Abstract B07: Loss of LKB1 promotes CXCL8 production via NF-κB and WNT signaling in human bronchial epithelial cells.
Authors: RUI LI, Tonya C. Walser, Kostyantyn Krysan, David Shackelford, Jill E. Larsen, John D. Minna, Steven M. Dubinett
Journal: Clinical Cancer Research (2014)

Abstract Loss of LKB1/STK11, a tumor suppressor gene, characterizes 5-39% of primary non-small cell lung cancers (NSCLC). In a murine model of lung carcinogenesis with inducible KRAS activation, concurrent mutation of LKB1 (KrasG12D, Lkb1-/-) yields a higher frequency of NSCLC tumors and metastasis compared to KRAS mutation only. In vitro studies have shown that following LKB1 loss, tumor cells acquire increased migration and invasion through activation of the SRC kinase family. Although these previous findings offer a possible explanation for LKB1-dependent tumor progression, few mechanisms have been proposed to delineate how LKB1 deficiency contributes to pulmonary carcinogenesis. In this study, we utilize human bronchial epithelial cells (HBECs) immortalized in the absence of viral onco-proteins that represent a useful model to study the early events of lung carcinogenesis. Knockdown of LKB1 in HBECs (LKB1-KD HBECs) leads to numerous cancer-associated phenotypes, including increased proliferation (when combined with KRAS mutation), preference for glycolytic metabolism and induction of epithelial-to-mesenchymal transition. More importantly, LKB1-KD HBECs secrete higher levels of multiple inflammatory factors, most prominent of which is the pro-angiogenic chemokine CXCL8. By binding to its membrane receptors CXCR1/2 which are universally expressed by neutrophils, macrophages, endothelial cells and pulmonary epithelial cells, CXCL8 is associated with chemotaxis, angiogenesis, tumorigenicity and metastasis. Our data indicate that knockdown of LKB1 in HBECs leads to transcriptional upregulation and elevated secretion of CXCL8. Moreover, the NF-κB and WNT pathways are activated and mediate the increased release of CXCL8 following LKB1 loss in HBECs. Conversely, re-introduction of wildtype LKB1 in LKB1-null NSCLC tumor cells decreases CXCL8 production and reduces NF-κB and WNT signaling activity. These findings suggest that LKB1 deficiency drives augmentation of CXCL8 in the developing tumor microenvironment via LKB1-dependent NF-κB and WNT signaling in HBECs. In future functional studies, we will determine if the LKB1-CXCL8 axis yields LKB1-dependent angiogenesis and tumorigenesis. Delineating the contribution of LKB1 to these malignant phenotypes may yield a more thorough understanding of the pathogenesis of NSCLC, which is needed to create a pathway for the application of novel early detection and chemoprevention strategies. NIH/NCI #U01CA152751 (SMD, TCW), NCI #U01CA152751-S1 (SMD, TCW), NCI #U01CA152751-AS (SMD, KK), NCI SPORE #P50CA70907 (JDM, JEL) Citation Format: RUI LI, Tonya C. Walser, Kostyantyn Krysan, David Shackelford, Jill E. Larsen, John D. Minna, Steven M. Dubinett. Loss of LKB1 promotes CXCL8 production via NF-κB and WNT signaling in human bronchial epithelial cells. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B07.