Slit2/Robo1 signaling inhibits small-cell lung cancer by targeting β-catenin signaling in tumor cells and macrophages.

Autor: Ahirwar DK; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, India., Peng B; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA., Charan M; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA., Misri S; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA., Mishra S; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA., Kaul K; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA., Sassi S; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA., Gadepalli VS; Biomedical Informatics, The Ohio State University, Columbus, OH, USA., Siddiqui J; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA., Miles WO; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA., Ganju RK; Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2023 May; Vol. 17 (5), pp. 839-856. Date of Electronic Publication: 2023 Jan 10.
DOI: 10.1002/1878-0261.13289
Abstrakt: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with poor patient prognosis. However, the mechanisms that regulate SCLC progression and metastasis remain undefined. Here, we show that the expression of the slit guidance ligand 2 (SLIT2) tumor suppressor gene is reduced in SCLC tumors relative to adjacent normal tissue. In addition, the expression of the SLIT2 receptor, roundabout guidance receptor 1 (ROBO1), is upregulated. We find a positive association between SLIT2 expression and the Yes1 associated transcriptional regulator (YAP1)-expressing SCLC subtype (SCLC-Y), which shows a better prognosis. Using genetically engineered SCLC cells, adenovirus gene therapy, and preclinical xenograft models, we show that SLIT2 overexpression or the deletion of ROBO1 restricts tumor growth in vitro and in vivo. Mechanistic studies revealed significant inhibition of myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (TAMs) in the SCLC tumors. In addition, SLIT2 enhances M1-like and phagocytic macrophages. Molecular analysis showed that ROBO1 knockout or SLIT2 overexpression suppresses the transforming growth factor beta 1 (TGF-β1)/β-catenin signaling pathway in both tumor cells and macrophages. Overall, we find that SLIT2 and ROBO1 have contrasting effects on SCLC tumors. SLIT2 suppresses, whereas ROBO1 promotes, SCLC growth by regulating the Tgf-β1/glycogen synthase kinase-3 beta (GSK3)/β-catenin signaling pathway in tumor cells and TAMs. These studies indicate that SLIT2 could be used as a novel therapeutic agent against aggressive SCLC.
(© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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