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EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation

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Abstract

EWI2 is a transmembrane immunoglobulin superfamily (IgSF) protein that physically associates with tetraspanins and integrins. It inhibits cancer cells by influencing the interactions among membrane molecules including the tetraspanins and integrins. The present study revealed that, upon EWI2 silencing or ablation, the elevated movement and proliferation of cancer cells in vitro and increased cancer metastatic potential and malignancy in vivo are associated with (i) increases in clustering, endocytosis, and then activation of EGFR and (ii) enhancement of Erk MAP kinase signaling. These changes in signaling make cancer cells (i) undergo partial epithelial-to-mesenchymal (EMT) for more tumor progression and (ii) proliferate faster for better tumor formation. Inhibition of EGFR or Erk kinase can abrogate the cancer cell phenotypes resulting from EWI2 removal. Thus, to inhibit cancer cells, EWI2 prevents EGFR from clustering and endocytosis to restrain its activation and signaling.

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Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Ab:

Antibody

BSA:

Bovine serum albumin

CAMs:

Cell adhesion molecules

CHC:

Clathrin heavy chain

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-to-mesenchymal transition

FBS:

Fetal bovine serum

FN:

Fibronectin

HB-EGF:

Heparin-binding EGF-like growth factor

IgSF:

Immunoglobulin superfamily

KO:

Knockout

KD:

Knockdown

LN:

Laminin

mAb:

Monoclonal antibody

MAPK:

Mitogen-activated protein kinase

pAb:

Polyclonal antibody

PBS:

Phosphate buffered saline

PFA:

Paraformaldehyde

PRAD:

Prostate adenocarcinoma

ROI:

Region of interest

STORM:

Stochastic optical reconstruction microscopy

SR:

Super-resolution

TEMD:

Tetraspanin-enriched membrane domain

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Acknowledgements

We thank Drs. Felipe V. Catalan and Shoshana Levy of Stanford University for providing EWI2 CRISPR/Cas9 KO system and comments, Ms. Kathy Kyler for English editing, the OMRF imaging facility for image acquisition and analysis, and OUHSC Stephenson Cancer Center tissue pathology core and functional genomics core facility.

Funding

This work was supported by OCAST grants HR13-207 and HR20-055, the research grants from OCASCR (a program of TSET), and the University of Oklahoma Health Science Center to XAZ. XAZ is an Oklahoma TSET Cancer Research Scholar.

Author information

Author notes

  1. Chenying Fu and Jie Wang have made equal contributions to this study.

Authors and Affiliations

  1. University of Oklahoma Health Sciences Center, Oklahoma City, USA

    Chenying Fu, Jie Wang, Yingjun Ding, Junxiong Chen, Yuchao Yang, Hiroyasu Kameyama, Muralidharan Jayaraman, Anupama Munshi, Takemi Tanaka & Xin A. Zhang

  2. University of New Mexico, Albuquerque, USA

    Sandeep Pallikkuth & Keith A. Lidke

  3. Oklahoma Medical Research Foundation, Oklahoma City, USA

    Jonathan D. Wren

  4. University of Texas MD Anderson Cancer Center, Houston, USA

    Kwong-Kwok Wong

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  1. Chenying Fu
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Contributions

CF, JW, and SP performed experiments, analyzed data, and wrote manuscript. JDW and K-KW analyzed data. YD, JC, and YY performed experiments. HK and MJ provided technical advice. AM and TT provided special reagent and/or technical advice. KAL designed experiments and analyzed data. XAZ designed experiments, analyzed data, and wrote manuscript.

Corresponding author

Correspondence to Xin A. Zhang.

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The authors declare no competing financial interests.

Ethics statement

All procedures involving animals were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC).

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Supplementary Information

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18_2022_4417_MOESM1_ESM.tif

Figure S1 EWI2 KD and KO in PC3 cells. A. EWI2 expression levels at the cell surface of PC3 cells upon EWI2 KD, as analyzed with flow cytometry and presented as MFI (mean±SD, n=3 individual measurements). ** p<0.01. Isotype matched IgG staining serves as a negative control. B. Western blot analysis of EWI2 protein levels in PC3 cells upon EWI2 KD. Actin serves as a protein loading control. C. EWI2 expression levels at the surfaces of PC3 cells upon EWI2 KO were measured by flow cytometry and expressed as MFI (mean±SD, n=3 individual measurements). ** p<0.01. D. Western blot analysis on EWI2 protein levels in PC3 cells upon EWI2 KO. Actin serves as a protein loading control (TIF 802 KB)

