Nesprin1 Deficiency Is Associated with Poor Prognosis of Renal Cell Carcinoma and Resistance to Sunitinib Treatment.

IF 2.5 3区医学 Q3 ONCOLOGY Oncology Pub Date : 2024-01-01 Epub Date: 2024-03-05 DOI:10.1159/000536539

Takafumi Fukushima, Kohei Kobatake, Kento Miura, Kenshiro Takemoto, Ryoken Yamanaka, Ryo Tasaka, Yuki Kohada, Shunsuke Miyamoto, Yohei Sekino, Hiroyuki Kitano, Keisuke Goto, Kenichiro Ikeda, Akihiro Goriki, Keisuke Hieda, Osamu Kaminuma, Nobuyuki Hinata

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Abstract

Introduction: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC).

Methods: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC.

Results: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival.

Conclusions: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment.

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Nesprin1缺乏症与肾细胞癌的不良预后和对舒尼替尼治疗的耐药性有关。

简介由 SYNE1 编码的核包膜谱林重复蛋白（Nesprin）1 对细胞的形态和功能起着至关重要的调节作用。SYNE1 基因突变与多种疾病相关，但其在肾细胞癌（RCC）中的意义尚不清楚。在这项研究中，我们调查了 SYNE1/Nesprin1 与透明细胞 RCC（ccRCC）的进展和预后的关系：方法：我们对公开的RCC患者数据集进行了硅学分析。在队列数据的基础上，采用免疫组化染色法分析了ccRCC患者肾切除组织样本中Nesprin1的表达情况。此外，还进行了RNA测序和基因组富集分析，以研究SYNE1/Nesprin1与RCC预后相关的分子机制：结果：与RCC相关的SYNE1基因突变患者的总生存率和无进展生存率明显较低。Nesprin1阴性ccRCC肿瘤患者的总生存率、癌症特异性生存率和无复发生存率明显低于Nesprin1阳性组。敲除 SYNE1 会增强 RCC 细胞的侵袭和迁移，但不会影响细胞的增殖。RNA测序和基因组富集分析（Gene Set Enrichment Analysis）显示，SYNE1基因敲除显著改变了氧化磷酸化相关基因的表达。同样，SYNE1低表达的RCC患者在接受血管内皮生长因子受体抑制剂舒尼替尼治疗后，无进展生存期更短：结果表明，SYNE1/Nesprin1的表达和SYNE1突变与RCC患者的预后和对舒尼替尼治疗的反应性密切相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncology 医学-肿瘤学

CiteScore

6.00

自引率

2.90%

发文量

审稿时长

6-12 weeks

期刊介绍： Although laboratory and clinical cancer research need to be closely linked, observations at the basic level often remain removed from medical applications. This journal works to accelerate the translation of experimental results into the clinic, and back again into the laboratory for further investigation. The fundamental purpose of this effort is to advance clinically-relevant knowledge of cancer, and improve the outcome of prevention, diagnosis and treatment of malignant disease. The journal publishes significant clinical studies from cancer programs around the world, along with important translational laboratory findings, mini-reviews (invited and submitted) and in-depth discussions of evolving and controversial topics in the oncology arena. A unique feature of the journal is a new section which focuses on rapid peer-review and subsequent publication of short reports of phase 1 and phase 2 clinical cancer trials, with a goal of insuring that high-quality clinical cancer research quickly enters the public domain, regardless of the trial’s ultimate conclusions regarding efficacy or toxicity.