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

Abstract

BackgroundGalectin-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2700-8) contains supplementary material, which is available to authorized users.

Analyzing epigenetic control of galectin expression indicates silencing of galectin‐12 by promoter methylation in colorectal cancer

“…Also, Gal‐7 expression was found to be regulated by DNA methylation in 7 tested cell lines. Such methylation‐dependent expression of Gal‐7 was already described for several tumor entities, including gastric cancer, lymphoma, cervical cancer and vulvar carcinoma , suggesting it as a general characteristic of neoplastic transformation. Although Gal‐4 was suggested to function as a tumor suppressor in CRC and its promoter hypermethylation is associated with poor prognosis in urothelial carcinoma , no or only moderate effects of 5‐Aza‐dC or TSA were observed.…”

Expression of galectin‑7 in vulvar lichen sclerosus and its effect on dermal fibroblasts

“…Since it is a pro-apoptosis protein, this may be associated with the progression of malignancy. Other reports have revealed a high expression of galectin-7 in certain cancer cell lines, including in breast cancer (19), cervical cancer (20), and late and poorly differentiated vulvar squamous cell carcinoma (18). Galectin-7 has also been associated with a poor prognosis in ovarian cancer (21).…”

Galectin-7 in Epithelial Homeostasis and Carcinomas

“…To investigate the function of galectin-7 in apoptosis, most researchers induce the ectopic expression of galectin-7 in diverse cancer cell lines and examine the sensitivity of the cells to apoptotic stimuli. As an illustration, de novo expression of galectin-7 in the cervical cancer HeLa cells and in the colorectal adenocarcinoma DLD-1 cell line makes these cells more sensitive to the induction of apoptosis by UVB irradiation or diverse chemical apoptotic stimuli [ 12 , 54 , 55 , 56 ]. Similarly, overexpression of galectin-7 in ST88-14 cells, a sarcoma-derived cell line, in the cervical carcinoma siHa cells or in the prostate cancer cells DU-145 results in an increased susceptibility of the cells to apoptotic stimuli [ 56 , 57 , 58 ].…”

“…As an illustration, de novo expression of galectin-7 in the cervical cancer HeLa cells and in the colorectal adenocarcinoma DLD-1 cell line makes these cells more sensitive to the induction of apoptosis by UVB irradiation or diverse chemical apoptotic stimuli [ 12 , 54 , 55 , 56 ]. Similarly, overexpression of galectin-7 in ST88-14 cells, a sarcoma-derived cell line, in the cervical carcinoma siHa cells or in the prostate cancer cells DU-145 results in an increased susceptibility of the cells to apoptotic stimuli [ 56 , 57 , 58 ]. Accordingly, galectin-7 downregulation in the cervical squamous carcinoma cells SiHa and C-33A increases cell viability in response to the apoptosis-inducing chemotherapeutic agent paclitaxel [ 59 ].…”