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The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth

Cancer Gene Therapy volume 30, pages 245–255 (2023)Cite this article

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A Correction to this article was published on 18 November 2022

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Abstract

Gastrointestinal stromal tumors (GISTs) are the most common neoplasms of mesenchymal origin, and most of them emerge due to the oncogenic activation of KIT or PDGFRA receptors. Despite their relevance in GIST oncogenesis, critical intermediates mediating the KIT/PDGFRA transforming program remain mostly unknown. Previously, we found that the adaptor molecule SH3BP2 was involved in GIST cell survival, likely due to the co-regulation of the expression of KIT and Microphthalmia-associated transcription factor (MITF). Remarkably, MITF reconstitution restored KIT expression levels in SH3BP2 silenced cells and restored cell viability. This study aimed to analyze MITF as a novel driver of KIT transforming program in GIST. Firstly, MITF isoforms were characterized in GIST cell lines and GIST patients’ samples. MITF silencing decreases cell viability and increases apoptosis in GIST cell lines irrespective of the type of KIT primary or secondary mutation. Additionally, MITF silencing leads to cell cycle arrest and impaired tumor growth in vivo. Interestingly, MITF silencing also affects ETV1 expression, a linage survival factor in GIST that promotes tumorigenesis and is directly regulated by KIT signaling. Altogether, these results point to MITF as a key target of KIT/PDGFRA oncogenic signaling for GIST survival and tumor growth.

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Fig. 1: Expression of MITF isoforms in GIST patients.
Fig. 2: MITF silencing reduces KIT, BCL2, and CDK2 expression.
Fig. 3: MITF silencing impairs cell proliferation.
Fig. 4: MITF silencing impairs the cell cycle.
Fig. 5: MITF induces apoptosis by caspases in GIST cells.
Fig. 6: MITF silencing induces ETV1 downregulation in GISTs.
Fig. 7: MITF silencing affects viability and the cell cycle in GIST48B cells.
Fig. 8: MITF silencing causes a reduction in GIST tumor growth.

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Data availability

The data sets used and analyzed during the current study are available in the article and supplementary files or from the corresponding author at reasonable request.

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Acknowledgements

We are indebted to the Cytomics core facility of the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for their technical support.

Funding

This study has been funded by grants from the Spanish Ministry of Science, Innovation and Universities and European Regional Development Fund/European Social Fund "Investing in your future": RTI2018-096915-B100 (M.M.) and PID2021-122898OB-100 (M.M.); PERIS SLT006/17/221 (C.S.), ISCIII PI19_01271 (C.S.) and ISCIII FI20/00275 (D.G.-P.).

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Authors and Affiliations

  1. Biochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

    Elizabeth Proaño-Pérez, Eva Serrano-Candelas, Arnau Navinés-Ferrer, Mario Guerrero & Margarita Martín

  2. Clinical and Experimental Respiratory Immunoallergy (IRCE), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Elizabeth Proaño-Pérez, Eva Serrano-Candelas, Arnau Navinés-Ferrer & Margarita Martín

  3. Faculty of Health Sciences, Technical University of Ambato, Ambato, Ecuador

    Elizabeth Proaño-Pérez

  4. ProtoQSAR SL., Centro Europeo de Empresas e Innovación (CEEI), Parque Tecnológico de Valencia, 46980 Paterna (Valencia), Spain

    Eva Serrano-Candelas

  5. Sarcoma Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, C/ Natzaret, 115-117, 08035, Barcelona, Spain

    Alfonso García-Valverde, Jordi Rosell, David Gómez-Peregrina & César Serrano

  6. Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    César Serrano

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Contributions

E.P.-P., E.S.-C. and M.M. conceived the experiments and wrote the manuscript, E.P.-P. and A.G.V. performed the experiments, A.N.F., M.G, J.R. and D.G.-P. provided technical support, C.S. provided reagents and technical support, and M.M. secured funding. All authors reviewed the manuscript.

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Correspondence to Margarita Martín.

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Competing interests

C.S. has received research funding (institution) from Karyopharm, Pfizer, Inc, Deciphera Pharmaceuticals, and Bayer AG; consulting fees (advisory role) from CogentBio, Immunicum AB, Deciphera Pharmaceuticals, and Blueprint Medicines; payment for lectures from PharmaMar, Bayer AG and Blueprint Medicines; and travel grants from PharmaMar, Pfizer, Bayer AG, Novartis, and Lilly. The remaining authors have declared that no conflict of interest exists.

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Proaño-Pérez, E., Serrano-Candelas, E., García-Valverde, A. et al. The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth. Cancer Gene Ther 30, 245–255 (2023). https://doi.org/10.1038/s41417-022-00539-1

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