Abstract C296: The contribution of LKB1/STK11-mediated CXCL8 dysregulation to lung carcinogenesis.
Authors: Li Rui , Walser Tonya C. , Krysan Kostyantyn , Shackelford David , Larsen Jill E. , Minna John D. , Dubinett Steven M. 
Published: August 2014

LKB1/STK11 is a tumor suppressor gene that was originally identified in an autosomal-dominant inherited disorder, Peutz-Jeghers Syndrome (PJS). Patients with PJS develop an overgrowth of differentiated tissues in the gastrointestinal tract with 100% penetration and demonstrate an increased predisposition toward a number of additional malignancies, including breast, ovarian, pancreatic and lung cancers. Loss-of-function in LKB1/STK11 characterizes up to 20-30% of non-small cell lung cancers (NSCLC). In a murine model of lung carcinogenesis with inducible Kras activation and biallelic deletion of LKB1(KrasG12D Lkb1-/-), loss of LKB1 yielded a high frequency of NSCLC tumors and metastasis. However, few mechanisms have been proposed to explain how LKB1 loss contributes to pulmonary tumorigenesis, especially during early stage of tumor development. In this study, we use human bronchial epithelial cells (HBECs) that were immortalized in the absence of viral onco-proteins and therefore represent an accurate model for studying early events during lung carcinogenesis. We knocked down LKB1 expression in HBECs (LKB1-KD HBECs) and observed numerous cancer-associated characteristics, including preference for glycolytic metabolism and induction of epithelial mesenchymal transition. Intriguingly, we also found dysregulation of several inflammatory factors in addition to these anticipated phenotypes. We have focused on the pro-angiogenic chemokine CXCL8, which is also associated with chemotaxis, tumorigenicity and metastasis via binding to its membrane receptors CXCR1/2. Knockdown of LKB1 leads to transcriptional upregulation and significantly elevated secretion of CXCL8, while re-introduction of wild type LKB1 decreases CXCL8 production in LKB1-null NSCLC tumor cell lines. Interestingly, the phosphorylation levels of GSK3β and β-catenin (S552) are elevated in LKB1-KD HBECs, and a TCF/β-catenin binding inhibitor abolishes the induction of CXCL8 upon LKB1 loss. This suggests that the WNT pathway may mediate these effects. Together, these findings suggest that loss of LKB1 promotes tumorigenesis and metastasis through a CXCL8 mediated-pro-inflammatory tumor microenvironment. Therefore, blocking CXCL8 function via neutralizing peptide or receptor antagonist may represent a novel therapeutic strategy for NSCLC prevention and treatment.These studies were supported by the DOD #LC120407 (SMD, DS, TCW), China Scholarship Council (CSC) #2010632164 (RL) and NCI SPORE P50CA70907 (JDM,JEL).

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C296.

Citation Format: Rui Li, Tonya C. Walser, Kostyantyn Krysan, David Shackelford, Jill E. Larsen, John D. Minna, Steven M. Dubinett. The contribution of LKB1/STK11-mediated CXCL8 dysregulation to lung carcinogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C296.