口服綠茶多酚透過細胞毒殺性T細胞活化作用及其在腫瘤細胞中之血管新生作用之抑制作用以防止紫外線照射誘發之老鼠皮膚癒

Orally Administered Green Tea Polyphenols Prevent Ultraviolet Radiation-Induced Skin Cancer in Mice through Activation of Cytotoxic T Cells and Inhibition of Angiogenesis in Tumors

劉紹毅 ； Sudheer K. Mantena ； Syed M. Meeran ； Craig A. Elmets ； Santosh K. Katiyar

《中華民國血液淨化醫學會雜誌》 14卷3-4期 (2009/12) Pp. 94-96

https://doi.org/10.30024/JFBPS.200912.0024

摘要

綠茶多酚(green tea polyphenols, GTPs)顯示大有希望成為對抗癌症形成的藥劑(anticarcinogenic agents)和其可能發展成為預防太陽紫外線照射－誘發的皮膚癌。在此，我們探討藉著小鼠使用GTPs在紫外線B-誘發(UVB-induced)皮膚癌防止作用之機轉。我們利用2組年齡6到7週大小之雌性SKH-1無毛髮的小鼠，以紫外線B(180mJ/平方公分)每週照射3次，共計24週。一組給予飲水；另一組給含有2公克／升GTPs之飲水。而控制組小鼠則給飲水，但沒有曝曬紫外線B(UVB)照射。以紫外線B照射誘發的腫瘤和來自控制組小鼠皮膚之切片，使用免疫染色法(immunostaining)、西方墨點法(Western to blotting)和溶膠的時譜(gelatinolytic zymography)方式來加以分析。結果發現，口服GTPs後，可以使得紫外線B照射所誘發之腫瘤減少35%發生率，腫瘤增長(tumor multiplicity)減少63%，和腫瘤成長(tumor growth)減少55%。在GTPs+UVB組，其基質金屬性蛋白脢(matrix metalloproteinase, MMP)之MMP-2與MMP-9之基因表現均減少，MMP-2與MMP-9與腫瘤成長及轉移具有緊要關鍵性的角色；以及GTPs+UVB組之MMP之組織抑制劑在腫瘤之表現與單獨使用UVB處理之小鼠比較之下有增加。在GTPs+UVB組中，亦有CD31與血管內皮細胞因子(vascular endothelial growth factor)表現之減少，它們是血管新生作用(angiogenesis)不可或缺的，以及GTPs+UVB組會比UVB組有著更明顯之腫瘤中增殖性細胞核抗原表現之抑制。除此之外，在GTPs+UVB組之腫瘤中，其所有之CD8+毒殺T-細胞之數目比UVB數目多，以及其腫瘤細胞中，呈現出較多的Caspase 3的活化作用，此情形指出腫瘤細胞發生了細胞自然凋亡性死亡(apoptotic death)。將以上之數據集合在一起，這些數據顯示出，在小鼠中，給予GTPs可影響到許多涉入紫外線－誘發之癌症新生作用，包括它可以控制血管新生因子和在腫瘤微細環境中，使殺手T細胞恢復正常的狀態。

並列摘要

Green tea polyphenols (GTPs) show promise as anticarcinogenic agents and may prevent the development of solar UV radiation-induced skin cancer. Here we investigated the mechanisms by which GTPs prevent UVB-induced skin cancer in mice. Two groups of 6-to 7-wk-old female SKH-1 hairless mice were UVB irradiated (180mJ/cm^2) 3 times each week for 24 wk. One group consumed water and the other, water containing 2 g/L GTPs. A control group drank water and was not exposed to UVB radiation. UVB-induced tumors and skin biopsies from the control group were analyzed using immunostaining, Western blotting, and gelatinolytic zymography. Oral administration of GTPs reduced UVB-induced tumor incidence (35%), tumor multiplicity (63%), and tumor growth (55%). The GTPs UVB group had reduced expression of the matrix metalloproteinases (MMP)-2 and MMP-9, which have crucial roles in tumor growth and metastasis, and enhanced expression of tissue inhibitor of MMP in the tumors compared with mice that were treated with UVB alone. The GTPs_UVB group also had reduced expressions of CD31 and vascular endothelial growth factor, which are essential for angiogenesis, and inhibited expression of proliferating cell nuclear antigen in the tumors compared with the UVB group. Additionally, there were more cytotoxic CD8(superscript +) T cells in the tumors of the GTPs_UVB group than in the UVB group and their tumor cells exhibited greater activation of caspase-3, indicating the apoptotic death of the tumor cells. Taken together, these data suggest that in mice, administration of GTPs affects several biomarkers that are involved in UV-carcinogenesis, including inhibition of angiogenic factors and recruitment of cytotoxic T cells in the tumor microenvironment.

並列關鍵字

green tea polyphenols ； matrix metalloproteinases ； ultraviolet radiation ； angiogenesis ； cytotoxic T cells