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      CLCA1 suppresses colorectal cancer aggressiveness via inhibition of the Wnt/beta-catenin signaling pathway

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          Abstract

          Background

          Chloride channel accessory 1 (CLCA1) belongs to the calcium-sensitive chloride conductance protein family, which is mainly expressed in the colon, small intestine and appendix. This study was conducted to investigate the functions and mechanisms of CLCA1 in colorectal cancer (CRC).

          Methods

          The CLCA1 protein expression level in CRC patients was evaluated by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and western blotting analysis. Using CRISPR/Cas9 technology, CLCA1-upregulated (CLCA1-ACT) and CLCA1-knockout cells (CLCA1-KO), as well as their respective negative controls (CLCA1-ACT-NC and CLCA1-KO-NC), were constructed from the SW620 cell line. Cell growth and metastatic ability were assessed both in vitro and in vivo. The association of CLCA1 with epithelial-mesenchymal transition (EMT) and other signaling pathways was determined by western blotting assays.

          Results

          The expression level of CLCA1 in CRC tissues was significantly decreased compared with that in adjacent normal tissue ( P< 0.05). Meanwhile, the serum concentration of CLCA1 in CRC patients was also significantly lower when compared with that of healthy controls (1.48 ± 1.06 ng/mL vs 1.06 ± 0.73 ng/mL, P = 0.0018). In addition, CLCA1 serum concentration and mRNA expression level in CRC tissues were inversely correlated with CRC metastasis and tumor stage. Upregulated CLCA1 suppressed CRC growth and metastasis in vitro and in vivo, whereas inhibition of CLCA1 led to the opposite results. Increased expression levels of CLCA1 could repress Wnt signaling and the EMT process in CRC cells.

          Conclusions

          Our findings suggest that increased expression levels of CLCA1 can suppress CRC aggressiveness. CLCA1 functions as a tumor suppressor possibly via inhibition of the Wnt/beta-catenin signaling pathway and the EMT process.

          Electronic supplementary material

          The online version of this article (dio: 10.1186/s12964-017-0192-z) contains supplementary material, which is available to authorized users.

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          Most cited references39

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          Epithelial-mesenchymal transitions in development and disease.

          Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)
          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Wnt signaling and cancer.

            Paul Polakis (2000)
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              Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer.

              A. B. Sparks, P J Morin, B Vogelstein … (1998)
              Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.
              Article 0 comments Cited 154 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jiekai Yu: +86-571-87784501 , yjk@zju.edu.cn
                Shu Zheng: +86-571-87784501 , zhengshu@zju.edu.cn
                Journal
                Journal ID (nlm-ta): Cell Commun Signal
                Journal ID (iso-abbrev): Cell Commun. Signal
                Title: Cell Communication and Signaling : CCS
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1478-811X
                Publication date (Electronic): 3 October 2017
                Publication date PMC-release: 3 October 2017
                Publication date Collection: 2017
                Volume: 15
                Electronic Location Identifier: 38
                Affiliations
                [1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, China), the Second Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, Zhejiang China
                [2 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, Department of Abdominal Oncology, West China Hospital, , Sichuan University, ; Chengdu, Sichuan China
                [3 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Medical Oncology, the Second Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, Zhejiang China
                Article
                Publisher ID: 192
                DOI: 10.1186/s12964-017-0192-z
                PMC ID: 5627483
                PubMed ID: 28974231
                SO-VID: 0d4caecf-7568-46a5-90ee-306b55c1362e
                Copyright © © The Author(s). 2017
                License:

                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
                Date received : 2 June 2017
                Date accepted : 19 September 2017
                Funding
                Funded by: Key Projects in the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period
                Award ID: 2014BAI09B07
                Award Recipient :
                Funded by: National High Technology Research and Development Program of China
                Award ID: 2012AA02A506
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Cell biology
                Keywords: chloride channel accessory 1,colorectal cancer,tumor suppressor,early detection
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: chloride channel accessory 1, colorectal cancer, tumor suppressor, early detection

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