The Function of SARI in Modulating Epithelial-Mesenchymal Transition and Lung Adenocarcinoma Metastasis

The SARI (suppressor of AP-1, regulated by IFN) gene, which is also called BATF2, is associated with the risk of several kinds of cancer, and loss of SARI expression is frequently detected in aggressive and metastatic cancer. However, the functional role of SARI in lung adenocarcinoma remains unknown. We have shown that loss of SARI expression initiates epithelial-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in lung adenocarcinoma cell lines and in clinical lung adenocarcinoma specimens. Using a human lung xenograft-mouse model, we observed that knocking down endogenous SARI in human carcinoma cells leads to the development of multiple lymph node metastases. Moreover, we showed that SARI functions as a critical protein in regulating EMT by modulating the (GSK)-3β-β-catenin signaling pathway. These results demonstrate the mechanism of SARI function in EMT and suggest that assessment of SARI may serve as a prognostic biomarker and potential therapeutic target for lung adenocarcinoma metastasis.

SARI（suppressor of AP-1, regulated by IFN）基因又名BATF2，其与多种癌症的发病风险相关，且在侵袭性及转移性癌症中常可检测到SARI表达缺失。然而，SARI在肺腺癌中的功能作用仍不明晰。我们的研究证实，在肺腺癌细胞系及临床肺腺癌标本中，SARI表达缺失会启动上皮间质转化（epithelial-mesenchymal transition，简称EMT），该过程可通过E-钙粘蛋白（E-cadherin）的表达下调以及波形蛋白（vimentin）的表达上调得以体现。利用人肺异种移植小鼠模型，我们观察到在人癌细胞中敲低内源性SARI会引发多枚淋巴结转移的发生。此外，我们的研究表明SARI通过调控糖原合成激酶3β（GSK-3β）-β连环蛋白信号通路，在EMT的调控中发挥关键作用。上述研究结果阐明了SARI调控EMT的分子机制，并提示SARI的检测可作为肺腺癌转移的预后生物标志物及潜在治疗靶点。