發(fā)布時間：2018-02-16 16:11

  本文關(guān)鍵詞： 黑素瘤 NFAT3 FK506 FK520 增殖 遷移　出處：《深圳大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：黑素瘤(Melanoma)是皮膚癌中惡性程度最高的一種亞型,擁有極高的致死率,接近五分之四的皮膚癌致死病例均由黑素瘤引起。2012年全世界共有203200例黑素瘤患者,造成55000人死亡。目前治療黑素瘤的主要手段為放化療或手術(shù)治療,但是常規(guī)的治療手段所取得的效果有限且具有極大的副作用,因此,研究發(fā)現(xiàn)黑素瘤發(fā)生發(fā)展中的關(guān)鍵靶標(biāo),進(jìn)而尋找特異性藥物,成為當(dāng)今黑素瘤治療的重要策略�；罨疶細(xì)胞核因子(Nuclear factor of activated T cells,NFAT)家族是一類在免疫反應(yīng)中能夠調(diào)節(jié)促炎細(xì)胞因子和其它基因表達(dá)的轉(zhuǎn)錄因子。除免疫細(xì)胞外,如今已經(jīng)被發(fā)現(xiàn)在肌肉、骨骼、神經(jīng)元、內(nèi)臟、皮膚中均有表達(dá)并與癌癥密切相關(guān)。相比較于其它NFAT家族成員,NFAT3在癌癥中的研究較少而且結(jié)論不一致。目前NFAT3在黑素瘤中的功能尚屬空白。他克莫斯(FK506)和子囊霉素(FK520)化學(xué)結(jié)構(gòu)相似,均為臨床上常見的抗器官移植后的免疫排斥反應(yīng)用藥。它們能夠通過抑制鈣調(diào)磷酸酶(CaN)的活性,降低NFAT蛋白去磷酸化的程度,抑制NFAT蛋白入核從而發(fā)揮免疫抑制作用。FK506目前被作為一種潛在的癌癥治療藥物被應(yīng)用于多種癌癥的臨床前研究,如膀胱癌、前列腺癌、乳腺癌等。FK506作用于黑素瘤細(xì)胞的黑素原生成也見于報(bào)道。但目前尚無FK520與黑素瘤治療相關(guān)的研究,且NFAT3與FK506、FK520的相關(guān)性不明。在前期NFAT3相關(guān)研究的基礎(chǔ)上,本研究檢測了NFAT3在黑素瘤細(xì)胞系的表達(dá),選取NFAT3高表達(dá)的黑素瘤細(xì)胞A375、SK-MEL-28構(gòu)建NFAT3敲低穩(wěn)定株并且進(jìn)行功能實(shí)驗(yàn)。我們發(fā)現(xiàn)敲低NFAT3的表達(dá)能抑制黑素瘤細(xì)胞的增殖和遷移,結(jié)果說明NFAT3作為一種促癌因子在黑素瘤中起作用。隨后使用FK506、FK520處理黑素瘤A375、SK-MEL-28細(xì)胞,結(jié)果發(fā)現(xiàn)FK506、FK520能抑制黑素瘤細(xì)胞的增殖和遷移;進(jìn)一步實(shí)驗(yàn)發(fā)現(xiàn)FK506、FK520抑制NFAT3的核定位而影響NFAT3的核質(zhì)分布;最后通過裸鼠皮下荷瘤實(shí)驗(yàn)顯示FK506、FK520在活體水平上對黑素瘤生長的抑制作用。綜上,可以得出結(jié)論,NFAT3在黑素瘤進(jìn)程中是一個促癌基因并且是一個潛在的黑素瘤治療靶點(diǎn),而FK506和FK520能夠通過抑制NFAT3的功能從而阻止黑素瘤的生長和遷移。
[Abstract]:Melanoma (melanoma) is the most malignant subtype of skin cancer, with a high mortality rate. Nearly 4/5 cases of skin cancer deaths are caused by melanoma. In 2012, there were 203200 cases of melanoma in the world. At present, the main treatment for melanoma is radiotherapy, chemotherapy or surgery, but the effect of conventional treatment is limited and has great side effects. Therefore, the study found that melanoma is a key target in the development of melanoma. And then looking for specific drugs, Nuclear factor of activated T cells (NFATs) family is a class of transcription factors that regulate the expression of proinflammatory cytokines and other genes in the immune response. Now it's been found in muscles, bones, neurons, viscera, Compared with other members of the NFAT family, NFAT3 is less studied in cancer and the results are inconsistent. At present, the function of NFAT3 in melanoma is still blank. Tacrolimus FK506) and ascomycetes. Its chemical structure is similar to that of FK520. They can reduce the degree of dephosphorylation of NFAT protein by inhibiting the activity of calmodulin. Inhibiting the entry of NFAT protein to play an immunosuppressive effect. FK506 is currently being used as a potential cancer treatment drug in preclinical studies of many cancers, such as bladder cancer, prostate cancer, The expression of melanin in melanoma cells induced by breast cancer. FK506 is also reported. However, there is no research on the relationship between FK520 and melanoma therapy, and the correlation between NFAT3 and FK506FK520 is not clear. In this study, we detected the expression of NFAT3 in melanoma cell line, and constructed the stable NFAT3 knockdown cell line A375 SK-MEL-28 with high NFAT3 expression. We found that low NFAT3 expression could inhibit the proliferation and migration of melanoma cells. The results showed that NFAT3 acts as a carcinogenic factor in melanoma, and then treated with FK506 and FK520 in melanoma cell line A375 SK-MEL-28. The results showed that FK506 and FK520 could inhibit the proliferation and migration of melanoma cells. It was further found that FK506FK520 inhibited the nuclear localization of NFAT3 and affected the distribution of nuclear and cytoplasm of NFAT3. Finally, it was shown that FK506FK520 inhibited the growth of melanoma in vivo by subcutaneous tumor implantation in nude mice. It can be concluded that NFAT3 is a carcinogenic gene and a potential target for melanoma therapy in the process of melanoma, while FK506 and FK520 can inhibit the growth and migration of melanoma by inhibiting the function of NFAT3.
【學(xué)位授予單位】：深圳大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R739.5

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 沈丹蓓,孫建方;以堿性成纖維細(xì)胞生長因子及其受體為靶點(diǎn)的黑素瘤治療[J];國外醫(yī)學(xué).皮膚性病學(xué)分冊;2003年06期

2 李玲,周華,宋偉民,蘇瑾;長波紫外線照射對小鼠黑素瘤細(xì)胞的影響[J];環(huán)境與職業(yè)醫(yī)學(xué);2004年01期

3 劉厚廣;李琛;尤艷;李海燕;孫桂珍;;黑素瘤細(xì)胞生長因子表達(dá)及微血管密度研究[J];臨床皮膚科雜志;2006年07期

4 朱健偉;駱丹;;黑素瘤細(xì)胞粘附與遷移相關(guān)表面分子研究進(jìn)展[J];腫瘤基礎(chǔ)與臨床;2006年06期

5 馬楓茹;劉琨;張毅;潘石;吳世法;;單個人體黑素瘤細(xì)胞的原子力顯微圖像及拉曼光譜的研究[J];電子顯微學(xué)報(bào);2007年01期

6 姜培紅;元雄良治;;白介素22在皮膚黑素瘤細(xì)胞中的表達(dá)[J];臨床皮膚科雜志;2007年06期

7 陸原;翁翊;李清;何雯;金麗;陳達(dá)燦;y⒐，

本文編號：1515913