Abstract
Abnormal expression of claudin-1 (CLDN1) has important roles in carcinogenesis and metastasis in various cancers. The role of CLDN1 in human oral squamous cell carcinoma (OSCC) remains unknown. Here, we report the functional role of CLDN1 in metastasis of human OSCC, as a potential target regulated by withaferin A. From gene expression profiling with microarray technology, we found that the majority of notable differentially expressed genes were classified into migration/invasion category. Withaferin A impaired the motility of human OSCC cells in vitro and suppressed metastatic nodule formation in an in vivo metastasis model, both associated with reduced CLDN1. CLDN1 overexpression enhanced metastatic nodule formation in vivo, resulting in severe metastatic lesions in lung tissue. Moreover, CLDN1 expression was positively correlated to lymphatic metastasis in OSCC patients. The impaired motility of human OSCC cells upon withaferin A treatment was restored by CLDN1 overexpression. Furthermore, upregulation of let-7a induced by withaferin A was inversely correlated to CLDN1 expression. Overall, these give us an insight into the function of CLDN1 for prognosis and treatment of human OSCC, substantiating further investigation into the use of withaferin A as good anti-metastatic drug candidate.
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The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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We would like to thank Editage (www.editage.co.kr) for English language editing.
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This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science ICT & Future Planning (2017R1D1A1B03029124 and 2019R1A2C1085896).
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Conceptualization of this research, acquisition and analysis of data, and drafting the manuscript, JAS and LHK; material support, interpretation of data, and performance of statistical analysis, MHR, SYC, and SDH; conduct of in vivo experiments, BJ, WL, and YCJ; acquisition and analysis of data, CHA, MHA, KOH, NS, and KC; reviewing and paraphrasing the revised manuscript, SCK; supervision and editing of final draft of the manuscript, SDC. All authors approved final version of the manuscript.
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Shin, JA., Kim, LH., Ryu, M.H. et al. Withaferin A mitigates metastatic traits in human oral squamous cell carcinoma caused by aberrant claudin-1 expression. Cell Biol Toxicol 38, 147–165 (2022). https://doi.org/10.1007/s10565-021-09584-2
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DOI: https://doi.org/10.1007/s10565-021-09584-2