Cheng Cheng, Cai Yuanxia, Liu Xiaowei, Wu Yangkun, Cheng Qianqian, Wu Yeming, Wu Zhixiang
Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, China; Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, 200092 Shanghai, China.
Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, China; Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, 200092 Shanghai, China; Department of Pediatric Surgery, Hangzhou Children's Hospital, Hangzhou, Hangzhou 310010, China.
Cell Signal. 2022 Dec;100:110447. doi: 10.1016/j.cellsig.2022.110447. Epub 2022 Aug 25.
Wilms tumor (WT) is the most common renal malignancy in children, and the survival rate of high-risk WT patients was still low despite multimodality therapy. KHSRP, an RNA-binding protein, has been proved to be relative to tumor progression in different kinds of malignancies, but the function of KHSRP in WT remained unclear. Here, our study aimed to explore and clarify the function of KHSRP in WT cells and its molecular mechanism. Thus, our results showed that KHSRP was highly expressed in WT tumor tissues compared to normal kidney tissues and correlated with poor prognosis in WT patients. Downregulation of KHSRP using siRNAs in WT cell line SK-NEP-1 and Wit49 resulted in inhibition of cell proliferation and cell cycle arrest via stabilizing and upregulating p27 protein. Furthermore, mechanistic analyses revealed that KHSRP bound to 3'UTR of PPP2CA mRNA and modulating its mRNA stability, resulting in regulation of the phosphorylation level and protein stability of p27 in WT cell lines. In conclusion, our results demonstrated that KHSRP played an important role in WT and modulated cell proliferation and cell cycle via regulating the expression of PPP2CA and p27.
肾母细胞瘤（WT）是儿童最常见的肾脏恶性肿瘤，尽管采用了多模式治疗，高危WT患者的生存率仍然很低。KHSRP是一种RNA结合蛋白，已被证明与不同类型恶性肿瘤的肿瘤进展相关，但KHSRP在WT中的功能仍不清楚。在此，我们的研究旨在探索和阐明KHSRP在WT细胞中的功能及其分子机制。因此，我们的结果表明，与正常肾组织相比，KHSRP在WT肿瘤组织中高表达，并且与WT患者的不良预后相关。在WT细胞系SK-NEP-1和Wit49中使用小干扰RNA（siRNA）下调KHSRP，通过稳定和上调p27蛋白导致细胞增殖受到抑制和细胞周期停滞。此外，机制分析表明，KHSRP与PPP2CA mRNA的3'非翻译区（3'UTR）结合并调节其mRNA稳定性，从而导致WT细胞系中p27的磷酸化水平和蛋白稳定性受到调控。总之，我们的结果表明，KHSRP在WT中起重要作用，并通过调节PPP2CA和p27的表达来调节细胞增殖和细胞周期。
