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
Tipo de recurso
artículo
Estado
Versión publicada
Año de publicación
2016
País
Argentina
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio
CONICET Digital (CONICET)
Descripción
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.
Idioma
inglés
OAI Identifier
oai:ri.conicet.gov.ar:11336/23687
Enlace del recurso
http://hdl.handle.net/11336/23687
Nivel de acceso
Acceso abierto
Materia
GALECTIN-7
CERVICAL CANCER
IMMUNE SYSTEM
TUMOR MICROENVIRONMENT
Bioquímica y Biología Molecular
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Patología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD