ECM1 Loss in Oral Keratinocytes Impairs Proliferation and Migration While Promoting Keratinization and EMT-Like Remodelling: A Cell-Based Model for the Oral Manifestations of Lipoid Proteinosis

Abstract

Lipoid proteinosis (LP) is a rare autosomal recessive disorder caused by loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene. While the clinical features of LP are well documented, the cellular mechanisms underlying its oral manifestations, particularly the direct consequences of ECM1 deficiency in oral keratinocytes, remain poorly understood. This study investigated the role of ECM1 in human oral keratinocytes (HOK) using an in vitro gain- and loss-of-function model. Functional assays were performed to evaluate proliferation, migration, keratinization and epithelial-mesenchymal transition (EMT)-like remodelling, complemented by transcriptomic sequencing (RNA-seq) to profile global transcriptional changes. ECM1 knockdown inhibited HOK proliferation and migration, while concomitantly promoting keratinization and an EMT-like remodelling response. Protein-level analyses confirmed activation of the TGF-β/Smad signalling pathway, with elevated p-Smad2/3 and increased secretion of TGF-β1 and MMP-9. RNA-seq analysis identified perturbations in genes and pathways governing cell cycle, motility and differentiation. Immunohistochemical validation in LP patient tissue showed COL4A1 deposition matching the characteristic PAS-positive hyaline material. Loss of ECM1 function may contribute to oral LP features through a dual mechanism: impairing tissue repair by hampering keratinocyte proliferation and migration, and promoting tissue remodelling through aberrant keratinization and an EMT-like phenotypic shift. These findings offer a cell-based model for understanding the oral manifestations of LP and highlight the epithelial contribution to LP-associated tissue remodelling.