Cell Biology and Toxicology ( IF 6.1 ) Pub Date : 2021-03-04 , DOI: 10.1007/s10565-021-09584-2 Ji-Ae Shin 1 , Lee-Han Kim 2 , Mi Heon Ryu 3 , So-Young Choi 4 , Bohwan Jin 5 , WonWoo Lee 5 , Yun Chan Jung 6 , Chi-Hyun Ahn 1 , Min-Hye Ahn 1 , Kyoung-Ok Hong 1 , Neeti Swarup 1 , Kunal Chawla 7 , Se Chan Kang 8 , Seong Doo Hong 1 , Sung-Dae Cho 1
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.
Graphical abstract
中文翻译:
Withaferin A 减轻由异常 claudin-1 表达引起的人口腔鳞状细胞癌的转移特征
claudin-1(CLDN1)的异常表达在各种癌症的癌变和转移中具有重要作用。CLDN1 在人口腔鳞状细胞癌 (OSCC) 中的作用仍然未知。在这里,我们报告了 CLDN1 在人类 OSCC 转移中的功能作用,作为由 withaferin A 调节的潜在靶标。通过微阵列技术的基因表达谱分析,我们发现大多数显着的差异表达基因被归类为迁移/侵袭类别。Withaferin A在体外损害人 OSCC 细胞的运动性并在体内转移模型中抑制转移结节的形成,两者都与减少的 CLDN1 相关。CLDN1过表达增强体内转移性结节形成,导致肺组织出现严重的转移性病变。此外,CLDN1 表达与 OSCC 患者的淋巴转移呈正相关。CLDN1 过表达恢复了人类 OSCC 细胞在 withaferin A 治疗后受损的运动性。此外,withaferin A 诱导的 let-7a 上调与 CLDN1 表达呈负相关。总的来说,这些让我们深入了解了 CLDN1 在人类 OSCC 预后和治疗中的功能,证实了对使用 withaferin A 作为良好的抗转移候选药物的进一步研究。