PlGF/Flt-1/MMP-1 axis in gingival carcinoma bone invasion

Gingival squamous cell carcinoma (SCC) frequently invades adjacent bone tissue, leading to significant morbidity and mortality. Understanding the molecular mechanisms driving bone invasion is crucial for developing targeted therapies. We investigated the role of placental growth factor (PlGF) in this process, focusing on its interaction with RANKL and MMP-1.

We examined the role of PlGF in bone invasion of gingival SCC through analysis of patient samples (n=55) and various in-vitro assays, including an in-vitro bone-cell coculture system. We investigated the molecular mechanisms underlying PlGF-mediated bone invasion and its relationship with RANKL and MMP-1 expression.

Our findings demonstrate that gingival SCC-secreted PlGF promotes local bone invasion through two possible ways: 1) direct induction of RANKL expression, activating osteoclast formation and bone resorption, and 2) indirect upregulation of RANKL via MMP-1 signaling. PlGF secretion by tumor cells triggered RANKL and MMP-1 production and significantly stimulated migration and osteoclastogenesis (p<0.05). Furthermore, PlGF is highly expressed in gingival SCC and significantly correlated with bone invasion. Finally, we also confirmed the significantly positive correlation between expression levels of MMP-1 with PlGF and Flt-1 expression.

This study identifies PlGF as a key regulator of osteoclastogenesis in gingival SCC through both direct and MMP-1-mediated pathways. Therefore, targeting PlGF activity may represent a potential therapeutic strategy for inhibiting bone invasion in gingival SCC.