Rab 18 Regulates Proliferation, Invasion and Cisplatin Sensitivity Through STAT3 Signaling in Head and Neck Squamous Cell Carcinoma

Introduction: The clinical significance, biological roles and potential mechanism of Rab18 remain unknown in most human cancers, including head and neck squamous cell carcinoma (HNSCC). Methods: We used immunohistochemistry to examine Rab18 protein expression in 112 cases of HNSCC specimens. We overexpressed and knockdown Rab18 in FaDu and Detroit562 cancer cell lines. Biological roles and mechanisms of Rab18 were examined using MTT, colony formation, Matrigel invasion assay, Western blotting, Annexin V and JC1 staining. Results: Rab18 was upregulated in 45/112 (40.2%) cases of HNSCC tissues, which correlated with advanced T classification, positive nodal metastasis and tumor node metastasis (TNM) stage. The Oncomine and The Cancer Genome Atlas (TCGA) analyses indicated that Rab18 was elevated in human HNSCC tissues and correlated with poor patient survival. Functionally, Rab18 overexpression increased growth rate, colony numbers, cell cycle progression and invading ability in FaDu cells. Rab18 downregulated cisplatin-induced apoptosis and upregulated the mitochondrial membrane potential (Awm). Western blot revealed that Rab18 overexpression induced epithelial-to-mesenchymal transition, with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin and Twist. Rab18 overexpression also upregulated Survivin protein and Rab18 knockdown showed the opposite effects on these proteins. Treatment of STAT3 inhibitor, SH-4-54, inhibited cell invasion, increased E-cadherin and downregulated N-cadherin, Twist and Survivin. SH-4-54 also abolished the effects of BCAT1 on these proteins, as well as cell invasion. Conclusion: In summary, our data showed that Rab18 was overexpressed in human HNSCC and functioned as an oncoprotein. Rab18 regulated HNSCC cell proliferation, invasion and cisplatin sensitivity through STAT3 signaling in HNSCC.