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Inhibition of protein tyrosine phosphatase receptor type F suppresses Wnt signaling in colorectal cancer

Oncogene volume 39, pages 6789–6801 (2020)Cite this article

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Abstract

Wnt signaling dysregulation promotes tumorigenesis in colorectal cancer (CRC). We investigated the role of PTPRF, a receptor-type tyrosine phosphatase, in regulating Wnt signaling in CRC. Knockdown of PTPRF decreased cell proliferation in patient-derived primary colon cancer cells and established CRC cell lines. In addition, the rate of proliferation as well as colony formation ability were significantly decreased in tumor organoids grown in 3D, whereas the number of differentiated tumor organoids were markedly increased. Consistently, knockdown of PTPRF resulted in a decrease in the expression of genes associated with cancer stem cells downstream of Wnt/β-catenin signaling. Treating PTPRF knockdown cells with GSK3 inhibitor rescued the expression of Wnt target genes suggesting that PTPRF functions upstream of the β-catenin destruction complex. PTPRF was found to interact with LRP6 and silencing PTPRF largely decreased the activation of LRP6. Interestingly, this PTPRF-mediated activation of Wnt signaling was blocked in cells treated with clathrin endocytosis inhibitor. Furthermore, knockdown of PTPRF inhibited xenograft tumor growth in vivo and decreased the expression of Wnt target genes. Taken together, our studies identify a novel role of PTPRF as an oncogenic protein phosphatase in supporting the activation of Wnt signaling in CRC.

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Fig. 1: Knockdown of PTPRF inhibits cell proliferation in colon cancer cells.
Fig. 2: Knockdown of PTPRF decreases tumor organoid formation.
Fig. 3: The expression of PTPRF positively regulates Wnt signaling.
Fig. 4: PTPRF regulates Wnt signaling at a step upstream of the β-catenin destruction complex.
Fig. 5: PTPRF interacts with LRP6.
Fig. 6: PTPRF-mediated activation of Wnt signaling requires clathrin-dependent endocytosis.
Fig. 7: Knockdown of PTPRF inhibits xenograft tumor growth and Wnt signaling.

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  • 29 July 2021

    The name of B. Mark Evers was given incorrect in HTML version of the article. Correct is: Given name: B. Mark Family name: Evers

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Acknowledgements

This work was supported by funding grants R01CA133429 (TG), R01CA208343 (BME and TG), T32CA160003 (BME), and F31CA196219 (PDS). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Award (#1839289). The studies were conducted with support provided by the Biospecimen Procurement and Translational Pathology and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558) at the University of Kentucky.

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  1. Payton D. Stevens

    Present address: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, 49503, USA

  2. These authors contributed equally: Tong Gan, Ashley T. Stevens

Authors and Affiliations

  1. Department of Surgery, University of Kentucky, Lexington, KY, 40536-0679, USA

    Tong Gan & B. Mark Evers

  2. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0679, USA

    Tong Gan, Ashley T. Stevens, Xiaopeng Xiong, Yang-An Wen, Trevor N. Farmer, Payton D. Stevens, Sanam Golshani, Heidi L. Weiss, B. Mark Evers & Tianyan Gao

  3. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536-0679, USA

    Ashley T. Stevens, Payton D. Stevens & Tianyan Gao

  4. Paul Laurence Dunbar High School, Lexington, KY, USA

    Austin T. Li

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Gan, T., Stevens, A.T., Xiong, X. et al. Inhibition of protein tyrosine phosphatase receptor type F suppresses Wnt signaling in colorectal cancer. Oncogene 39, 6789–6801 (2020). https://doi.org/10.1038/s41388-020-01472-z

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