Zeb1 for RCP-induced oral cancer cell invasion and its suppression by resveratrol

Oral cancer: Stopping the spread Resveratrol, a naturally occurring compound present in grape skins, peanuts, and blueberries, reduces the ability of oral squamous cell carcinoma (OSCC) cells to spread to other parts of the body. Over half a million new cases of OSCC are diagnosed each year, and spread beyond the mouth is the most common cause of death. Hoi Young Lee at Konyang University, Daejon, Republic of Korea, and co-workers investigated whether a protein called RCP, which increases the invasiveness of many but not all types of cancer, is implicated in aggressive spread of OSCC. They found that RCP does increase the invasiveness of OSCC. Resveratrol is known to suppress the spread of many cancers, and strongly curtailed the spread of OSCC by blocking RCP activity. These results shed light on OSCC invasiveness, and offer a potential new treatment. Rab coupling protein (RCP) is upregulated in head and neck squamous cell carcinoma (HNSCC) and is correlated with the progression and survival of patients. However, the role of RCP in one of the aggressive types of HNSCC, oral squamous cell carcinoma (OSCC), remains elusive. In the present study, we identified the important role of Zeb1 in RCP-induced OSCC epithelial-to-mesenchymal transition (EMT) and invasion. RCP induces Zeb1 expression, and silencing Zeb1 expression significantly inhibits RCP-induced OSCC invasion. In addition, Zeb1 upregulates MT1-MMP expression to promote OSCC EMT and invasion. Furthermore, we observed that the beta 1 integrin/EGFR/beta-catenin signaling cascade mediates RCP-induced Zeb1 expression to promote OSCC invasion. Notably, we provide evidence that resveratrol (REV) strongly inhibits RCP-induced Zeb1 expression through blocking beta 1 integrin endosome recycling and EGFR activation, leading to suppression of RCP-induced OSCC invasion, demonstrating the important role of RCP in OSCC invasion and its reversion by REV. Collectively, the present study provides evidence for the first time that RCP aggravates OSCC invasion through increasing Zeb1 expression and subsequently upregulating MT1-MMP expression and that this process is reversed by REV, providing novel biomarkers and indicating the therapeutic potential of REV in OSCC.