Abstract
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 β1 integrin/EGFR/β-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 β1 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.
Highlights
Head and neck squamous cell carcinoma (HNSCC)stems from the epithelia of the aerodigestive tract, including the oral cavity[1]
Compared to the vector control, overexpression of Rab coupling protein (RCP) resulted in a higher invasive potential in cells cocultured with oral cancer-associated fibroblasts (CAFs) in 3D Matrigel (Fig. 1e), indicating that RCP reorganizes the microenvironment to augment the invasiveness of oral squamous cell carcinoma (OSCC)
While the majority of studies have pointed out the oncogenic function of RCP, a recent report showed that RCP exerts a tumor suppressive role in mammary tumors through destabilizing ErBB215, indicating the types of cancer- and context-dependent characteristics of RCP in cancer progression
Summary
Head and neck squamous cell carcinoma (HNSCC)stems from the epithelia of the aerodigestive tract, including the oral cavity[1]. The prevalence of HNSCC is increasing worldwide, with nearly 800,000 new diagnoses and 350,000 cancer-associated deaths annually[1,2,3]. Similar to other types of cancer, metastasis to distant organs is the most common cause of death in HNSCC patients. Identified as a Rab[4] and Rab[11] effector protein, Rab coupling protein (RCP) originates from the RAB11FIP1 gene and is associated with the proliferation and progression of various cancers[6,7]. RCP is Mechanistically, RCP promotes cancer cell EMT and metastasis by protecting β1 integrin from lysosomal digestion and activating EGFR6,11. RCP participates in EphA2 trafficking during cell repulsion[12] and mediates mutant p53-induced cancer invasiveness[13,14]
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