Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdańsk, Poland.
Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
J Cell Sci. 2018 Oct 29;131(21):jcs220640. doi: 10.1242/jcs.220640.
Expression of the tetraspanin CD151 is frequently upregulated in epithelial malignancies and correlates with poor prognosis. Here, we report that CD151 is involved in regulation of the expression of fibroblast growth factor receptor 2 (FGFR2). Depletion of CD151 in breast cancer cells resulted in an increased level of FGFR2. Accordingly, an inverse correlation between CD151 and FGFR2 was observed in breast cancer tissues. CD151-dependent regulation of the FGFR2 expression relies on post-transcriptional mechanisms involving HuR (also known as ELAVL1), a multifunctional RNA-binding protein, and the assembly of processing bodies (P-bodies). Depletion of CD151 correlated with inhibition of PKC, a well-established downstream target of CD151. Accordingly, the levels of dialcylglycerol species were decreased in CD151-negative cells, and inhibition of PKC resulted in the increased expression of FGFR2. Whereas expression of FGFR2 itself did not correlate with any of the clinicopathological data, we found that FGFR2/CD151 patients were more likely to have developed lymph node metastasis. Conversely, FGFR2/CD151 patients demonstrated better overall survival. These results illustrate functional interdependency between CD151 complexes and FGFR2, and suggest a previously unsuspected role of CD151 in breast tumorigenesis.
四跨膜蛋白 CD151 的表达在许多上皮性恶性肿瘤中常被上调，且与预后不良相关。在这里，我们报告 CD151 参与调节成纤维细胞生长因子受体 2（FGFR2）的表达。乳腺癌细胞中 CD151 的耗竭导致 FGFR2 水平升高。相应地，在乳腺癌组织中观察到 CD151 与 FGFR2 呈负相关。CD151 对 FGFR2 表达的依赖性调节依赖于涉及多功能 RNA 结合蛋白 HuR（也称为 ELAVL1）和加工体（P 体）组装的转录后机制。CD151 的耗竭与 PKC 的抑制相关，PKC 是 CD151 的一个成熟的下游靶点。因此，CD151 阴性细胞中二脂酰甘油的水平降低，而 PKC 的抑制导致 FGFR2 的表达增加。虽然 FGFR2 的表达本身与任何临床病理数据均不相关，但我们发现 FGFR2/CD151 患者更有可能发生淋巴结转移。相反，FGFR2/CD151 患者的总生存时间更好。这些结果说明了 CD151 复合物与 FGFR2 之间的功能相互依赖性，并提示 CD151 在乳腺癌发生中具有先前未被怀疑的作用。
