PLAGL2 promotes epithelial–mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1

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Abstract

Background

We previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease. Enhanced PLAGL2 expression was observed in several malignant tumours. However, the exact function of PLAGL2 and its underlying mechanism in colorectal cancer (CRC) remain largely unknown.

Methods

Immunohistochemical analysis of PLAGL2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of PLAGL2 in the progression of CRC.

Results

Enhanced PLAGL2 expression was significantly associated with EMT-related proteins in CRC. The data revealed that PLAGL2 promotes CRC cell proliferation, migration, invasion and EMT both in vitro and in vivo. Mechanistically, PLAGL2 promoted the expression of ZEB1. PLAGL2 enhanced the expression and nuclear translocation of β-catenin by decreasing its phosphorylation. The depletion of β-catenin neutralised the regulation of ZEB1 that was caused by enhanced PLAGL2 expression. The small-molecule inhibitor PNU-74654, also impaired the enhancement of ZEB1 that resulted from the modified PLAGL2 expression. The depletion of ZEB1 could block the biological function of PLAGL2 in CRC cells.

Conclusions

Collectively, our findings suggest that PLAGL2 mediates EMT to promote colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1.

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Most cited references 27

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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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New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer

Anushka Dongre, Robert Weinberg (2018)

Epithelial-mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell-cell and cell-extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas.

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Wnt/beta-catenin signaling in cancer stemness and malignant behavior.

Riccardo Fodde, Thomas Brabletz (2007)

Stem cells are defined by their intrinsic capacity to self-renew and differentiate. Cancer stem cells retain both these features but have lost homeostatic mechanisms which maintain normal cell numbers. The canonical Wnt/beta-catenin signaling pathway plays a central role in modulating the delicate balance between stemness and differentiation in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, and the intestinal crypt. Accordingly, constitutive Wnt signaling activation, resulting from mutations in genes encoding its downstream components, underlies tumorigenesis in these tissues. In the majority of sporadic colorectal cancer cases, the rate-limiting event is either loss of APC function or oncogenic beta-catenin mutations. However, although the presence of these initiating mutations would predict nuclear beta-catenin accumulation throughout the tumor mass, heterogeneous intracellular distributions of this key Wnt signaling molecule are observed within primary tumors and their metastases. In particular, tumor cells located at the invasive front and those migrating into the adjacent stromal tissues show nuclear beta-catenin staining. Hence, different levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively. Several intrinsic (cell-autonomous and/or autocrine) and extrinsic (paracrine, derived from the tumor microenvironment) factors may explain this heterogeneity of Wnt/beta-catenin signaling activity within the tumor mass.

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Author and article information

Contributors

Xiaogang Shu: +8613971537678 , sxg678@yahoo.com

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Electronic): 12 December 2019

Publication date PMC-release: 12 December 2019

Publication date (Print): 18 February 2020

Volume: 122

Issue: 4

Pages: 578-589

Affiliations

[1 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Gastrointestinal Surgery, , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430022 China

[2 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Emergency Surgery, , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430022 China

[3 ]ISNI 0000 0004 1758 2270, GRID grid.412632.0, Department of Gastrointestinal Surgery II, , Renmin Hospital of Wuhan University, ; Wuhan, 430060 China

[4 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Gastrointestinal Surgery, , The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430022 China

Author information

Liang Wu http://orcid.org/0000-0001-9367-7368

Article

Publisher ID: 679

DOI: 10.1038/s41416-019-0679-z

PMC ID: 7028997

PubMed ID: 31827238

SO-VID: 9a4c892b-520d-4cff-a8dd-18cdb9464a96

License:

Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 May 2019

Date revision received : 11 October 2019

Date accepted : 22 November 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81772581

Award ID: 81271199

Award Recipient : Xiaogang Shu

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colorectal cancer,oncogenes

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colorectal cancer, oncogenes

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PLAGL2 promotes epithelial–mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1

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Abstract

Background

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Conclusions

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Karger: Oncology

Most cited references 27

Epithelial-mesenchymal transitions in development and disease.

New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer

Wnt/beta-catenin signaling in cancer stemness and malignant behavior.

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