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      TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway

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          Abstract

          Background

          Tissue inhibitor matrix metalloproteinase 1 (TIMP1) plays a vital role in carcinogenesis, yet its precise functional roles and regulation remain unclear. In this study, we aim to investigate its biological function and clinical significance in human colon cancer.

          Methods

          We analyzed the expression of TIMP1 in both public database (Oncomine and TCGA) and 94 cases of primary colon cancer and matched normal colon tissue specimens. The underlying mechanisms of altered TIMP1 expression on cell tumorigenesis, proliferation, and metastasis were explored in vitro and in vivo.

          Results

          TIMP1 was overexpressed in colon tumorous tissues and lymph node metastasis specimens than in normal tissues. The aberrant expression of TIMP1 was significantly associated with the regional lymph node metastasis ( p = 0.033), distant metastasis ( p = 0.039), vascular invasion ( p = 0.024) and the American Joint Committee on Cancer (AJCC) stage ( p = 0.026). Cox proportional hazards model showed that TIMP1 was an independent prognostic indicator of disease-free survival (HR = 2.603, 95 % CI: 1.115–6.077, p = 0.027) and overall survival (HR = 2.907, 95 % CI: 1.254–6.737, p = 0.013) for patients with colon cancer. Consistent with this, our findings highlight that suppression of TIMP1 expression decreased proliferation, and metastasis but increased apoptosis by inducing TIMP1 specific regulated FAK-PI3K/AKT and MAPK pathway.

          Conclusion

          TIMP1 might play an important role in promoting tumorigenesis and metastasis of human colon cancer and function as a potential prognostic indicator for colon cancer.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13046-016-0427-7) contains supplementary material, which is available to authorized users.

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          Most cited references28

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          A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics.

          Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 x 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the ;Connectivity Map' with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC.
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            BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.

            Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors. Here we undertook a proteomic analysis to assess whether BAD might also participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A and protein phosphatase 1 (PP1) catalytic units, Wiskott-Aldrich family member WAVE-1 as an A kinase anchoring protein, and glucokinase (hexokinase IV). BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient for BAD or bearing a non-phosphorylatable BAD(3SA) mutant display abnormal glucose homeostasis including profound defects in glucose tolerance. This combination of proteomics, genetics and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis.
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              Genetics, diagnosis and management of colorectal cancer (Review)

              Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. Surgery represents the mainstay of treatment in early cases but often patients are primarily diagnosed in an advanced stage of disease and sometimes also distant metastases are present. Neoadjuvant therapy is therefore needed but drug resistance may influence response and concur to recurrent disease. At molecular level, it is a very heterogeneous group of diseases with about 30% of hereditary or familial cases. During colorectal adenocarcinomas development, epithelial cells from gastrointestinal trait acquire sequential genetic and epigenetic mutations in specific oncogenes and/or tumour suppressor genes, causing CRC onset, progression and metastasis. Molecular characterization of cancer associated mutations gives valuable information about disease prognosis and response to the therapy. Very early diagnosis and personalized care, as well as a better knowledge of molecular basis of its onset and progression, are therefore crucial to obtain a cure of CRC. In this review, we describe updated genetics, current diagnosis and management of CRC pointing out the extreme need for a multidisciplinary approach to achieve the best results in patient outcomes.
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                Author and article information

                Contributors
                docsong2013@hotmail.com
                drshifengxu@outlook.com
                Hong_zhangyq92@hotmail.com
                Wypyiyun08@hotmail.com
                xiaochaochn@163.com
                TJ364702503@163.com
                wll1120809019@sjtu.edu.cn
                zhangtao886532@aliyun.com
                lxingsunhao888@126.com
                Zhonglin7738321@hotmail.com
                Bchongzhien2016@aliyun.com
                XSSGDSB_001@126.com
                Zhi_hai_peng0816@aliyun.com
                yufuchenjian@163.com
                xiaoliangwang1975@hotmail.com
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                20 September 2016
                20 September 2016
                2016
                : 35
                : 148
                Affiliations
                [1 ]Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080 People’s Republic of China
                [2 ]Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021 People’s Republic of China
                [3 ]School of Medicine, Örebro University, Örebro, SE 70182 Sweden
                [4 ]School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200031 People’s Republic of China
                Article
                427
                10.1186/s13046-016-0427-7
                5028967
                27644693
                48436aa1-7f4e-4d75-a8bc-7bf5dd52d9cf
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 July 2016
                : 14 September 2016
                Funding
                Funded by: National Nature Science Foundation of China
                Award ID: 81472241 and 81270557
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                timp1,colon cancer,prognosis,tumorigenesis
                Oncology & Radiotherapy
                timp1, colon cancer, prognosis, tumorigenesis

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