Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness

• Published in: Oncogene 2015-09, Vol.34 (36), p.4692-4701
• Main Authors: Gong, X, Yi, J, Carmon, K S, Crumbley, C A, Xiong, W, Thomas, A, Fan, X, Guo, S, An, Z, Chang, J T, Liu, Q J
• Format: Article
• Language: English
• Subjects: 13; 13/51; 38; 38/91; 42; 42/109; 631/67/1612/1350; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Animals; Apoptosis; Cancer; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Cell survival; Cellular signal transduction; Colon cancer; Colorectal carcinoma; Demethylation; Development and progression; Gene expression; Gene Expression Regulation, Neoplastic; Gene fusion; Genetic aspects; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; IQGAP1 protein; Kelch-Like ECH-Associated Protein 1; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Neoplasm Staging; Oncogene Proteins, Fusion - biosynthesis; Oncogene Proteins, Fusion - genetics; Oncology; original-article; Receptors, G-Protein-Coupled - biosynthesis; Receptors, G-Protein-Coupled - genetics; Risk factors; Signal Transduction; Stem cells; Thrombospondins - biosynthesis; Thrombospondins - genetics; Tumor cell lines; Tumorigenesis; Tumors; Wnt protein; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.417

The four R-spondins (RSPO1–4) and their three related receptors LGR4, 5 and 6 (LGR4–6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P