CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway

Clinical and Translational Oncology, Jan 2019

Purpose To study the detailed mechanisms of tumorigenesis and clinical outcomes of centrosomal protein 55 (CEP55) overexpression in renal cell carcinoma. Materials and methods Microarray analysis was performed to explore differentially expressed genes in five pairs of RCC tissues. Data of CEP55 expression and corresponding clinical information for 532 RCC patients of TCGA database were downloaded from cBioPortal. The expression of CEP55 in RCC tissues and cells was determined by real-time quantitative reverse transcription PCR (qRT-PCR), Western blot analysis and immunohistochemistry (IHC). Cells were transfected with siRNAs or lentivirus to regulate the expression of CEP55. The effects of CEP55 on proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of RCC cells were determined by MTS, migration and invasion assay and Western blot analysis. Results CEP55, one of the most upregulated genes in microarray analysis, was overexpressed in RCC tissues and cells. CEP55 expression was significantly correlated with poor outcome including neoplasm disease stage, histologic grade and TNM status, as well as survival status of patients. In vitro experiments showed that downregulation of CEP55 could dramatically inhibit RCC cell proliferation, migration and invasion, while overexpression of CEP55 could promote these biological behaviors. We further demonstrated that CEP55 knockdown suppressed epithelial–mesenchymal transition (EMT), which was mediated via upregulation of E-cadherin and downregulation of N-cadherin and ZEB1, through PI3K/AKT/mTOR pathway. In contrast, overexpression of CEP55 could promote EMT in RCC cells via the activation of PI3K/AKT/mTOR pathway. Importantly, inhibition of PI3K/AKT/mTOR pathway reduced the effects of CEP55 on the migration, invasion and EMT of RCC cells. Conclusion Our study showed that CEP55 could promote EMT through PI3K/AKT/mTOR pathway and might be an effective prognostic marker in RCC.

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CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway

Clinical and Translational Oncology pp 1–11 | Cite as CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway AuthorsAuthors and affiliations H. ChenD. ZhuZ. ZhengY. CaiZ. ChenW. Xie Open Access Research Article First Online: 03 January 2019 231 Downloads Abstract Purpose To study the detailed mechanisms of tumorigenesis and clinical outcomes of centrosomal protein 55 (CEP55) overexpression in renal cell carcinoma. Materials and methods Microarray analysis was performed to explore differentially expressed genes in five pairs of RCC tissues. Data of CEP55 expression and corresponding clinical information for 532 RCC patients of TCGA database were downloaded from cBioPortal. The expression of CEP55 in RCC tissues and cells was determined by real-time quantitative reverse transcription PCR (qRT-PCR), Western blot analysis and immunohistochemistry (IHC). Cells were transfected with siRNAs or lentivirus to regulate the expression of CEP55. The effects of CEP55 on proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of RCC cells were determined by MTS, migration and invasion assay and Western blot analysis. Results CEP55, one of the most upregulated genes in microarray analysis, was overexpressed in RCC tissues and cells. CEP55 expression was significantly correlated with poor outcome including neoplasm disease stage, histologic grade and TNM status, as well as survival status of patients. In vitro experiments showed that downregulation of CEP55 could dramatically inhibit RCC cell proliferation, migration and invasion, while overexpression of CEP55 could promote these biological behaviors. We further demonstrated that CEP55 knockdown suppressed epithelial–mesenchymal transition (EMT), which was mediated via upregulation of E-cadherin and downregulation of N-cadherin and ZEB1, through PI3K/AKT/mTOR pathway. In contrast, overexpression of CEP55 could promote EMT in RCC cells via the activation of PI3K/AKT/mTOR pathway. Importantly, inhibition of PI3K/AKT/mTOR pathway reduced the effects of CEP55 on the migration, invasion and EMT of RCC cells. Conclusion Our study showed that CEP55 could promote EMT through PI3K/AKT/mTOR pathway and might be an effective prognostic marker in RCC. KeywordsRenal cell carcinoma CEP55 Epithelial–mesenchymal transition Proliferation Metastasis  Abbreviations CEP55 Centrosomal protein 55 RCC Renal cell carcinoma EMT Epithelial–mesenchymal transition INF-α Interferon-α IL-2 Interleukin-2 ORRs Overall response rates ZEB1 Zinc-finger E-box-binding 1 ANT Adjacent normal tissue IHC Immunohistochemistry EMT-TFs EMT-associated transcription factors OD Optical density qRT-PCR Real-time quantitative reverse transcription PCR FBS Fetal bovine serum Haicheng Chen, Dingjun Zhu and Zaosong Zheng contributed equally to this work. Introduction Renal cell carcinoma (RCC) is a malignant cancer of the tubular cells of the kidney, which accounts for 2–3% of adult malignant tumors and its morbidity and mortality are still increasing [1]. Although most incidentally detected lesions are small low-grade tumors, up to 17% of all renal cell carcinomas have distant metastases at the time of diagnosis [2]. However, there is no effective treatment for metastatic renal cell carcinoma. Interferon-α (INF-α) and interleukin-2 (IL-2), which were the standard for the treatment of metastatic RCC, fail to provide satisfactory clinical benefit because of their known significant toxicity and modest overall response rates (ORRs) [3]. Molecular-targeted therapy is one of the major strategies for the treatment of metastatic RCC. Several molecular-targeted therapies such as the mTOR inhibitor temsirolimus and the VEGF inhibitor bevacizumab have been proved to improve the clinical outcomes of RCC patients [4, 5]. Because of the complexity of the pathogenesis of malignant tumors, molecular-targeted therapies still have the limitations including low efficiency and drug resistance [6]. In the past decades, although several breakthroughs have been achieved in the study of RCC, the underlying mechanisms of metastasis in renal cell carcinoma remain unclear. Therefore, it is important to explore the mechanism of metastasis and find a new molecular target for RCC. CEP55 has been initially identified as an important component of abscission, participating in the separation of two daughter cells [7]. Currently, it has been found that CEP55 serves a pivotal role in multiple cancers, such as oral squamous cell carcinoma and breast cancer [8, 9]. Previous studies reported that neoplasms with high levels of CEP55 are typically associated with patients’ clinical characteristics and poor outcomes. CEP55 not only could promote the proliferation of cancer cells, but also promotes invasion and metastasis via the increasing of FOXM1 and the activation of MMP-2 in oral squamous cell carcinoma [9, 10]. However, the detailed mechanisms (...truncated)


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H. Chen, D. Zhu, Z. Zheng, Y. Cai, Z. Chen, W. Xie. CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway, Clinical and Translational Oncology, 2019, pp. 1-11, DOI: 10.1007/s12094-018-02012-8