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      Correlation Between IGFs-Related Proteins Expression and Incidence of Colorectal Cancer in Diabetic Patients and Related Mechanisms

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          Abstract

          Background

          Diabetes mellitus a common metabolic disorder with hyperglycemia, is caused by the interaction of genetic and environmental factors. Approximately 12~20% of diabetic patients have risk of colorectal cancer. Recent studies revealed that the insulin-like growth factor system (IGFs) plays an important role in tumor occurrence. This study thus investigated the relationship between IGFs-related proteins in diabetic patients and the incidence of colorectal carcinoma.

          Material/Methods

          A retrospective study was performed in a total of 206 individuals, including 85 diagnosed with diabetes. The incidence of colorectal cancer was tracked, along with the detection of IGFs expression in serum. During the surgical resection, tumor tissues and adjacent tissues were collected and quantified for IGFs expression level.

          Results

          We found no significant difference in age or sex between the diabetic and control groups. Diabetic patients, however, had elevated body weight and higher incidence of colorectal cancer compared to non-diabetic controls (p<0.05). The diabetic group also had higher IGF-I and IGF-IR mRNA levels in serum, while IGFBP-6 expression was down-regulated. In comparison to adjacent healthy tissues, tumor tissue had higher levels of IGF-I and IGF-IR but lower levels of IGFBP-6 (p<0.05).

          Conclusions

          Our study showed higher incidence of colorectal cancer in diabetics compared to non-diabetics. The occurrence of colorectal cancer in diabetic patients may be associated with elevated IGFs-related protein expression level.

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          Most cited references23

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          Islet inflammation and CXCL10 in recent-onset type 1 diabetes.

          Type 1 diabetes results from a T cell-mediated destruction of insulin-producing pancreatic beta cells. Little is known on local factors contributing to migration of T cells to pancreatic tissue. We recently demonstrated evidence of viral infection in beta cells in several recent-onset type 1 diabetes patients. Islet inflammation was analysed in a series of new- or recent-onset type 1 diabetic patients and non-diabetic control subjects. Autoimmune T cell reactivity was studied in lymphocytes derived from pancreas-draining lymph nodes of one recent-onset type 1 diabetes patient in partial clinical remission. Insulitic lesions were characterized by presence of beta cells, elevated levels of the chemokine CXCL10 and infiltration of lymphocytes expressing the corresponding chemokine receptor CXCR3 in all pancreatic lesions of type 1 diabetes patients, regardless of enterovirus infection of beta cells. CXCR3 and CXCL10 were undetectable in pancreata of non-diabetic control subjects. T cells isolated from draining lymph nodes of a recent-onset patient with virally infected beta cells and in clinical remission reacted with multiple islet autoantigens and displayed a mixed interferon (IFN)-gamma/interleukin (IL)-10 cytokine pattern. Our data point to CXCL10 as an important cytokine in distressed islets that may contribute to inflammation leading to insulitis and beta cell destruction, regardless of local viral infection. We demonstrate further pro- and anti-inflammatory islet autoreactivity, indicating that different adaptive and innate immune responses may contribute to insulitis and beta cell destruction.
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            IGF-1R, IGF-1 and IGF-2 expression as potential prognostic and predictive markers in colorectal-cancer.

            Insulin-like growth factors (IGF-1 and IGF-2) and the IGF-1 membrane receptor (IGF-1R) have been found to play a critical role in the carcinogenesis of several tumors, among them colorectal cancer (CRC). To study the prognostic impact of these molecules, a total number of 713 cases of CRC were examined for the expression of IGF-1, IGF-2, and IGF-1R. The results were correlated with other clinicopathological data and clinical follow-up. IGF-1 expression was noted in 53 (7.5%), IGF-2 in 88 (12.6%), and IGF-1R in 698 (99.6%) of the cases. There were significant associations between the two growth factors ( P<0.00001), between IGF-1 and Ki-67 proliferation activity ( P<0.05), and between IGF-2 and tumor stage ( P<0.005). IGF-2 positivity was significantly correlated to a worse clinical outcome ( P<0.005) only in univariate, but not in multivariate, survival analysis. A similar trend was obtained for patients with IGF-1-positive CRC, but reached statistical significance only in limited tumor stages (pT1/pT2; P<0.01). Although the synchronous expression of IGF-1, IGF-2, and IGF-1R in a subset of CRC is consistent with an auto-/paracrine loop of cancer cell autostimulation, the prognostic effect of IGF-1 and IGF-2 expression seems to be of limited value. However, the identification of IGF-positive CRC might be beneficial for predictive reasons, as new molecular therapeutic approaches are aimed at the IGF system and related pathways.
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              IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration.

              The RON receptor tyrosine kinase (RTK) is overexpressed in the majority of pancreatic cancers, yet its role in pancreatic cancer cell biology remains to be clarified. Recent work in childhood sarcoma identified RON as a mediator of resistance to insulin-like growth factor receptor (IGF1-R)-directed therapy. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants. Using multidimensional protein identification analysis, IGF-1R was identified and confirmed to interact with RON in pancreatic cancer cell lines. IGF-1 induces rapid phosphorylation of RON, but RON signaling did not activate IGF-1R indicating unidirectional signaling between these RTKs. We next demonstrate that IGF-1 induces pancreatic cancer cell migration that is RON dependent, as inhibition of RON signaling by either shRNA-mediated RON knockdown or by a RON kinase inhibitor abrogated IGF-1 induced wound closure in a scratch assay. In pancreatic cancer cells, unlike childhood sarcoma, STAT-3, rather than RPS6, is activated in response to IGF-1, in a RON-dependent manner. The current study defines a novel interaction between RON and IGF-1R and taken together, these two studies demonstrate that RON is an important mediator of IGF1-R signaling and that this finding is consistent in both human epithelial and mesenchymal cancers. These findings demand additional investigation to determine if IGF-1R independent RON activation is associated with resistance to IGF-1R-directed therapies in vivo and to identify suitable biomarkers of activated RON signaling.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2016
                15 March 2016
                : 22
                : 848-854
                Affiliations
                [1 ]Department of Endocrine, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China
                [2 ]Department of Cadres Health, The First Hospital of Shijiazhuang, Shijiazhuang, Hebei, P.R. China
                Author notes
                Corresponding Author: Aige Yang, e-mail: yangaige258@ 123456126.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                [*]

                Xu Han and Sufang Hou contributed equally to this work

                Article
                895837
                10.12659/MSM.895837
                4795090
                26976474
                48e1e6c2-c777-44dc-9b06-ce1750b2c98d
                © Med Sci Monit, 2016

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License

                History
                : 01 September 2015
                : 23 September 2015
                Categories
                Clinical Research

                colorectal neoplasms,diabetes insipidus, nephrogenic,insulin lispro

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