- Gelatinases, a subgroup of matrix metalloproteinases (MMPs), primarily include MMP-2 (gelatinase A) and MMP-9 (gelatinase B).
- These enzymes are specialized in degrading gelatin, the denatured form of collagen, particularly type IV collagen, which is a key structural component of the basement membrane.
- During epithelial-to-mesenchymal transition (EMT), the expression and activity of gelatinases are often upregulated, facilitating extracellular matrix (ECM) remodeling, cell detachment, and tissue invasion, which are hallmarks of the mesenchymal phenotype.
- The induction of MMP-2 and MMP-9 is regulated by several EMT-associated transcription factors such as Snail, Twist, and ZEB1, as well as pro-inflammatory cytokines, growth factors (like TGF-β, EGF, and VEGF), and oncogenic signaling pathways (including NF-κB, MAPK, and PI3K/Akt). These pathways activate gene expression or post-translational mechanisms that increase the proteolytic activity of gelatinases, which then degrade components of the basement membrane and interstitial matrix, enabling cell migration and tissue infiltration.
- In physiological contexts, gelatinases are essential for normal tissue remodeling, such as in embryogenesis, angiogenesis, and wound healing. However, in pathological conditions, including fibrosis and cancer, their overexpression contributes to excessive tissue remodeling, metastasis, and invasion. For instance, elevated levels of MMP-9 have been observed in gastric, breast, colorectal, and lung cancers, often correlating with advanced tumor grade, EMT markers, and poor prognosis.
- The action of gelatinases during EMT is also tightly regulated by tissue inhibitors of metalloproteinases (TIMPs), particularly TIMP-1 and TIMP-2. An imbalance between gelatinases and TIMPs can drive aberrant EMT, contributing to chronic disease and tumor progression. Moreover, gelatinases not only degrade the matrix but also release and activate latent growth factors, such as TGF-β, further amplifying EMT signaling in a feed-forward loop.
- In summary, gelatinases (MMP-2 and MMP-9) are critical functional mediators of EMT, enabling epithelial cells to acquire invasive capabilities by remodeling the ECM and degrading the basement membrane. Their regulation is tightly linked to transcriptional, signaling, and inflammatory networks that govern EMT, making them potential biomarkers and therapeutic targets in EMT-associated diseases.
