Systems-level effects of ectopic galectin-7 reconstitution in cervical cancer and its microenvironment

• Autores: Higareda Almaraz, Juan Carlos; Ruiz Moreno, Juan S.; Klimentova, Jana; Barbieri, Daniela; Salvador Gallego, Raquel; Ly, Regina; Valtierra Gutierrez, Ilse A.; Dinsart, Christiane; Rabinovich, Gabriel Adrián; Stulik, Jiri; Rösl, Frank; Rincon Orozco, Bladimiro
• Año de publicación: 2016
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: GALECTIN-7; CERVICAL CANCER; IMMUNE SYSTEM; TUMOR MICROENVIRONMENT
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

ckgroundGalectin-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.MethodsMeta-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.ResultsGal-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.ConclusionsGal-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.
Fil: Higareda Almaraz, Juan Carlos. German Cancer Research Center DKFZ; Alemania. Helmholtz Zentrum München; Alemania
Fil: Ruiz Moreno, Juan S.. German Cancer Research Center DKFZ; Alemania. Infectious Diseases and Respiratory Medicine; Alemania
Fil: Klimentova, Jana. University of Defence Czech Republic; Eslovaquia
Fil: Barbieri, Daniela. German Cancer Research Center DKFZ; Alemania. Policlinico S.Orsola Malpighi; Italia
Fil: Salvador Gallego, Raquel. German Cancer Research Center DKFZ; Alemania. Eberhard Karls Universität Tübingen ; Alemania
Fil: Ly, Regina. German Cancer Research Center DKFZ; Alemania
Fil: Valtierra Gutierrez, Ilse A.. Ludwig Maximilians Universität München; Alemania
Fil: Dinsart, Christiane. German Cancer Research Center DKFZ; Alemania
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Stulik, Jiri. University of Defence Czech Republic; Eslovaquia
Fil: Rösl, Frank. German Cancer Research Center DKFZ; Alemania
Fil: Rincon Orozco, Bladimiro. German Cancer Research Center DKFZ; Alemania. Universidad Industrial de Santander; Colombia