Abstract 5315: Interactions between LRIG proteins and LMO7 and the expression of LMO7 in human lung cancer.

Abstract

Abstract The Leucine-rich repeats and immunoglobulin-like domains proteins (LRIG) 1, 2 and 3 are integral membrane proteins that have been implicated in human cancer. We and others have shown that LRIG1 is a negative regulator of receptor tyrosine kinase (RTK) signaling. LRIG1 is down regulated in many tumors; the expression of LRIG1 is often associated with long patient survival; and LRIG1 has been shown to be a tumor suppressor in the mouse intestine. Cytoplasmic expression of LRIG2 is associated with a poor survival for oligodendroglioma patients and perinuclear expression of LRIG3 in astrocytic tumors is associated with a better survival for the patients. LRIG3 is involved in the formation of the inner ear during embryology and a study suggests that LRIG3 is a serum biomarker for NSCLC. To further elucidate the functions of the LRIG proteins we performed a yeast two hybrid (YTH) screen in which we identified LMO7 and LIMCH1 as interaction partners to LRIG3. LMO7 is a cytoskeletal binding protein and functions as a transcription factor. A study in which LMO7 was deleted in mice showed that these mice developed spontaneous lung cancers, especially adenocarcinomas, at high age. Using laser confocal microscopy we found that LRIG3 and LMO7 co-localized in cytoskeletal like structures, the border of the cell and at the perinuclear region. To analyze the possible interaction between LRIG1, 2 and 3 and LMO7, we used the proximity ligation assay (PLA) technique. Endogenously expressed LRIG1, 2 and 3 all appeared to interact with endogenous LMO7 in all cell lines tested. LMO7 down regulation by siRNA resulted in fewer apparent LMO7-LRIG interactions, confirming the specificity of the PLA assays. Using QRT-RTPCR we found that LMO7 mRNA was highly expressed in small intestine, lung and colon. Comparison of the mRNA level of LMO7 in normal human lung and a panel of different human lung tumors showed a dramatic decrease of LMO7 mRNA expression in the human lung tumors. Analysis of the cancer genome atlas (TCGA) database indicated that LMO7 gene expression was high in human normal colorectal and lung tissues, and the expression of LMO7 was dramatically decreased in malignant colorectal and lung tissues. To further study LMO7 in lung cancer, we stained a tissue microarray with 364 lung cancer tissue samples and 17 normal human lung tissue samples for LMO7. LMO7 was rarely expressed in the human lung tumors. Multivariate Cox regression analysis indicated that LMO7 was a prognostic factor in human lung cancer (p = 0.013). In summary LMO7 interacted with all three LRIG proteins, the expression of LMO7 was decreased in malignant colorectal and lung tissues compared to normal tissues and LMO7 appeared to be a prognostic factor in human lung cancer. Citation Format: Terese Karlsson, Samuel Kvarnbrink, Camilla Holmlund, Johan Botling, Patrick Micke, Mikael Johansson, Roger Henriksson, Håkan Hedman. Interactions between LRIG proteins and LMO7 and the expression of LMO7 in human lung cancer. [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 5315. doi:10.1158/1538-7445.AM2013-5315