Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, Baltimore, MD, USA.
Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, School of Stomatoloty, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatoloty and Shanghai Research Institute of Stomatology, Shanghai, China.
Oncogene. 2014 Jul 17;33(29):3839-50. doi: 10.1038/onc.2013.354. Epub 2013 Aug 26.
Podoplanin is highly expressed in human cancers. However, mechanisms regulating podoplanin expression remain elusive. Here we show that podoplanin promotes tumorigenesis of oral squamous cell carcinoma (OSCC) and precancerous cells both in vitro and in vivo, and the ErbB3-binding protein-1 (Ebp1) can be activated in oral tumorigenesis and can serve as a transcriptional activator to drive podoplanin expression in the malignant progression. Most of the OSCC cell lines have no detectable podoplanin protein in low-density cultures. However, the protein becomes detectable in high-density cultures and is required for in-vivo tumor formation of OSCC and oral premalignancies. In a high-density culture condition, podoplanin expression can be triggered at both mRNA and protein levels. In this condition, we showed that Ebp1 is upregulated, translocated from the cytoplasm to the nucleus and binds to the podoplanin promoter to result in a dramatic increase of podoplanin mRNA and protein. Ebp1 downregulation significantly reduced podoplanin expression levels in OSCC cells with a decreased anchorage-dependent growth, invasion and wound healing. Conversely, Ebp1 overexpression enhanced these malignant features through podoplanin upregulation both in vitro and in vivo. In 81 patients with oral premalignant lesions, we found that Ebp1 expression is strongly related to OSCC development. We conclude that Ebp1 has a key role in the upregulation of podoplanin and may contribute to oral tumorigenesis.
Podoplanin 在人类癌症中高度表达。然而，调节 podoplanin 表达的机制仍然难以捉摸。在这里，我们表明 podoplanin 促进了口腔鳞状细胞癌（OSCC）和癌前细胞的体外和体内肿瘤发生，并且 ErbB3 结合蛋白-1（Ebp1）可以在口腔肿瘤发生中被激活，并可以作为转录激活剂来驱动恶性进展中的 podoplanin 表达。大多数 OSCC 细胞系在低密度培养中没有检测到可检测的 podoplanin 蛋白。然而，在高密度培养中，该蛋白变得可检测，并且对于 OSCC 和口腔癌前病变的体内肿瘤形成是必需的。在高密度培养条件下，podoplanin 的表达可以在 mRNA 和蛋白质水平上被触发。在这种情况下，我们表明 Ebp1 上调，从细胞质易位到细胞核，并与 podoplanin 启动子结合，导致 podoplanin mRNA 和蛋白质的显著增加。Ebp1 的下调显著降低了具有依赖锚定的生长、侵袭和伤口愈合减少的 OSCC 细胞中的 podoplanin 表达水平。相反，Ebp1 的过表达通过 podoplanin 的上调增强了这些恶性特征，无论是在体外还是体内。在 81 名口腔癌前病变患者中，我们发现 Ebp1 的表达与 OSCC 的发展密切相关。我们得出结论，Ebp1 在 podoplanin 的上调中起关键作用，可能有助于口腔肿瘤发生。
