Genetic Polymorphisms of the TGFB1 Signal Peptide and Promoter Region: Role in Wilms Tumor Susceptibility?

The aim of the present study was to investigate the rs1800468 (G-800A), rs1800469 (C-509T), rs1800470 (C29T), and rs1800471 (G74C) TGFB1 genetic polymorphisms and their haplotype structures in patients with Wilms Tumor (WT) and neoplasia-free controls. The genomic DNA was extracted from 35 WT patients and 160 neoplasia-free children, and the TGFB1 polymorphisms were genotyped by polymerase chain reaction, followed by restriction fragment length polymorphism. The haplotype structures were inferred, and permutation and logistic regression tests were performed to check for differences in haplotype distribution between the control and WT individuals. Positive associations were found in the recessive model for rs1800469 T allele (OR: 8.417; 95% CI: 3.177 to 22.297; P < 0.001) and for the rs1800470 C allele (OR: 3.000; 95% CI: 1.296 to 6.944; P = 0.01). Haplotype analysis revealed a significant negative association between GCTG and WT (OR: 0.236, 95% CI: 0.105 to 0.534; P = 0.0002); by contrast, the GTTG haplotype was associated with increased risk for WT (OR: 12.0; 95% CI: 4.202 to 34.270; P < 0.001). Furthermore, rs1800469 was negatively correlated with tumor size and a trend toward a positive correlation for capsular invasion was observed in the dominant model (Tau-b: −0.43, P = 0.02 and tau-b: 0.5, P = 0.06, respectively). This is the first study with rs1800468, rs1800469, rs1800470, and rs1800471 TGFB1 polymorphisms in WT, and our results suggest that the TGFB1 promoter and signal peptide region polymorphisms may be associated with WT susceptibility and clinical presentation

Genetic Polymorphism and Expression of CXCR4 in Breast Cancer

CXCR4 genetic polymorphisms, as well as their expression level, have been associated with cancer development and prognosis. The present study aimed to investigate the influence of CXCR4 rs2228014 polymorphism on its mRNA and protein expression in breast cancer samples. It was observed that patients presented higher CXCR4 mRNA relative expression (5.7-fold) than normal mammary gland, but this expression was not correlated with patients clinicopathological features (nuclear grade, nodal status, ER status, PR status, p53 staining, Ki67 index, and HER-2 status). Moreover, CXCR4 mRNA relative expression also did not differ regarding the presence or absence of T allele (p=0.301). In the immunohistochemical assay, no difference was observed for CXCR4 cytoplasmic protein staining in relation to different genotypes (p=0.757); however, high cytoplasmic CXCR4 staining was verified in invasive breast carcinoma (p<0.01). All in all, the results from present study indicated that rs2228014 genetic variant does not alter CXCR4 mRNA or protein expression. However, this receptor was more expressed in tumor compared to normal tissue, in both RNA and protein levels, suggesting its promising applicability in the general context of mammary carcinogenesis

IL-10 in cancer: Just a classical immunosuppressive factor or also an immunostimulating one?

It is generally well-accepted and established the IL-10-mediated protumor function in cancer, based on its immunosuppressive properties. However, new evidences from in vitro and in vivo murine models have emerged showing a potential immunostimulating activity of this cytokine, which may sustain IL-10-mediated antitumor function in cancer, hence favoring tumor regression. Here, we attempt to clarify IL-10’s role in cancer, by conducting a literature review of previously published studies, presenting information about IL-10 immunosuppressive and/or immunostimulating properties. Different and contradictory IL-10 effects leading to tumor growth (e.g., suppression of pro-inflammatory cytokines or inhibition of immune response recognition steps) or tumor regression (e.g., stimulation of cytotoxic and cytolytic activities of immune cells or inhibition of angiogenic factors) were found in distinct scenarios, hindering the establishment of a general role for IL-10 in cancer. Such definition is still a challenge, maybe due to a lack of sufficient information to support it, or perhaps based on the fact that IL-10 role in distinct cancer contexts may vary, switching from a classical immunosuppressive factor to an immunostimulating one

Involvement of CXCL12 Pathway in HPV-related Diseases

Human Papillomavirus (HPV) is a necessary cause of cervical cancer in women worldwide. However, the HPV infection is not sufficient to cause neoplasia, and immune mediators, such as chemokines, are important in this context, since they are involved in the regulation of leukocyte trafficking in many essential biological processes, including inflammation. Prolonged inflammation is thought to facilitate carcinogenesis by providing a microenvironment that is ideal for tumor cell development and growth. Chemokines also contribute to tumor development by promoting angiogenesis and metastasis. Among these molecules we highlight the chemokine CXCL12, also called stromal-derived factor 1 alpha (SDF1-α), a pleiotropic chemokine capable of eliciting multiple signal transduction cascades and functions, via interaction with either CXCR4 or CXCR7, which have been implicated in malignant cell survival, proliferation and migration. This review will focus on our current knowledge in the pathogenesis of HPV infection, the main aspects of CXCL12 signaling, its participation in tumor development and immunodeficiencies that may enable the HPV infection. We also discuss how CXCL12 gene expression and polymorphisms may influence tumor development, especially cervical cancer. Finally, we highlight how the inhibition of CXCL12 pathway may be an attractive alternative for cancer therapeutics

