Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

Lu Pei; Qingfeng Zhu; Xiaoping Zhuang; Honglian Ruan; Zhiguang Zhao; Haide Qin; Qiongqiong Lin

doi:10.1016/j.tranon.2022.101474

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

Transl Oncol. 2022 Sep:23:101474. doi: 10.1016/j.tranon.2022.101474. Epub 2022 Jul 8.

Authors

Lu Pei¹, Qingfeng Zhu², Xiaoping Zhuang³, Honglian Ruan⁴, Zhiguang Zhao⁵, Haide Qin⁶, Qiongqiong Lin⁷

Affiliations

¹ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
² Department of Urology, Lishui Municipal Central Hospital, Lishui, China.
³ Department of Pathology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, China.
⁴ School of Public Health, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou, Guangdong 511436, China.
⁵ Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou 325027, China.
⁶ 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, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: qinhd3@mail.sysu.edu.cn.
⁷ Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou 325027, China. Electronic address: linqiongqiong@wmu.edu.cn.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Endoplasmic reticulum stress; Leucine-rich repeat-containing protein; Prognosis; Ubiquitination; Urothelial carcinoma.