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BMC Cancer. 2016 Aug 24;16:680. doi: 10.1186/s12885-016-2700-8.

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

Author information

1
Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.
2
Institute for Diabetes and Cancer, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764, Neuherberg, Germany.
3
Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité, 10117, Berlin, Germany.
4
Department of Molecular Pathology and Biology, Faculty of Military Health Sciences, University of Defense, 500 01, Hradec Králové, Czech Republic.
5
Unit of Microbiology, Department of Diagnostic Medicine and Prevention, S. Orsola-Malpighi University Hospital, Bologna, Italy.
6
Interfaculty Institute of Biochemistry, University of Tübingen, 72076, Tübingen, Germany.
7
Department Biologie II, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
8
Division of Tumor Virology, German Cancer Research Center (DKFZ), 69,120, Heidelberg, Germany.
9
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas, C1428, Ciudad de Buenos Aires, Argentina.
10
Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany. f.roesl@dkfz-heidelberg.de.
11
Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany. blrincon@uis.edu.co.
12
Microbiology School, Universidad Industrial de Santander, Carrera 27 con calle 9, 680,011, Bucaramanga, Colombia. blrincon@uis.edu.co.

Abstract

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.

KEYWORDS:

Cervical cancer; Differential network analysis; Galectin-7; Microenvironment crosstalk

PMID:
27558259
PMCID:
PMC4997669
DOI:
10.1186/s12885-016-2700-8
[Indexed for MEDLINE]
Free PMC Article

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