Research Project: 以Epigenetic為標的探討Stilbenoids化合物抑制結腸直腸癌之化學預防功效與機制研究(2/3)
Loading...
Contributors
Funders
ID
Description
摘要：結腸直腸癌（Colorectal cancer）為各個國家普遍盛行的癌症，亦為台灣地區癌症死亡的主要原因。研究顯示飲食與生活習慣是造成結腸直腸癌的高危險因子；而其形成與發展為遵循腺瘤腺癌理論（adenoma carcinoma sequence），且為一漫長且複雜的病理變化過程，牽涉到許多分子層次的變化與異常訊息傳遞調控。流行病學與分子醫學研究發現，癌症的起始形成並非只有單純的基因改變（genetic change），可逆性epigenetics調控機制或許才足以解釋現代疾病的多樣性與複雜性。Epigenetic之定義為在不涉及改變DNA序列的狀態下調控基因表現的作用，包括DNA甲基化（DNA methylation）、組蛋白修飾作用（histone modification）和microRNA，皆在生物體的發育生長過程中具有重要功能，且參與許多疾病和癌症形成。研究數據指出異常的epigenetic作用會導致抑癌基因（tumor suppressor gene）與致癌基因（oncogene）的表現失調，影響腸道細胞的發炎反應、DNA修復、增生、存活、分化、死亡、侵入和轉移等行為，促進結腸直腸癌的形成與發展。由於epigenetic作用是可逆的，相較於改變基因序列或抑制突變基因表現，適度的調節epigenetic作用或許可更有效的抑制結腸直腸癌。此外結腸直腸癌的高發生率與死亡率歸因於其早期診斷不易、高度轉移性和復發性；因此就疾病化學預防的立場觀之，藉由調節epigenetics控制基因表現，進而抑制結腸直腸癌形成應為更適切的預防策略。Stilbenoid化合物廣泛的存在於蔬菜、水果和可食性食物中，常見的包括resveratrol、piceatannol和 pterostilbene等，已被證實具有許多生物活性，包括抑制結腸直腸癌形成、誘導腸癌細胞週期停滯和死亡。因stilbenoids的高度生理活性，故有許多結構相似的hydroxystilbenoids和methoxystilbenoids被鑑定或合成，期望能提高生物活性或生物利用性（bioavailability）；然而在相關的研究中，目前僅有resveratrol被發現可藉由調節epigenetic作用而抑制結腸直腸癌細胞的生長。我們先前研究發現餵食pterostilbene（3,5-dimethoxy-4′-hydroxystilbene）能有效抑制偶氮甲烷（azomethane；AOM）誘發小鼠腸道腫瘤形成，且抑制活性高於resveratrol（3, 4′, 5- trihydroxylstilbene）；初步實驗結果也發現，3`-hydroxypterostilbene（3,5-dimethoxy-3`,4`-hydroxystilbene）誘導結腸直腸癌細胞凋亡、自體吞噬、抑制AOM/dextran sodium sulfate（DSS）誘導腸道腫瘤形成和COLO205腫瘤組織生長的活性皆顯著較pterostilbene佳，且可能與調節epigenetic作用有關；顯示stilbenoids的官能基種類、數量與位置可能會影響其結腸直腸癌的化學預防功效。因此，我們將延續先前的研究成果與初步實驗數據提出三年研究計畫，著重探討飲食性stilbenoids藉由調節epigenetic作用進而抑制結腸直腸癌形成和發展的癌症化學預防功效，以及其分子機制探討；我們也將分析stilbenoids官能基差異對其生物活性的影響。我們的計畫時程與目標包括: 【第一年】以細胞模式探討stilbenoids抑制癌細胞之特徵（hallmarks of cancer）以及調控epigenetic作用之活性與機制; 【第二年】餵食stilbenoids調控epigenetic作用與抑制AOM/DSS誘導腸道腫瘤形成、發展之活性與機制;【第三年】餵食stilbenoids抑制結腸直腸癌腫瘤生長、轉移以及調控epigenetic作用之活性與機制。我們期望藉由此計畫釐清與找出影響結腸直腸癌形成的作用標的分子與epigenetic機制，提出飲食保健與預防對降低結腸直腸癌的重要性；並證實stilbenoids的抑制結腸直腸癌的化學預防功效與機制，期望未來能提出適合的預防與改善策略，進而降低結腸直腸癌的盛行。<br> Abstract: Colorectal cancer (CRC) is one of major causes of cancer-related mortality in the world. Accumulating evidence suggests that diet and lifestyle are high risk factors for CRC. The adenoma-carcinoma sequence is the basis for development of CRC and involves various molecular changes and deregulation of multiple signaling pathways. Recent survey of the global incidence of cancer show that genetic change per se cannot explain the vast diversity of phenotypes such as heritable disease but affect via reversible epigenetic mechanisms. Epigenetic is defined as the study of mitotically and meiotically heritable changes in gene function that are not dependent on DNA sequence, including DNA methylation, histone modification and microRNA that are important for organism development. Cumulative new evidence suggests that epigenetic changes caused abnormal expression of tumor suppressor genes and oncogenes, which further contribute to development of CRC by infiltration of inflammatory/immune cell within colon, impair DNA repair, reduce cell death, and enhance transformation and proliferation of colonic crypt cells, angiogenesis, invasion and ultimately metastasis. Thus, modulation of reversible epigenetic could be effective approach for prevention CRC. Furthermore, based on the principles of cancer chemoprevention, targeting on modulation of epigenetics-mediated gene expression and colonic tumorigenesis will be more beneficial strategy for CRC prevention. Stilbenoids widely exist in various fruits, vegetable and edible plants and have been demonstrated exert multiple beneficial properties, including suppression of tumorigenesis, induction of cell cycle arrest and apoptosis in CRC. Several other natural or synthetic hydroxystilbenoids and methoxystilbenoids of are identified or prepared with the aim of improving biological activity and bioavailability. However, only resveratrol is reported to inhibit proliferation of colon cancer cell by regulation of epigenetic but not other stilbenoids so far. Our previous studies showed that dietary pterostilbene (3,5-dimethoxy-4`-hydroxystilbene）is more potent and effective than resveratrol (3, 4`, 5- trihydroxylstilbene) on against AOM-induced colonic tumorigenesis. In preliminary study, we also found 3`-hydroxypterostilbene (3,5-dimethoxy-3`,4`-hydroxystilbene) is more effective than pterostilbene on induction of programmed cell death in colon cancer cells, reduction of AOM/DSS-induced colonic tumorigenesis and COLO205 xenografic tumor growth. In addition, we also found 3`-hydroxypterostilbene exhibits epigenetic regulation property. These results indicating the functional group of stilbenoids might affect their CRC chemopreventive efficacy. Here we extend the preliminary study and design a three-year project to investigate the chemopreventive efficacy of dietary stilbenoids on inhibition of CRC by targeting epigenetic as well as their molecular mechanisms. The individual goal and study design are: 1st year, investigate the anti-CRC activities of stilbenoids and regulation mechanism involved by cell-based assay. 2nd year, inhibitory effects of dietary stilbenoids on AOM/DSS-induced colonic tumorigenesis. 3rd year, anti-CRC tumor growth and metastasis efficacy of dietary stilbenoids in xenograft nude mice. We will also investigate the chemopreventive and bioavailability effect of stilbenoids based on different functional groups. We expect to clarify the promising epigenetic and molecular targets of CRC as well as explore the cancer chemopreventive mechanism of dietary stilbenoids. These results will be useful for further application of novel approach in the field of CRC chemoprevention or treatment.
Keywords
結腸直腸癌
表觀遺傳學
天然化合物
Colorectal cancer
Epigenetic
Stilenoids
表觀遺傳學
天然化合物
Colorectal cancer
Epigenetic
Stilenoids