BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Department Biologie 2 Ludwig Maximilians Universität München Planegg Martinsried Germany

Department of Molecular Pathology and Biology Faculty of Military Health Sciences University of Defense 500 01 Hradec Králové Czech Republic

Division of Tumor Virology German Cancer Research Center 69 120 Heidelberg Germany

Division of Viral Transformation Mechanisms German Cancer Research Center 85764 Neuherberg Germany

Division of Viral Transformation Mechanisms German Cancer Research Center Im Neuenheimer Feld 242 69120 Heidelberg Germany

Division of Viral Transformation Mechanisms German Cancer Research Center Im Neuenheimer Feld 242 69120 Heidelberg Germany Department of Internal Medicine Infectious Diseases and Respiratory Medicine Charité 10117 Berlin Germany

Division of Viral Transformation Mechanisms German Cancer Research Center Im Neuenheimer Feld 242 69120 Heidelberg Germany Interfaculty Institute of Biochemistry University of Tübingen 72076 Tübingen Germany

Division of Viral Transformation Mechanisms German Cancer Research Center Im Neuenheimer Feld 242 69120 Heidelberg Germany Microbiology School Universidad Industrial de Santander Carrera 27 con calle 9 680 011 Bucaramanga Colombia

Division of Viral Transformation Mechanisms German Cancer Research Center Im Neuenheimer Feld 242 69120 Heidelberg Germany Unit of Microbiology Department of Diagnostic Medicine and Prevention S Orsola Malpighi University Hospital Bologna Italy

Laboratorio de Inmunopatología Instituto de Biología y Medicina Experimental Consejo Nacional de Investigaciones Científicas y Técnicas C1428 Ciudad de Buenos Aires Argentina

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