title: Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610-3633, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.forename: S
authors.initials: S
authors.lastname: Lin
authors.forename: J-L
authors.initials: JL
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Jin
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.forename: D A
authors.initials: DA
authors.lastname: Ucar
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: S N
authors.initials: SN
authors.lastname: Hochwald
authors.forename: F J
authors.initials: FJ
authors.lastname: Kaye
authors.forename: L
authors.initials: L
authors.lastname: Wu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D015815:Cell Adhesion Molecules / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000473:pathology*; D058851:GPI-Linked Proteins / Q000502:physiology; D006801:Humans; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C115163:CREB1 protein, human; C500984:CRTC1 protein, human; D015815:Cell Adhesion Molecules; D017362:Cyclic AMP Response Element-Binding Protein; D058851:GPI-Linked Proteins; C472589:LYPD3 protein, human; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases