Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis.

Autor: Bhatia R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Siddiqui JA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA., Ganguly K; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Thompson CM; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Cannon A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Aithal A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Perumal N; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Maurya SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Li X; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Cox JL; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Gurumurthy CB; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., Rachagani S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Jain M; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA., Nasser MW; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. sbatra@unmc.edu.; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA. sbatra@unmc.edu.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. sbatra@unmc.edu., Kumar S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. skumar@unmc.edu.; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA. skumar@unmc.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2023 Mar; Vol. 42 (10), pp. 759-770. Date of Electronic Publication: 2023 Jan 09.
DOI: 10.1038/s41388-022-02587-1
Abstrakt: Mucin4 (MUC4) appears early during pancreatic intraepithelial neoplasia-1 (PanIN1), coinciding with the expression of epidermal growth factor receptor-1 (EGFR). The EGFR signaling is required for the onset of Kras-driven pancreatic ductal adenocarcinoma (PDAC); however, the players and mechanisms involved in sustained EGFR signaling in early PanIN lesions remain elusive. We generated a unique Esai-CRISPR-based Muc4 conditional knockout murine model to evaluate its effect on PDAC pathology. The Muc4 depletion in the autochthonous murine model carrying K-ras and p53 mutations (K-ras G12D ; TP53 R172H ; Pdx-1cre, KPC) to generate the KPCM4 -/- murine model showed a significant delay in the PanIN lesion formation with a significant reduction (p < 0.01) in EGFR (Y1068) and ERK1/2 (T202/Y204) phosphorylation. Further, a significant decrease (p < 0.01) in Sox9 expression in PanIN lesions of KPCM4 -/- mice suggested the impairment of acinar-to-ductal metaplasia in Muc4-depleted cells. The biochemical analyses demonstrated that MUC4, through its juxtamembrane EGF-like domains, interacts with the EGFR ectodomain, and its cytoplasmic tail prevents EGFR ubiquitination and subsequent proteasomal degradation upon ligand stimulation, leading to sustained downstream oncogenic signaling. Targeting the MUC4 and EGFR interacting interface provides a promising strategy to improve the efficacy of EGFR-targeted therapies in PDAC and other MUC4-expressing malignancies.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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