Immunohistochemical Expression of CXCR4 on Breast Cancer and Its Clinical Significance

Many tumor cells express chemokines and chemokine receptors, and, for this reason, these molecules can affect the tumor progression. It is known that breast cancer is a complex and heterogeneous neoplasia comprising distinct diseases, histological characteristics, and clinical outcomes. The most studied role for CXCL12 chemokine and its receptor CXCR4 in breast cancer pathogenesis is the metastasis event, although several reports have demonstrated its involvement in other processes, such as angiogenesis and tumor growth. It has been found that CXCR4 is required for breast cancer cell migration to other sites such as lung, bone, and lymph nodes, which express high levels of CXCL12 chemokine. Therefore, CXCR4 is being considered a prognostic marker in breast cancer. Within this context, this review summarizes established studies involving expression of CXCR4 on breast cancer, focusing on its clinical significance

<strong>Investigating the association of chemokine receptor 5 (CCR5) polymorphism with cervical cancer in human papillomavirus (HPV) positive patients</strong> - DOI: 10.4025/actascihealthsci.v30i2.944 <b>Investigating association of chemokine receptor 5 (CCR5) polymorphism with cervical cancer in human papillomavirus (HPV) suggestive patients</b> - DOI: 10.4025/actascihealthsci.v30i2.944

HPV is one of the most frequent causes for the development of cervical cancer. It is known that chemokines are important determinants of early inflammatory responses. The CC chemokine receptor 5 (CCR5) gene is involved in the chemotaxis of leukocytes toward inflammation sites. In the present study, polymerase chain reactions (PCR) in genomic DNA samples, using specific CCR5 oligonucleotide primers surrounding the breakpoint deletion, detected a 225 bp product from the normal CCR5 allele and a 193 bp product from the 32 bp deletion allele. The wild type genotype was prevalent in both group, but it was not statistically significant, with χ² = 1.519 (2 degrees of freedom; p > 0.05). As there are a small number of 32 allele carriers, further studies are needed to clarify the role of CCR5 in the cervical cancer.<br>HPV is the most responsible of cervical cancer. It is known that chemokines are important determinants of the early inflammatory response. The CC chemokine receptor 5 (CCR5) gene is involved in the chemotaxis of leukocytes toward inflammation sites. In the present study, polymerase chain reactions (PCR) in genomic DNA samples, using specific CCR5 oligonucleotide primers surrounding the breakpoint deletion, detected a 225bp product from the normal CCR5 allele and a 193bp product from the 32bp deletion allele. The wild type genotype was prevalent in both group, but it wasn’t statistically significant with χ² =1,519 (2 degrees of freedom; p>0.05). Once there is a small number of 32 allele carriers, further studies are needed to clarify the role of CCR5 in the cervical cancer

Immunohistochemical Expression of CXCR4 on Breast Cancer and Its Clinical Significance

Many tumor cells express chemokines and chemokine receptors, and, for this reason, these molecules can affect the tumor progression. It is known that breast cancer is a complex and heterogeneous neoplasia comprising distinct diseases, histological characteristics, and clinical outcomes. The most studied role for CXCL12 chemokine and its receptor CXCR4 in breast cancer pathogenesis is the metastasis event, although several reports have demonstrated its involvement in other processes, such as angiogenesis and tumor growth. It has been found that CXCR4 is required for breast cancer cell migration to other sites such as lung, bone, and lymph nodes, which express high levels of CXCL12 chemokine. Therefore, CXCR4 is being considered a prognostic marker in breast cancer. Within this context, this review summarizes established studies involving expression of CXCR4 on breast cancer, focusing on its clinical significance

FOXP3 Allelic Variants and Haplotype Structures Are Associated with Aggressive Breast Cancer Subtypes

FOXP3 genetic polymorphisms have been associated with cancer development and prognosis. In this context, the present study aimed to evaluate the g.10403A>G (rs2232365) polymorphisms and g.8048A>C (rs3761548), in aggressive breast cancer (BC) subtypes, including, Luminal B HER2+ (LB), HER2-enriched (HER2+), and triple-negative (TN). Polymerase chain reaction followed by enzymatic restriction was performed to genotyping 117 BC samples and 300 controls. A significant association of AA genotype (g.10403A>G) in relation to BC susceptibility (OR = 1.93; 95% CI = 1.01–3.66; p=0.046) was observed. The GG (g.10403A>G) genotype was correlated with higher proliferation index (Ki-67) in HER2+ subtype (τ = 0.47; p=0.019) and advanced TNM staging in TN (τ = 0.23; p=0.032). A correlation of AA genotype (g.8048A>C) with higher Ki-67 (τ = −0.47; p=0.018) and lower histological grade (τ = 0.39; p=0.026) in HER2+ was also found. GA haplotype was correlated with lower histological grade (τ = −0.15; p=0.009) and higher Ki-67 (τ = 0.43; p=0.036) in HER2+ and advanced staging in TN (τ = 0.29; p=0.044). On the other hand, AC haplotype was correlated with lower Ki-67 (τ = −0.54; p=0.005) and staging (τ = −0.29; p=0.027) in HER2+ and TN respectively. Results showed that FOXP3 influence regarding clinical outcome depends greatly on the BC subtype and indicated this transcription factor as a promising marker in aggressive BC subtypes