title: Systems-level effects of ectopic galectin-7 reconstitution in cervical cancer and its microenvironment.
abstract: Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited.
  
  
  
  Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn's Multiple Comparison and T tests. Kaplan-Meier and log-rank tests were used to determine overall survival.
  
  
  
  Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples.
  
  
  
  Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected.
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.|Institute for Diabetes and Cancer, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764, Neuherberg, Germany.
authors: Juan Carlos
authors: JC
authors: Higareda-Almaraz
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.|Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité, 10117, Berlin, Germany.
authors: Juan S
authors: JS
authors: Ruiz-Moreno
authors: Department of Molecular Pathology and Biology, Faculty of Military Health Sciences, University of Defense, 500 01, Hradec Králové, Czech Republic.
authors: Jana
authors: J
authors: Klimentova
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.|Unit of Microbiology, Department of Diagnostic Medicine and Prevention, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors: Daniela
authors: D
authors: Barbieri
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.|Interfaculty Institute of Biochemistry, University of Tübingen, 72076, Tübingen, Germany.
authors: Raquel
authors: R
authors: Salvador-Gallego
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.
authors: Regina
authors: R
authors: Ly
authors: Department Biologie II, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
authors: Ilse A
authors: IA
authors: Valtierra-Gutierrez
authors: Division of Tumor Virology, German Cancer Research Center (DKFZ), 69,120, Heidelberg, Germany.
authors: Christiane
authors: C
authors: Dinsart
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas, C1428, Ciudad de Buenos Aires, Argentina.
authors: Gabriel A
authors: GA
authors: Rabinovich
authors: Department of Molecular Pathology and Biology, Faculty of Military Health Sciences, University of Defense, 500 01, Hradec Králové, Czech Republic.
authors: Jiri
authors: J
authors: Stulik
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany. f.roesl@dkfz-heidelberg.de.
authors: Frank
authors: F
authors: Rösl
authors: Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany. blrincon@uis.edu.co.|Microbiology School, Universidad Industrial de Santander, Carrera 27 con calle 9, 680,011, Bucaramanga, Colombia. blrincon@uis.edu.co.
authors: Bladimiro
authors: 0000-0001-5323-0422
authors: B
authors: Rincon-Orozco
mesh_terms: D005260:Female; D037161:Galectins / Q000378:metabolism*; D006801:Humans; D059016:Tumor Microenvironment / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D037161:Galectins; C092525:LGALS7 protein, human
keywords: Cervical cancer; Differential network analysis; Galectin-7; Microenvironment crosstalk