18_2022_4417_MOESM2_ESM.tif

Figure S2 Effects of EWI2 removals on the movement of PC3 cells. A. PC3 cells transfected with control siRNA (NEG) or EWI-2 siRNA (KD) were analyzed in Transwell migration and invasion assays. The cells that moved through the insert pores and adhered onto the bottom of the inserts were photographed. Scale bars: 500 µm for Transwell migration on FN, 250 µm for Transwell migration on LN111, and 100 µm for invasion. B. PC3-control (NEG) and -EWI2-null (KO) cells were examined for the migration through Transwell inserts, which were coated with either FN (10 μg/ml) or LN111 (10 μg/ml). The cells that migrated through the insert pores and adhered onto the bottom of the inserts were photographed. Scale bars: 300 µm for Transwell migration on FN and LN111. Scale bars: 200 µm for Transwell migration on LN411. C. Immunohistochemical analyses of Ki67 and cleaved Caspase-3 in primary tumor tissues. Xenografts of PC3 cells from athymic nude mice were dissected, sectioned, and immune-stained with Ki67 and cleaved Caspase-3 Abs. Arrows indicate the cells positive in cleaved caspase-3. Scale bars: 75 µm. D. Immunofluorescence staining of the FN and collagen-IV deposited by the cells on the glass coverslips, as described in Figure 3F, were imaged by fluorescence microscopy and quantified with ImageJ as fluorescence units (mean±SD, n=3 individual experiments, 5 random microscopic fields per experiment). The cells on the glass coverslips were stained with crystal violet and quantified as optical density (mean±SD, n=3 individual experiments). ** p<0.01, *** p<0.001, and **** p<0.0001. Scale bars: 50 µm. E. Tumor tissues sections were stained by Sirius Red. Scale bars: 75 µm (TIF 5990 KB)

18_2022_4417_MOESM3_ESM.tif

Figure S3 Examination of PC3 transfectant cells with CD9 mAbs ALB6 and C9BB. A. Flowstream analysis of PC3-Mock and PC3-EWI2 KO cells with CD9 mAbs ALB6 (for total CD9) and C9BB (for homo-clustered CD9). CD9 levels at the cell surfaces were presented as MFI (mean±SD, n=3 individual experiments). ** p<0.05 and ** p<0.01. B. Flowstream images of the representative PC3 cells immune-stained with CD9 mAbs. Scale bars: 10 µm (TIF 766 KB)

18_2022_4417_MOESM4_ESM.tif

Figure S4 Colocalizations of CD9 with clathrin heavy chain and caveolin-1 in PC3-Mock and -EWI2 KO cells. A and B. Colocalizations of CHC (A) and caveolin-1 (B) with total and homo-clustered CD9, stained by CD9 mAbs ALB6 and C9BB, respectively, were examined in immunofluorescence, imaged with confocal microscopy, and quantified as Manders colocalization coefficients (mean±SD, n=3 individual experiments, nine cells per experiment). M1=CHC or caveolin-1-colocalized CD9/CD9, and M2 CD9-colocalized CHC or caveolin-1/CHC or caveolin-1. Scale bar: 6 µm (TIF 5778 KB)

18_2022_4417_MOESM5_ESM.tif

Figure S5 Relationship between EWI2 gene expression and PRAD. A. MEXPRESS (https://mexpress.be/) was used to analyze the relationship between EWI2 mRNA levels and PRAD based on TCGA (https://www.cancer.gov/) data (PRAD: n=617). B. EWI2 alteration in different types of cancers was obtained from cBioPortal (https://www.cbioportal.org/). SKCM: Skin Cutaneous Melanoma. STAD: Stomach adenocarcinoma. C. TCGA data of EWI2 and PRAD were obtained from UALCAN (http://ualcan.path.uab.edu/analysis.html), by grouping them based on sample types (normal: n=52, PRAD: n=497). ****: p<0.0001. D. Kaplan-Meier survival curves for EWI2 in TCGA data were plotted using GEPIA (http://gepia.cancer-pku.cn/) (PRAD: n=246). Patients were divided by median EWI2 expression levels. E. Correlations of EWI2 with EGFR, HER2, and HER3 in gene expression in PRAD were examined in GEPIA (PRAD: n=252). F. Correlations of EWI2 with MEK1, MEK2, Erk1, and Erk2 in gene expression in PRAD were examined in GEPIA (PRAD: n=252) (TIF 1064 KB)

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Fu, C., Wang, J., Pallikkuth, S. et al. EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation. Cell. Mol. Life Sci. 79, 389 (2022). https://doi.org/10.1007/s00018-022-04417-9

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