癌基因Stat3在人乳腺癌发生发展中的作用

The role of oncogene Stat3 in carcinogenesis and progression of human breast cancer

目的研究新辅助化疗和酪氨酸激酶 (januskinases,JAKs)抑制剂AG4 90对人乳腺癌组织中信号传导子和激活子 3(signaltransducersandactivatorsoftranscription 3,STAT3)表达的影响。方法应用Westernblot检测 5 1例人乳腺癌组织STAT3蛋白的表达。应用四唑盐 (methylthiazo letrazolium ,MTT)比色试验检测细胞增殖能力 ,流式细胞术 (flowcytometry)检测细胞周期和凋亡。结果乳腺癌组织中STAT3蛋白表达水平高于正常乳腺组织 (t=5 5 4 0 ,P <0 0 1) ;TNM分期Ⅲ、Ⅳ期的乳腺癌中Stat3蛋白表达水平高于Ⅰ、Ⅱ期乳腺癌 ,有淋巴结转移的乳腺癌STAT3蛋白表达水平高于无淋巴结转移的病例 (t =2 16 0 ,P <0 0 5 ) ;新辅助化疗后乳腺癌组织中STAT3蛋白表达水平明显低于未化疗组 (t=3 4 0 1,P <0 0 5 )。雌孕激素受体双阴性的乳腺癌中STAT3蛋白表达水平高于雌孕激素受体双阳性的肿瘤 (t=2 0 7,P <0 0 5 ) ;酪氨酸激酶 (JAKs)抑制剂AG4 90可抑制SK BR 3细胞增殖 ,使细胞周期阻滞、凋亡增加 ,并可使JAK2、STAT3、p STAT3、Bcl xL蛋白表达水平明显降低。结论 新辅助化疗可抑制人乳腺癌中STAT3蛋白的表达 ;阻断JAKs/STAT3通路可抑制人乳腺癌细胞的增殖 ,促进其凋亡。

Objective The aim of this study is to investigate STAT3 expression and the relationship between protein levels of STAT3 and clinicopathological parameters together with preoperative chemotherapy in human breast cancer. Methods Samples were obtained from 51 patients with breast carcinoma in which 7 patients had received preoperative chemotherapy. Western blot was used to measure the protein expression in tissue and SK-BR-3 cell line. MTT method was used to evaluate the proliferation. Cell-cycle and apoptosis were quantified by flow cytometry. Results STAT3 protein levels increased in breast cancer tissues compared with adjacent normal tissues(t=5.540,P<0.01); Overexpression of STAT3 was significantly correlated with TNM staging and lymph node metastasis(t=2.160,P<0.05);The expression of STAT3 protein in the ER and PR negative patients was higher than that in the ER and PR positive ones (t=3.401, P<0.05).STAT3 protein levels in patients who received preoperative chemotherapy were lower than that in the patients who did not(t=2.07,P<0.05).AG490 could downregulate JAK2, STAT3, p-STAT3 and Bcl-x L protein expression and could inhibit proliferation and augment apoptosis of SK-BR-3 cell. Conclusions The constitutive activation of STAT3 pathway may play an essential role in the tumorigenesis and progression of human breast cancer. Neoadjuvant chemotherapy can inhibit STAT3 expression. Blocking STAT3 pathway can inhibit the proliferation, augment the apoptosis of human breast cancer cells.