Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610-3633, USA.
Oncogene. 2012 Jan 26;31(4):469-79. doi: 10.1038/onc.2011.247. Epub 2011 Jun 27.
LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.
LKB1 是 Peutz-Jeghers 癌症综合征的肿瘤易感性基因，也是散发性人类恶性肿瘤中突变失活的靶点。LKB1 编码一种丝氨酸/苏氨酸激酶，在细胞生长、极性和代谢中具有关键作用。LKB1 的一个新的重要功能是其调节 CREB 调节转录共激活因子（CRTCs）磷酸化的能力，CRTCs 的异常激活与致癌活性有关。然而，LKB1 和 CRTC 在食管癌发病机制中的作用和机制尚未得到研究。在这项研究中，我们观察到在一组人类食管癌细胞系和患者样本中存在改变的 LKB1-CRTC 信号。LKB1 负调节体外食管癌细胞的迁移和侵袭。在机制上，我们确定由于 LKB1 的缺失，CRTC 信号被激活，导致特定下游靶基因包括 LYPD3 的转录激活，LYPD3 是 LKB1 功能丧失的关键介质。我们的数据表明，失调的 LKB1-CRTC 信号可能代表食管癌进展的关键机制。
