Abstract

BackgroundCisplatin remains the mainstay of endometrial cancer (EC) chemotherapy. Wilms’ tumor 1-associated protein (WTAP), playing a critical role in transcriptional and post-transcriptional regulation, has been reported as an oncogene, and its expression is elevated in multiple types of human tumors. Recent evidence has shown that the increased expression of WTAP is also closely related to chemo-resistance. However, its specific role in the susceptibility of human EC cells to cisplatin remains largely unexplored.MethodsWTAP over-expression and WTAP depletion cell lines as well as their corresponding controls were constructed by transfection with lentivirus. Western blotting analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to detect the expression of WTAP. Cell proliferation assay, colony formation assay, cell cycle assay, and apoptosis analysis were adopted to evaluate the effect of WTAP on the chemo-sensitivity of EC cells to cisplatin as well as its underlying mechanism. Immunofluorescence staining was used to assess the translocation of β-catenin. Moreover, a subcutaneous xenograft tumor model was established to assess the effect of WTAP on tumor growth after cisplatin treatment.ResultsDepletion of WTAP in RL95-2 cells significantly enhanced the chemo-susceptibility of cells to cisplatin and increased the cell apoptosis, while WTAP over-expression in ARK-2 cells exhibited the opposite effects. Additionally, WTAP depletion significantly suppressed xenograft-tumor growth and enhanced sensitivity and apoptosis of tumor cells in vivo. Mechanistic analysis exhibited that WTAP over-expression facilitated the cytoplasm-to-nucleus translocation of β-catenin and enhanced the GSK3β phosphorylation at Ser9, while WTAP depletion revealed the opposite results, indicating that WTAP rendered chemo-resistance of EC cells to cisplatin by promoting the Wnt/β-catenin pathway.ConclusionsWTAP might promote the chemo-resistance of EC cells to cisplatin through activating the Wnt/β-catenin pathway. Collectively, our findings offered novel insights into EC treatment.

Highlights

  • Endometrial cancer (EC) is a common gynecological malignancy in the United States, with more than 65,620 newly diagnosed cases every year [1]

  • Besides its essential physiological processes in cell cycle regulation [4], mRNA stabilization [5], RNA alternative splicing [6], m6A methylation [7], and eye development [8], Wilms’ tumor 1-associated protein (WTAP) has been demonstrated to act as an oncogene in the tumorigenesis of malignant cancers, such as renal cell carcinoma (RCC), glioma, colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma (CCA), ovarian cancer, bladder cancer, and acute myelogenous leukemia (AML) [9,10,11,12,13,14,15,16,17]

  • WTAP, playing a critical role in transcriptional and post-transcriptional regulation, has been reported as an oncogene, its expression is elevated in multiple types of human tumors, and such up-regulation is associated with poor prognosis as well [9,10,11,12,13,14,15,16,17]

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Summary

Introduction

Endometrial cancer (EC) is a common gynecological malignancy in the United States, with more than 65,620 newly diagnosed cases every year [1]. Surgery is the typical therapeutic strategy for early-stage EC, while those with advanced and/or recurrent EC are mainly subjected to systemic chemotherapy in combination with radiotherapy [2]. The curative effect of most current chemotherapeutic drugs, including cisplatin, the first-line chemotherapy regimen for EC treatment, is less evident for advanced EC patients, and cisplatin resistance remains a common challenge in EC treatment. Wilms’ tumor 1-associated protein (WTAP), a nuclear protein, can interact with WT1 as its name implies [3]. Cisplatin remains the mainstay of endometrial cancer (EC) chemotherapy. Wilms’ tumor 1-associated protein (WTAP), playing a critical role in transcriptional and post-transcriptional regulation, has been reported as an oncogene, and its expression is elevated in multiple types of human tumors. Its specific role in the susceptibility of human EC cells to cisplatin remains largely unexplored

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