Faculty, Staff and Student Publications

Publication Date

6-2-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI180570

PMID

40178908

PMCID

PMC12126249

PubMedCentral® Posted Date

4-3-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Hyaluronan (HA) in the extracellular matrix promotes epithelial-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-α-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when cocultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and invasion of lung cancer cells. Furthermore, ZEB1 facilitates alternative splicing and isoform expression of CD44, an HA receptor, and CD44 knockdown suppresses the motility and invasiveness of lung cancer cells. Using a deep learning-based drug-target interaction algorithm, we identified an ITIH2 inhibitor (sincalide) that inhibited HA matrix formation and migration of lung cancer cells, preventing metastatic colonization of lung cancer cells in mouse models. These findings suggest that ZEB1 remodels the HA network in the TME through the regulation of ITIH2, HAS2, and CD44, presenting a strategy for targeting this network to suppress lung cancer progression.

Keywords

Zinc Finger E-box-Binding Homeobox 1, Humans, Cell Movement, Neoplasm Invasiveness, Hyaluronic Acid, Lung Neoplasms, Animals, Mice, Hyaluronan Receptors, Epithelial-Mesenchymal Transition, Hyaluronan Synthases, Cell Line, Tumor, Neoplasm Proteins, Tumor Microenvironment, Gene Expression Regulation, Neoplastic, Cell biology, Oncology, Extracellular matrix, Lung cancer

Published Open-Access

yes

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