Abstract A154: PDLIM2 is required for regulating inflammation and cellular redox levels in mouse colorectal epithelial model

Abstract

Abstract PDLIM2 is a cytoskeletal and nuclear protein present in hematopoietic and epithelial cells that regulates cell differentiation and the protein stability of transcription factors including NF-κB, STATs, and β-catenin (1). PDLIM2 expression is repressed in certain cancers, but is highly expressed in cancer cells that exhibit a metastatic phenotype (2). PDLIM2 is also highly expressed in the tumour microenvironment of breast cancer, particularly in the pro-wound healing M2 macrophage population. In line with this, bone-marrow derived macrophages from PDIM2 knockout (KO) mice have impaired differentiation towards the M2 macrophage phenotype (3). Here we investigated the effects of PDLIM2 loss in epithelial and immune cells in a colitis-associated cancer model using PDLIM2 wild type (WT) and KO mice exposed to dextran sodium sulphate (DSS) and azoxymethane (AOM). We observed that PDLIM2 KO mice exhibited a strong response to DSS alone. Colon tissue from DSS-treated mice exhibited impaired epithelium repair, sustained inflammation, and low levels of wound-healing M2 macrophages compared to WT tissues. To address the molecular mechanisms associated with PDLIM2 KO in colon epithelial cells, we suppressed or knocked out PDLIM2 in the Caco2 cell line. Caco-2 cells lacking PDLIM2 displayed dysregulated adhesion signalling, which was accompanied by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction and increased dependence on glycolysis. Overall, we conclude that PDLIM2 is required for the resolution of inflammation and to promote intestinal epithelial repair through regulating cell adhesion signalling and cellular redox balance. 1. Guo ZS, Qu Z. PDLIM2: Signaling pathways and functions in cancer suppression and host immunity. Biochim Biophys Acta Rev Cancer. 2021 Dec;1876(2):188630. doi: 10.1016/j.bbcan.2021.188630. 2. Cox OT, Edmunds SJ, Simon-Keller K, Li B, Moran B, Buckley NE, Bustamante-Garrido M, Healy N, O'Flanagan CH, Gallagher WM, Kennedy RD, Bernards R, Caldas C, Chin SF, Marx A, O'Connor R. PDLIM2 Is a Marker of Adhesion and β-Catenin Activity in Triple-Negative Breast Cancer. Cancer Res. 2019 May 15;79(10):2619-2633. doi: 10.1158/0008-5472.CAN-18-2787. 3. Cox OT, O'Sullivan N, Tresse E, Ward S, Buckley N, O'Connor R. PDLIM2 is highly expressed in Breast Cancer tumour-associated macrophages and is required for M2 macrophage polarization. Front Oncol. 2022 Nov 30;12:1028959. doi: 10.3389/fonc.2022.1028959. Citation Format: Stephanie Ward, Silvia Melgar, Orla T Cox, Raffaella Morelli, Rosemary O'Connor. PDLIM2 is required for regulating inflammation and cellular redox levels in mouse colorectal epithelial model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A154.