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EMP2 induces cytostasis and apoptosis via the TGFβ/SMAD/SP1 axis and recruitment of P2RX7 in urinary bladder urothelial carcinoma

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Abstract

Purpose

Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease, and its high recurrence rates impose a heavy clinical burden. The objective of this study was to identify signaling pathways downstream of epithelial membrane protein 2 (EMP2), which induces cytostasis and apoptosis in UBUC.

Methods

A series of in vitro and in vivo assays using different UBUC-derived cell lines and mouse xenograft models were performed, respectively. In addition, primary UBUC specimens were evaluated by immunohistochemistry.

Results

Exogenous expression of EMP2 in J82 UBUC cells significantly decreased DNA replication and altered the expression levels of several TGFβ signaling-related proteins. EMP2 knockdown in BFTC905 UBUC cells resulted in opposite effects. EMP2-dysregulated cell cycle progression was found to be mediated by the TGFβ/TGFBR1/SP1 family member SMAD. EMP2 or purinergic receptor P2X7 (P2RX7) gene expression upregulation induced apoptosis via both intrinsic and extrinsic pathways. In 242 UBUC patient samples, P2RX7 protein levels were found to be significantly and positively correlated with EMP2 protein levels. Low P2RX7 levels conferred poor disease-specific and metastasis-free survival rates, and significantly decreased apoptotic cell rates. EMP2 was found to physically interact with P2RX7. In the presence of a P2RX7 agonist, BzATP, overexpression of both EMP2 and P2RX7 significantly increased apoptotic cell rates compared to overexpression of EMP2 or P2RX7 alone.

Conclusions

EMP2 induces cytostasis via the TGFβ/SMAD/SP1 axis and recruits P2RX7 to enhance apoptosis in UBUC. Our data provide new insights that may be employed for the design of UBUC targeting therapies.

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Data availability

The raw data used to support the conclusions of this article will be made available by the corresponding author, without undue reservation to any qualified researcher.

Abbreviations

UBUC:

urinary bladder urothelial carcinoma

EMP2:

epithelial membrane protein 2

PI3K:

phosphatidylinositol 3-kinase

AKT:

AKT serine/threonine kinase

TGFBR1:

transforming growth factor beta receptor 1

SMAD:

SMAD family member

SP1:

Sp1 transcription factor

CKI:

cyclin-dependent kinase inhibitor

CDKN1A:

cyclin dependent kinase inhibitor 1A

TGFB2:

transforming growth factor beta 2

P2RX7:

purinergic receptor P2 × 7

BzATP:

2’(3’)-O-(4-benzoylbenzoly) ATP

CDK:

cyclin-dependent kinases

PI:

propidium iodide

FITC:

fluorescein isothiocyanate

TGFBR1:

transforming growth factor beta receptor 1

TP53:

tumor protein p53

ChIP:

chromatin immunoprecipitation

RIPA:

radioimmunoprecipitation assay

Co-IP:

coimmunoprecipitation

BMP:

bone morphogenetic protein

MYC:

MYC proto-oncogene, bHLH transcription factor

WEE1:

WEE1 G2 checkpoint kinase

PIK3R1:

phosphoinositide-3-kinase regulatory subunit 1

GSK3B:

glycogen synthase kinase 3 beta

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Funding

This work was supported by the Ministry of Science and Technology, Taiwan (107-2314-B-110-001-MY3) to YL Shiue.

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Author notes

  1. Chien-Feng Li, Ti-Chun Chan and Cheng-Tang Pan contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan

    Chien-Feng Li & Ti-Chun Chan

  2. National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan

    Chien-Feng Li & Ti-Chun Chan

  3. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

    Chien-Feng Li

  4. Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan

    Cheng-Tang Pan & Yow-Ling Shiue

  5. Department of Mechanical and Electro-Mechanical Engineering, National Sun Yat-sen University, Kaohsiung, Taiwan

    Cheng-Tang Pan

  6. Institute of Biomedical Sciences, National Sun Yat-sen University, 70 Lienhai Rd, 80424, Kaohsiung, Taiwan

    Pichpisith Pierre Vejvisithsakul, Jia-Chen Lai, Szu-Yu Chen, Ya-Wen Hsu & Yow-Ling Shiue

  7. Section for Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Pichpisith Pierre Vejvisithsakul

  8. Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Meng-Shin Shiao

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Contributions

CF, CT and YL conceived the indications. TC, PP, JC, SY, YW and MS performed the experiments. CF and CT analyzed the data. CF, CT and YL contributed to the preparation of the manuscript, and read and approved the submitted version.

Corresponding author

Correspondence to Yow-Ling Shiue.

Ethics declarations

This study was approved by the Affidavit of Approval (#109041701) of Animal Use Protocol, Chi-Mei Medical Center (Tainan, Taiwan). For immunohistochemistry, the Institutional Review Board of Chi Mei Medical Center approved the retrospective retrieval (IRB10302015) of 242 UBUCs with available tissue blocks, of patients who underwent surgical treatment with curative intent between 1996 and 2004, while those who underwent palliative resection were excluded. This article does not contain any studies involving human participants performed by any of the authors.

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Li, CF., Chan, TC., Pan, CT. et al. EMP2 induces cytostasis and apoptosis via the TGFβ/SMAD/SP1 axis and recruitment of P2RX7 in urinary bladder urothelial carcinoma. Cell Oncol. 44, 1133–1150 (2021). https://doi.org/10.1007/s13402-021-00624-x

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