Pei Lu, Zhu Qingfeng, Zhuang Xiaoping, Ruan Honglian, Zhao Zhiguang, Qin Haide, Lin Qiongqiong
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Urology, Lishui Municipal Central Hospital, Lishui, China.
Transl Oncol. 2022 Sep;23:101474. doi: 10.1016/j.tranon.2022.101474. Epub 2022 Jul 8.
Urothelial carcinoma (UC) is one of the most common cancers worldwide. The biological heterogeneity of UCs causes considerable difficulties in predicting treatment outcomes and usually leads to clinical mismanagement. The identification of more sensitive and efficient predictive biomarkers is important in the diagnosis and classification of UCs. Herein, we report leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel predictive factor and potential therapeutic target for UCs.
Using whole-slide image analysis in our cohort of 107 UC samples, we performed immunohistochemistry to evaluate the prognostic value of LRRC59 expression in UCs. In vitro experiments using RNAi were conducted to explore the role of LRRC59 in promoting UC cell proliferation and migration.
A significant correlation between LRRC59 and unfavorable prognosis of UCs in our cohort was demonstrated. Subsequent clinical analysis also revealed that elevated expression levels of LRRC59 were significantly associated with higher pathological grades and advanced stages of UC. Subsequently, knockdown of LRRC59 in UM-UC-3 and T24 cells using small interfering RNA significantly inhibited cell proliferation and migration, resulting in cell cycle arrest at the G1 phase. Conversely, the overexpression of LRRC59 in UC cells enhanced cell proliferation and migration. An integrated bioinformatics analysis revealed a significant functional network of LRRC59 involving protein misfolding, ER stress, and ubiquitination. Finally, in vitro experiments demonstrated that LRRC59 modulates ER stress signaling.
LRRC59 expression was significantly correlated with UC prognosis. LRRC59 might not only serve as a novel prognostic biomarker for risk stratification of patients with UC but also exhibit as a potential therapeutic target in UC that warrants further investigation.
尿路上皮癌（UC）是全球最常见的癌症之一。UC的生物学异质性在预测治疗结果方面造成了相当大的困难，通常会导致临床管理不当。识别更敏感和有效的预测生物标志物对于UC的诊断和分类很重要。在此，我们报告位于内质网中的富含亮氨酸重复序列蛋白59（LRRC59）作为UC的一种新型预测因子和潜在治疗靶点。
在我们的107例UC样本队列中使用全玻片图像分析，我们进行了免疫组织化学以评估LRRC59表达在UC中的预后价值。进行了使用RNA干扰的体外实验以探索LRRC59在促进UC细胞增殖和迁移中的作用。
在我们的队列中证实了LRRC59与UC的不良预后之间存在显著相关性。随后的临床分析还显示，LRRC59表达水平升高与UC的更高病理分级和晚期显著相关。随后，使用小干扰RNA敲低UM-UC-3和T24细胞中的LRRC59显著抑制了细胞增殖和迁移，导致细胞周期停滞在G1期。相反，UC细胞中LRRC59的过表达增强了细胞增殖和迁移。综合生物信息学分析揭示了LRRC59涉及蛋白质错误折叠、内质网应激和泛素化的重要功能网络。最后，体外实验表明LRRC59调节内质网应激信号。
LRRC59表达与UC预后显著相关。LRRC59不仅可能作为UC患者风险分层的新型预后生物标志物，而且还可能作为UC的潜在治疗靶点，值得进一步研究。
