The Dual Role of TGF-β and Hypoxia on MMP14-Mediated Invasion in PC3 Cells.

Authors

Derya Okuyan, Hanife Aktaş, Fatma Poyrazlı, Sümeyye Aydoğan Türkoğlu

Published in

Cell biochemistry and biophysics. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

The MMP14 gene, which encodes the only membrane-bound collagenase, is highly expressed in malignant tumors and plays a decisive role in invasiveness. This study investigated the transcriptional regulation of MMP14 by the TGF-β cytokine and hypoxia in PC3 prostate carcinoma cells. Bioinformatic analysis confirmed the presence of key regulatory elements in the MMP14 promoter, specifically the HRE (for HIF-1α) and SMAD binding sites. Three 5' deletion fragments of the MMP14 promoter (P1: -1251/+75; P2: -649/+75; P3: -176/+75) were cloned for functional analysis. PC3 cells were treated with TGF-β, the hypoxia-mimetic CoCl₂, and the combination. Gene and protein expression were analyzed using Real-Time PCR and Immunofluorescence Cytochemistry (IFC), respectively, while promoter activities were assessed via a Luciferase reporter assay. COL1A expression was also evaluated to explore its association with MMP14-mediated extracellular matrix remodeling. Hypoxia emerged as the dominant inductive factor. MMP14 mRNA and protein levels were significantly elevated under hypoxic and combined TGF-β/CoCl₂ conditions. Promoter analysis revealed that the full-length P1 construct was consistently upregulated by all treatments. However, the shorter P2 and P3 fragments exhibited a decrease in activity with TGF-β alone, suggesting a complex, region-specific regulation predominantly influenced by hypoxic signaling. Critically, COL1A1 mRNA expression was observed in hypoxic groups with elevated MMP14 levels, indicating a possible inverse relationship between MMP14 induction and COL1A-associated extracellular matrix remodeling. Hypoxia is the primary driver of MMP14 induction and protein accumulation in PC3 cells, with TGF-β acting as a complex co-regulator whose activating effect is potentiated under low-oxygen stress. These findings highlight the contribution of the HIF/MMP14 axis to invasion-associated molecular regulation in prostate cancer.

PMID:
42348116
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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