目的 探讨全反式维A酸(all-trans retinoic acid,ATRA)对胃癌干细胞相关基因CD133、Sox2及GSK3B表达的影响,为胃癌治疗提供新的切入点。方法 建立人胃癌裸鼠移植瘤模型,分为对照组、氟尿嘧啶组、ATRA组、氟尿嘧啶+ATRA组,采用ATRA腹腔注射,观察裸鼠一般状况,取出肿瘤组织,HE染色,检测各组胃癌细胞坏死情况;采用半定量反转录聚合酶链反应(RT-PCR)、实时定量PCR方法,分析检测CD133mRNA、Sox2mRNA及GSK3BmRNA基因表达,并通过免疫组化法检测CD133、Sox2及GSK3B蛋白表达。结果 与对照组相比较,氟尿嘧啶组、ATRA组、氟尿嘧啶+ATRA组肿瘤体积缩小,差异有统计学意义(P<0.05);氟尿嘧啶组、ATRA组、氟尿嘧啶+ATRA组高表达CD133、Sox2干细胞相关因子;ATRA组、氟尿嘧啶+ATRA组高表达GSK3B,差异有统计学意义(P<0.05)。结论 ATRA作用后胃癌干细胞标志物CD133、Sox2、GSK3B表达增加;CD133、Sox2、GSK3B表达增加可以抑制肿瘤细胞生长;ATRA老药新用对胃癌的治疗预后有一定的作用。
Abstract
Objective To investigate the effect of all-trans retinoic acid (ATRA) on related genes CD133,Sox2 and GSK3B of gastric cancer stem cells in order to find a new starting point for the treatment of gastric cancer.Methods Human gastric cancer xenografts in nude mice were divided into control group, 5-FU group, ATRA group and 5-FU+ATRA group. After intraperitoneal injection of ATRA, the general condition of nude mice were observed before the tumor-bearing mice were sacrificed to remove the tumor tissue. HE staining was used to detect gastric cancer cell necrosis of the tissue. The expression of CD133mRNA, Sox2mRNA and GSK3BmRNA was detected using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative PCR analysis while immunohistochemistry was adopted to detect the expression of CD133, Sox2 protein and GSK3B.Results Compared with the control group, the tumor shrank in 5-Fu group, ATRA group, and 5-Fu+ATRA group. The difference was significant (P<0.05). The expressions of CD133, Sox2 stem cell-related factors were high in 5 -Fu group, ATRA group, and 5-Fu+ATRA group. However, there was significant difference in GSK3B expression between ATRA group and 5-Fu+ATRA group, (P<0.05).Conclusions After the administration of ATRA, gastric cancer stem cell markers, such as CD133 and Sox2, have a higher expression. The increased expression of CD133, Sox2 and GSK3B might inhibit the growth of tumor cells. The new use of ATRA can contribute to the prognosis of gastric cancer.
关键词
胃癌干细胞 /
CD133 /
GSK3B /
全反式维甲酸
Key words
gastric cancer stem cell /
CD133 /
GSK3B /
All-trans Retinoic Acid
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Subramaniam D,Ramalingam S,Houchen C W,et al.Cancer stem cells:a novel paradigm for cancer prevention and treatment [J].Mini Rev Med Chen,2010,10(5):359-371.
[2] Bonnet D,Dick J E.Human acute myeloid leukemia is organized as a hierarchy that originatrs from a primitive hematopoietic cell [J].Nat Med,1997,3(2):730-737.
[3] Lapidot T,Sirard C,Vormoor J,et al.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice [J].Nature,1994,36(7):645-648.
[4] Takaishi O,Wang T C.Gastric cancer stem cells [J].Clin Oncol,2008,26(17):2876-2882.
[5] Richardson G D,Robson C N,Lang S H,et al.CD133,a novel marker for human prostatic epithelial stem cells [J].Cell Sci,2004,1117(Pt 16):3539-3545.
[6] 吴 婷,李锦毅,陆士新.人胃癌侧群细胞的分离鉴定和生物学特性分析[J].中华肿瘤杂志,2012,34(4):264-268.
[7] 俞 薇,吴 婷,司 今.人胃癌细胞株MGC-803侧群细胞的分选与生物学特性[J].山东医药,2012,52(1):4-6.
[8] 姜 伟,李锦毅,吴 婷.胃癌侧群细胞的耐药性及致瘤性的初步研究[J].临床肿瘤学杂志,2012,17(8):673-677.
[9] Takaishi S,Okumura T,Tu S,et al.Identification of gastric cancer stem cells using the cell surface marker CD44+[J].J Clin Oncol,2008,26(17):2876-2882.
[10] Lawson J C,Blatch G L.Cancer stem cells in breast cancer and metastasis [J].Breast Cancer Res Tr,2009,118(2):241-254.
[11] Charafe-jauffret E,Ginestier C,Iovino F,et al.Aldehyde dehydrogenasel 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer [J].Clin Cancer Res,2010,16(1):45-55.
[12] Lukas B,Rupert L,Karen B,et al.Expression profiling of stem cell-Related genes in neoadjuvant-treated gastric cancer:a NOTCH2,GSK3B and catenin gene signature predicts survival [J].Plos One,2012,7(9):44-66.
基金
国家自然科学基金项目( 81072969,81273980)
PDF(1929 KB)
