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      ADIPOQ rs266729 G/C gene polymorphism and plasmatic adipocytokines connect metabolic syndrome to colorectal cancer

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          Abstract

          Background: ADIPOQ gene, which encode for Adiponectin (APN), is sited on chromosome 3q27 and linked to a susceptibility locus for metabolic syndrome (MetS). The ADIPOQ rs266729 G/C gene polymorphism is significantly associated with low APN levels and linked to susceptibility to develop cancer. In addition, decreased APN serum levels are linked with tumor development and progression and inversely associated with markers of inflammation. Here, we investigate the influence of APN rs266729 G/C polymorphism on adipocytokine circulating levels and their association with MetS in colorectal cancer patients (CRC).

          Methods: Blood samples from 105 CRC patients (50 women and 55 men) with and without MetS were genotyped for APN rs266729 G/C polymorphism by TETRA ARMS PCR. ELISA assay was used to measure plasma levels of APN and inflammatory TNF-α cytokine. Biochemical and anthropometric parameters of MetS were also analyzed.

          Results: We found that CRC patients (N=75) with genotype rs266729G/C or carriers of G allele were associated with a significantly increased risk of MetS development (OR =2.9) compared to those with CC genotype (N=30). Also, CG/GG genotypes were associated with significantly lower plasma APN levels and higher TNF-α levels in comparison to CC genotype (P=0.034) and APN levels were decreased in relation to BMI increases (P=0.001).

          Conclusions: Our findings show that APN rs266729 G/C polymorphism is associated with lower APN levels in CRC patients, indicating that decreased circulating levels of APN may be a determinant risk factor for CRC in MetS patients.

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          Most cited references47

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          Adipose tissue and adipocytes support tumorigenesis and metastasis.

          Adipose tissue influences tumor development in two major ways. First, obese individuals have a higher risk of developing certain cancers (endometrial, esophageal, and renal cell cancer). However, the risk of developing other cancers (melanoma, rectal, and ovarian) is not altered by body mass. In obesity, hypertrophied adipose tissue depots are characterized by a state of low grade inflammation. In this activated state, adipocytes and inflammatory cells secrete adipokines and cytokines which are known to promote tumor development. In addition, the adipocyte mediated conversion of androgens to estrogen specifically contributes to the development of endometrial cancer, which shows the greatest relative risk (6.3-fold) increase between lean and obese individuals. Second, many tumor types (gastric, breast, colon, renal, and ovarian) grow in the anatomical vicinity of adipose tissue. During their interaction with cancer cells, adipocytes dedifferentiate into pre-adipocytes or are reprogrammed into cancer-associated adipocytes (CAA). CAA secrete adipokines which stimulate the adhesion, migration, and invasion of tumor cells. Cancer cells and CAA also engage in a dynamic exchange of metabolites. Specifically, CAA release fatty acids through lipolysis which are then transferred to cancer cells and used for energy production through β-oxidation. The abundant availability of lipids from adipocytes in the tumor microenvironment, supports tumor progression and uncontrolled growth. Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes, should reveal new therapeutic possibilities. This article is part of a Special Issue entitled Lipid Metabolism in Cancer. Copyright © 2013 Elsevier B.V. All rights reserved.
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            Tumor necrosis factor and cancer, buddies or foes?

            Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK). NF-kappaB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the NF-kappaB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates the growth, proliferation, invasion and metastasis, and tumor angiogenesis of cancer cells. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-kappaB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy.
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              Adipose tissue-resident immune cells: key players in immunometabolism.

              Adipose tissue (AT) plays a pivotal role in whole-body lipid and glucose homeostasis. AT exerts metabolic control through various immunological mechanisms that instigated a new research field termed immunometabolism. Here, we review AT-resident immune cells and their role as key players in immunometabolism. In lean subjects, AT-resident immune cells have housekeeping functions ranging from apoptotic cell clearance to extracellular matrix remodeling and angiogenesis. However, obesity provides bacterial and metabolic danger signals that mimic bacterial infection, and drives a shift in immune-cell phenotypes and numbers, classified as a prototypic T helper 1 (Th1) inflammatory response. The resulting AT inflammation and insulin resistance link obesity to its metabolic sequel, and suggests that targeted immunomodulatory interventions may be beneficial for obese patients. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2017
                25 March 2017
                : 8
                : 6
                : 1000-1008
                Affiliations
                [1 ]Clinical Pathology Laboratory, Department of Experimantal Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy;
                [2 ]Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy;
                [3 ]Department of Surgery Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy;
                [4 ]Unit of Medical Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 Bari, Italy.
                Author notes
                ✉ Corresponding author: Rosa Divella, Ph.D., Department of Experimantal Oncology, Clinical Pathology Laboratory National Cancer Institute Giovanni Paolo II, Viale Orazio Flacco, 65, 70100 - Bari, Italy. Tel. +39 805555259; E-mail: rosadive@ 123456inwind.it

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav08p1000
                10.7150/jca.17515
                5436252
                9ace6d1d-be28-4462-b7be-ccc5bde1f921
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 8 September 2016
                : 27 November 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                adiponectin,adipoq gene,tnf-α,colorectal cancer,metabolic syndrome.
                Oncology & Radiotherapy
                adiponectin, adipoq gene, tnf-α, colorectal cancer, metabolic syndrome.

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