Yoon Jiyeon, Ko Young San, Cho Sung Jin, Park Jinju, Choi Young Sun, Choi Yiseul, Pyo Jung-Soo, Ye Sang-Kyu, Youn Hong-Duk, Lee Jae-Seon, Chang Mee Soo, Kim Min A, Lee Byung Lan
Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea.
APMIS. 2015 May;123(5):373-82. doi: 10.1111/apm.12370. Epub 2015 Apr 4.
The transcription factor signal transducers and activators of transcription 3 (STAT3) can promote cancer metastasis, but its underlying regulatory mechanisms in gastric cancer cell invasiveness still remain obscure. We investigated the relationship between STAT3 and glycogen synthase kinase-3β (GSK-3β) and its significance in metastatic potential in gastric cancer cells. Immunohistochemical tissue array analysis of 267 human gastric carcinoma specimens showed that the expressions of active forms of STAT3 (pSTAT3) and GSK-3β (pGSK-3β) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p < 0.001). Cell culture experiments using gastric cancer cell lines SNU-638 and SNU-668 revealed that STAT3 suppression did not affect pGSK-3β expression, whereas GSK-3β inhibition reduced pSTAT3 expression. With respect to metastatic potential in gastric cancer cells, both STAT3 suppression and GSK-3β inhibition decreased cell migration, invasion, and mesenchymal marker (Snail, Vimentin, and MMP9) expression. Moreover, the inhibitory effects of STAT3 and GSK-3β on cell migration were synergistic. These results demonstrated that STAT3 and GSK-3β are positively associated and synergistically contribute to metastatic potential in gastric cancer cells. Thus, dual use of STAT3 and GSK-3β inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
转录因子信号转导与转录激活因子3（STAT3）可促进癌症转移，但其在胃癌细胞侵袭中的潜在调控机制仍不清楚。我们研究了STAT3与糖原合酶激酶-3β（GSK-3β）之间的关系及其在胃癌细胞转移潜能中的意义。对267例人类胃癌标本进行免疫组织化学组织芯片分析，结果显示，在267例胃癌病例中，分别有68例（25%）和124例（46%）检测到活性形式的STAT3（pSTAT3）和GSK-3β（pGSK-3β）表达，二者呈正相关（p<0.001）。使用胃癌细胞系SNU-638和SNU-668进行的细胞培养实验表明，抑制STAT3不影响pGSK-3β的表达，而抑制GSK-3β则降低pSTAT3的表达。关于胃癌细胞的转移潜能，抑制STAT3和GSK-3β均可降低细胞迁移、侵袭及间充质标志物（Snail、波形蛋白和基质金属蛋白酶9）的表达。此外，STAT3和GSK-3β对细胞迁移的抑制作用具有协同性。这些结果表明，STAT3和GSK-3β呈正相关，并协同促进胃癌细胞的转移潜能。因此，联合使用STAT3和GSK-3β抑制剂可能会提高胃癌抗转移治疗的疗效。
