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      Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

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          Abstract

          Background

          The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC).

          Objective

          Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer.

          Methods

          Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer.

          Results

          Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca 2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC.

          Conclusion

          The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.

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          Most cited references273

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          Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

          The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
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            Targeting the Wnt/β-catenin signaling pathway in cancer

            The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.
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              CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer

              Background Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. Methods CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. Results CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients. Conclusions CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1019-x) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                zhaohui814@126.com
                1628068619@qq.com
                1770297998@qq.com
                917358987@qq.com
                3154793338@qq.com
                1275440748@qq.com
                1343651968@qq.com
                haibo.xu@cdutcm.edu.cn
                Journal
                Mol Cancer
                Mol Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                14 July 2022
                14 July 2022
                2022
                : 21
                : 144
                Affiliations
                GRID grid.411304.3, ISNI 0000 0001 0376 205X, State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, , Chengdu University of Traditional Chinese Medicine, ; Chengdu, 611137 China
                Article
                1616
                10.1186/s12943-022-01616-7
                9281132
                35836256
                89c3b502-c68c-4c11-9671-8df92a932142
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 5 June 2022
                : 1 July 2022
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Oncology & Radiotherapy
                wnt pathway,biochemical process,drugs and inhibitors,colorectal cancer
                Oncology & Radiotherapy
                wnt pathway, biochemical process, drugs and inhibitors, colorectal cancer

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