Abstract 4900: Functional and mechanism analysis of LGR4 in human lung cancer cells.

Abstract

Abstract LGR4 (leucine-rich repeat containing G protein-coupled receptor 4) and its two closely related homologues LGR5 and LGR6 (LGR4-6) are members of the seven transmembrane domain (7TM) receptors with critical functions in embryonic development and adult stem cells. Recently, we and others discovered that LGR4-6 function as receptors of R-spondins (RSPO) to potentiate Wnt signaling. RSPOs are a group of four secreted proteins (RSPO1-4) with essential roles in organ development, sex determination, carcinogenesis, etc. Particularly, RSPO2 is required for normal lung development through enhancement of Wnt signaling and LGR6 is expressed in adult lung stem cells in the mouse. Among the 900 or so 7TM receptors, LGR4 was found to be one of the few that were highly upregulated in both squamous cell carcinoma (SqCC) and adenocarcinoma (AC) of the lung. Alterations in the Wnt signaling pathways were found in a small percentage of lung cancer. Concurrent activation of β-catenin signaling enhances tumor growth and metastasis of lung cancer cells with KRAS mutation. Furthermore, RSPO3 and LGR4 are co-expressed at high levels in ∼20% of lung cancer cell lines. However, potential roles of RSPO3-LGR4 in lung carcinogenesis have not been investigated. We developed and validated a panel of LGR4 antibodies that can detect either native or denatured LGR4 with high specificity and sensitivity. Immunohistochemistry analyses confirmed that LGR4 was highly expressed in the majority of SqCC and AC of the lung. Knockdown of LGR4 in a lung cancer cell line with high levels of and LGR4 and RSPO3 leads to dramatic decrease in endogenous Wnt signaling and significant reduction in cell growth, migration, and colony formation in vitro. The effect of knockdown on tumor growth in vivo is being tested. Data from these expression and functional analyses of LGR4 in human lung cancer will be presented and discussed. Citation Format: Xing Gong, Wei Xiong, Jing Yi, Kendra S. Carmon, Qingyun Liu. Functional and mechanism analysis of LGR4 in human lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4900. doi:10.1158/1538-7445.AM2013-4900