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Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

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A Correction to this article was published on 19 April 2021

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Abstract

Inactivation of the transforming growth factor-β (TGF-β) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/− and elf+/−/Smad4+/− mutant mice. We found that embryonic liver fodrin (ELF), a β-Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell–cell contacts and E-cadherin-β-catenin-dependent epithelial cell–cell adhesion is disrupted in elf+/−/Smad4+/− mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-β stimulation. In contrast, elf+/−/Smad4+/− mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-β signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

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Abbreviations

ELF:

embryonic liver fodrin

TGF-β:

transforming growth factor-β

TβRII:

transforming growth factor-β receptor II

TβRI:

transforming growth factor-β receptor I

MEFs:

mouse embryonic fibroblasts

HNPCC:

hereditary nonpolyposis colorectal cancer

BrdU:

5-bromo-2′-deoxyuridine

TUNEL:

TdT-mediated dUTP-biotin nick-end labeling

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Acknowledgements

We thank Dr M Zasloff, Dr R Schlegel and Dr S Baker for critical review of the manuscript, and Dr Eugene A Volpe and Anan H Said for their technical support.

This work was supported by NIH Grants RO1 CA106614A (LM), RO1 DK56111 (LM), RO1 DK58637 (BM), VA Merit Award (LM) and R Robert and Sally D Funderburg Research Scholar (LM).

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Author notes

  1. V Katuri and Y Tang: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Surgery, Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA

    V Katuri, Y Tang, W Jogunoori, S Evans, B Mishra & L Mishra

  2. Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA

    C Li & C-X Deng

  3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Rashid

  4. Department of Surgery, Washington, DC, USA

    A N Sidawy & L Mishra

  5. Department of Veterans Affairs, Washington, DC, USA

    A N Sidawy & L Mishra

  6. Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA

    E P Reddy

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  1. V Katuri
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  2. Y Tang
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  3. C Li
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  10. B Mishra
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Correspondence to B Mishra or L Mishra.

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Katuri, V., Tang, Y., Li, C. et al. Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression. Oncogene 25, 1871–1886 (2006). https://doi.org/10.1038/sj.onc.1209211

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  • DOI: https://doi.org/10.1038/sj.onc.1209211

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