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      Signaling pathways involved in colorectal cancer progression

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          Abstract

          Colorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-β (TGF-β), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

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          Most cited references60

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          Molecular genetics of colorectal cancer.

          Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes-most prominently the APC, KRAS, and p53 genes-are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.
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            Wnt signaling in cancer.

            Aberrant regulation of the Wnt signaling pathway is a prevalent theme in cancer biology. From the earliest observation that Wnt overexpression could lead to malignant transformation of mouse mammary tissue to the most recent genetic discoveries gleaned from tumor genome sequencing, the Wnt pathway continues to evolve as a central mechanism in cancer biology. This article summarizes the evidence supporting a role for Wnt signaling in human cancer. This includes a review of the genetic mutations affecting Wnt pathway components, as well as some of epigenetic mechanisms that alter expression of genes relevant to Wnt. I also highlight some research on the cooperativity of Wnt with other signaling pathways in cancer. Finally, some emphasis is placed on laboratory research that provides a proof of concept for the therapeutic inhibition of Wnt signaling in cancer.
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              The role of TGF-β/SMAD4 signaling in cancer

              Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.
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                Author and article information

                Contributors
                zahrakoveitypour1371@yahoo.com
                farnoush_panahi@yahoo.com
                mehrdad_vakilian@yahoo.com
                m.peymani@iaushk.ac.ir
                fsforootan@royaninstitute.org
                mh.nasr-esfahani@royaninstitute.org
                kamranghaedi@royaninstitiute.org , kamranghaedi@sci.ui.ac.ir
                Journal
                Cell Biosci
                Cell Biosci
                Cell & Bioscience
                BioMed Central (London )
                2045-3701
                2 December 2019
                2 December 2019
                2019
                : 9
                : 97
                Affiliations
                [1 ]Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran
                [2 ]Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, P.O. Box: 88137-33395, Shahrekord, Iran
                [3 ]ISNI 0000 0001 0454 365X, GRID grid.411750.6, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, , University of Isfahan, ; Isfahan, Iran
                [4 ]GRID grid.417689.5, Department of Cellular Biotechnology, Cell Science Research Center, , Royan Institute for Biotechnology, ACECR, ; P.O. Box: 816513-1378, Isfahan, Iran
                [5 ]Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
                [6 ]ISNI 0000 0001 2200 2355, GRID grid.15449.3d, Department of Cell Regeneration and Advanced Therapies, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), , University of Pablo de Olavide-University of Seville-CSIC, ; Seville, Spain
                [7 ]ISNI 0000 0001 2298 7828, GRID grid.10215.37, Department of Cellular Biology, Genetics and Physiology, Faculty of Science, , University of Malaga (UMA), ; Malaga, Spain
                Author information
                http://orcid.org/0000-0002-9790-5644
                Article
                361
                10.1186/s13578-019-0361-4
                6889432
                30622695
                562283b3-8f30-4cdb-9086-3db8c6835dbb
                © The Author(s) 2019

                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
                : 2 October 2019
                : 22 November 2019
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Cell biology
                colorectal cancer,egfr,mapk,notch,tgf-β
                Cell biology
                colorectal cancer, egfr, mapk, notch, tgf-β

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