用來評估靜脈注射太平洋紫杉醇在治療胃癌轉移上的效果，發現該治療方式能夠有效抑制擴散型胃癌的轉移。另一方面，利用互補去氧核醣核酸微陣列(cDNA microarray)分析MKN45-GFP、MKN45-GFP-4、MKN45-GFP-10及MKN45-GFP-12細胞亞株的全基因訊息核糖核酸(mRNA)表現量，藉此找出基因表現與細胞轉移能力的關係。研究發現有許多可能與擴散型胃癌細胞轉移有關的基因表現特殊，其中包含從未發現或研究過的新基因。這些基因及蛋白質產物將可進一步用來研究其與癌症轉移的機轉，藉由分析病患組織的分子資訊、基因轉譯及蛋白質表現，這些基因可能成為有用的生物標記，用來評估、治療及預防胃癌。更重要的是，可以利用這些分子標記研究與開發治療胃癌轉移的藥物。

關鍵字

癌症 ； 腫瘤 ； 轉移 ； 正位 ； 胃 ； 太平洋紫杉醇 ； 腹腔內 ； 瀰漫 ； 微陣列

並列摘要

Gastric cancer is one of the leading causes of cancer death and its malignancy, resulted from the disseminated cancer cells of diffuse type, is clinically manifested as metastases to the liver and peritoneum. The present study is to investigate the efficacy of intravenously administered paclitaxel treatment and identify putative tumor metastasis-associated genes in human gastric cancer cells of diffuse type. MKN45 cell line constitutively expressing green fluorescent proteins (MKN45-GFP) was established and selected using orthotopically animal and Transwell® system for invasive sublines MKN45-GFP-ip4, MKN45-GFP-4, MKN45-GFP-10 and MKN45-GFP-12. MKN45-GFP-ip4 and MKN45-GFP-12 are highly invasive compared to the others. The effects of intravenously administered paclitaxel against the growing peritoneally disseminated and metastasized tumors in nude mice were monitored by MKN45-GFP-ip4 subline. The intravenous paclitaxel is active against the metastases of human gastric cancer of peritoneal diffuse type, which encourages further investigations on optimizing the perioperative paclitaxel therapeutic regimens for gastric cancer in patients. On the other hand, the mRNA levels of whole genes were measured with cDNA microarray and correlated with their invasion abilities in MKN45-GFP, MKN45-GFP-4, MKN45-GFP-10 and MKN45-GFP-12 sublines. The putative gastric tumor metastasis-associated genes, including novel genes, were identified. These genes and their protein products are to be further explored for functional roles associated with tumor metastasis. The molecular profiles of these identified genes, gene transcripts, and proteins in the patient specimens are likely to be useful biomarkers for diagnostic, therapeutic, and/or prognostics. Most importantly, they may be used as molecular targets for discovery of anti-tumor metastasis drugs against human gastric cancer.

並列關鍵字

cancer ； tumor ； metastasis ； orthotopic ； stomach ； gastric ； paclitaxel ； intraperitoneal ； dissemination ； microarray

參考文獻

Yeh KH and Cheng AL. Recent advances in therapy for gastric cancer. J Formos Med Assoc 2004; 103:171-185.

Akhtar S, Meeran SM, Katiyar N, Katiyar SK. Grape seed proanthocyanidins inhibit the growth of human non-small cell lung cancer xenografts by targeting insulin-like growth factor binding protein-3, tumor cell proliferation, and angiogenic factors. Clin Cancer Res 2009; 15:821-831.

Amoh Y, Katsuoka K, Hoffman RM. Color-coded fluorescent protein imaging of angiogenesis: the AngioMouse models. Curr Pharm Des 2008; 14:3810-3819.

Archie V, Kauh J, Jones DV Jr, Cruz V, Karpeh MS Jr, Thomas CR Jr. Gastric cancer: standards for the 21st century. Crit Rev Oncol Hematol 2006; 57:123-131.

Bogenrieder T and Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 2003; 22:6524-6536.