LMNTD2-AS1 regulates immune cell infiltration and promotes prostate cancer progression by targeting FUS to regulate NRF2 signal pathway

Haoming Wu; Ning Liu; Aifeng He; Haiyang Li; Hui Liu; Jinke Qian; Weipu Mao; Guangbo Fu

LMNTD2-AS1 regulates immune cell infiltration and promotes prostate cancer progression by targeting FUS to regulate NRF2 signal pathway

Am J Cancer Res. 2023 Aug 15;13(8):3384-3400. eCollection 2023.

Authors

Haoming Wu^{1

2}, Ning Liu³, Aifeng He⁴, Haiyang Li⁵, Hui Liu¹, Jinke Qian¹, Weipu Mao³, Guangbo Fu^{2

6}

Affiliations

¹ Department of Urology, Binhai County People's Hospital Yancheng 224500, Jiangsu, China.
² Medical College, Xuzhou Medical University Xuzhou 221000, Jiangsu, China.
³ Department of Urology, Affiliated Zhongda Hospital of Southeast University Nanjing 210009, Jiangsu, China.
⁴ Department of Emergency, Binhai County People's Hospital Yancheng 224500, Jiangsu, China.
⁵ Department of Radiotherapy, Binhai County People's Hospital Yancheng 224500, Jiangsu, China.
⁶ Department of Urology, Huai'an First People's Hospital Huai'an 223300, Jiangsu, China.

PMID: 37693143
PMCID: PMC10492130

Abstract

Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) play crucial roles in tumor progression. This study aimed to identify lncRNAs associated with overall survival (OS) and progression-free interval (PFI) in prostate cancer (PCa) patients and to elucidate the driving mechanisms and functions of these lncRNAs. We utilized the TCGA database to screen for lncRNAs linked with OS and PFI. KM survival analysis, ROC curve analysis, and Cox survival analysis were employed to assess the prognostic significance of lncRNAs in PCa patients. We conducted a loss-of-function assay to explore the role of lncRNAs in PCa. Correlation analysis was performed to study the relationship between lncRNAs and immune cell infiltration. Lasso regression analysis was performed to screen proteins which might interact with lncRNAs, while rescue experiments verified the integrity of the signaling pathway. LMNTD2-AS1 was found to be the only lncRNA in PCa patients associated with both OS and PFI with significantly elevated levels in PCa. Elevated LMNTD2-AS1 expression was significantly linked to advanced stage, grade, primary treatment outcomes, residual tumors, and Gleason scores in PCa patients. Moreover, multivariate Cox regression analysis revealed that high LMNTD2-AS1 expression independently predicted PFI in PCa patients. The AUC of LMNTD2-AS1 for predicting 3-year OS and 5-year OS in PCa patients was 0.877 and 0.807, respectively, while for 3-year PFI and 5-year PFI it was 0.751 and 0.727, respectively. Overexpression of LMNTD2-AS1 correlated with infiltration of neutrophils, macrophages, pDC, NK CD56bright cells, and other immune cells. Furthermore, FUS and NRF2 are both potential binding proteins and related signaling pathways downstream of LMNTD2-AS1. Functional experiments demonstrated that LMNTD2-AS1 knockdown significantly inhibited migration, invasion, and proliferation of PCa cells while overexpression of FUS was found to rescue the functional inhibition caused by LMNTD2-AS1 knockdown. LMNTD2-AS1 functions as an oncogene in PCa, influencing patient prognosis and the immune microenvironment; it may regulate immune cell infiltration and promote PCa progression by interacting with the NRF2 signaling pathway via FUS binding.

Keywords: FUS; LMNTD2-AS1; Prostate cancer; immune cell infiltration.