通过SEC14L3/RPS3/NFκB正反馈回路,SEC14L3基因敲除抑制了透明细胞肾细胞癌的增殖、转移和舒尼替尼耐药性。

IF 11.4 1区 医学 Q1 ONCOLOGY
Ziming Jiang, Guangcan Yang, Guangchun Wang, Jiayi Wan, Yifan Zhang, Wei Song, Houliang Zhang, Jinliang Ni, Haipeng Zhang, Ming Luo, Keyi Wang, Bo Peng
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引用次数: 0

摘要

背景:透明细胞肾细胞癌(ccRCC)产生于肾实质上皮,是肾癌中最主要的恶性实体,其发病率和死亡率随着时间的推移不断上升。SEC14-like 3(SEC14L3)已成为癌症干预的一个引人注目的靶点;然而,SEC14L3在ccRCC中的确切临床意义和分子基础仍未确定:方法:通过利用临床数据以及来自 TCGA-ccRCC 和 GEO 数据集的数据,我们研究了 SEC14L3 表达水平与 ccRCC 患者总生存率之间的关系。我们通过体内和体外实验研究了SEC14L3在ccRCC中的生物学作用和机制。此外,还合成了 siRNA-SEC14L3@PDA@MUC12 纳米颗粒(SSPM-NPs),并通过体内和体外实验评估了其对 SEC14L3 的治疗潜力:我们的研究发现,SEC14L3在ccRCC组织中表达上调,外源性下调SEC14L3能有效抑制ccRCC细胞的恶性特征。从机理上讲,敲除 SEC14L3 可促进核糖体蛋白 S3(RPS3)泛素化介导的降解,并增加 IκBα 在 ccRCC 中的积累。这种协同作用阻碍了 P65 的核转位,从而抑制了核因子卡巴 B(NFκB)信号通路的激活,阻碍了 ccRCC 细胞的增殖和转移。此外,SEC14L3水平的降低对NFκB信号级联中NFKB1的表达也有抑制作用。NFKB1 是一种转录调节因子,能与 SEC14L3 增强子和启动子结合,从而促进 SEC14L3 的表达。因此,对 SEC14L3 表达的抑制作用被进一步加强,从而形成了一个正反馈回路。此外,我们还观察到,下调 SEC14L3 能显著提高 ccRCC 细胞对舒尼替尼的敏感性。对SSPM-NPs纳米疗法的评估强调了它与舒尼替尼联合抑制ccRCC生长的有效性:我们的研究结果不仅强调了SEC14L3作为治疗靶点的前景,还揭示了SEC14L3/RPS3/NFκB的正反馈回路,该回路可抑制ccRCC的进展。调节 SEC14L3 的表达以参与这一正反馈环路可能预示着治疗 ccRCC 的新途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
SEC14L3 knockdown inhibited clear cell renal cell carcinoma proliferation, metastasis and sunitinib resistance through an SEC14L3/RPS3/NFκB positive feedback loop.

Background: Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive.

Methods: By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays.

Results: Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth.

Conclusion: Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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