LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis

Wei, Wensu; Wang, Ning; Deng, Minhua; Dong, Pei; Liu, Jianye; Xiang, Zhen; Li, Xiangdong; Li, Zhiyong; Liu, Zhenhua; Peng, Yulu; Li, Zhen; Jiang, Lijuan; Yao, Kai; Ye, Yunlin; Lu, Wenhua; Zhang, Zhiling; Liu, Zhuowei; Xie, Dan; Yu, Chunping

doi:10.1016/j.redox.2021.102201

Cited by 35 publications

(31 citation statements)

References 57 publications

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“…Leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) is a multifunctional protein localized to the mitochondria, endoplasmic reticulum, outer and inner nuclear membranes, nucleoplasm, and cytoskeleton [ 40 , 41 ]. Besides being a prognostic factor, LRPPRC has recently been demonstrated to enhance tumorigenesis in bladder cancer [ 42 ].…”

Section: Roles Of Mitochondria In Ucmentioning

confidence: 99%

Updates on the Pivotal Roles of Mitochondria in Urothelial Carcinoma

et al. 2022

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Mitochondria are important organelles responsible for energy production, redox homeostasis, oncogenic signaling, cell death, and apoptosis. Deregulated mitochondrial metabolism and biogenesis are often observed during cancer development and progression. Reports have described the crucial roles of mitochondria in urothelial carcinoma (UC), which is a major global health challenge. This review focuses on research advances in the role of mitochondria in UC. Here, we discuss the pathogenic roles of mitochondria in UC and update the mitochondria-targeted therapies. We aim to offer a better understanding of the mitochondria-modulated pathogenesis of UC and hope that this review will allow the development of novel mitochondria-targeted therapies.

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Section: Roles Of Mitochondria In Ucmentioning

confidence: 99%

Updates on the Pivotal Roles of Mitochondria in Urothelial Carcinoma

et al. 2022

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“…Many studies have demonstrated that circRNAs can act as sponges for microRNAs (miRNAs) or bind to proteins, and altered circRNA levels can lead to aberrant expression of gene products 3 . Importantly, an increasing number of studies have shown that circRNAs are widely expressed in mammals and are expressed to varying degrees in various cancers, such as esophageal squamous cell carcinoma, urothelial carcinoma, and colorectal cancer [4][5][6] . In addition, many circRNAs have been reported to participate in the development of HCC, regulating cell proliferation, tumor metastasis, and glycolysis [7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

M6A-Mediated Upregulation of CircMDK Promotes Tumorigenesis and Acts as a Nanotherapeutic Target in Hepatocellular Carcinoma

Zhou

et al. 2022

Preprint

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Background: Emerging evidences suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown.Methods: RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms.Results: Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1, resulting to the activation of PI3K/Akt/mTOR signaling pathway to promote cell proliferation and migration. Poly (β-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models without obvious adverse effects.Conclusions: CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC.

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“…Pentatricopeptide repeat (PPR) proteins are a large class of RNA-binding proteins characterized by a typical thirty-five residue repeat motif [ 13 ]. Only seven PPR proteins are found in human beings, all of which are located in mitochondria and involved in various cell procedures, notably in RNA supersession [ 14 , 15 ]. The discovery of essential role of PPR proteins in mitochondria gene expression and energy metabolism underscores its biological importance [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Only seven PPR proteins are found in human beings, all of which are located in mitochondria and involved in various cell procedures, notably in RNA supersession [ 14 , 15 ]. The discovery of essential role of PPR proteins in mitochondria gene expression and energy metabolism underscores its biological importance [ 15 ]. For example, mitochondrial RNA polymerase regulates the transcription of mitochondrial mRNA (mt-mRNA) [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, an increasing number of PPRs have been identified with important regulation effects of BLCA carcinogenesis. For instance, LRPPRC promotes BLCA tumorigenesis by regulating redox homeostasis through the circANKHD1/FOXM1 [ 15 ]. Black et al reported that FOXM1 translocated into mitochondria and inhibited mitochondria respiration and oxidative phosphorylation by enhancing PTCD1 and may be a promising molecular target [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of PTCD1 in Bladder Urothelial Carcinoma Predicts Poor Prognosis and Levels of Immune Infiltration

Zhou

et al. 2022

Journal of Oncology

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Pentatricopeptide repeat domain 1 (PTCD1) was reported to regulate mitochondrial metabolism and oxidative phosphorylation. However, the effect and mechanism of PTCD1 in the development of bladder urothelial carcinoma (BLCA) remain unclear. The databases from The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were used to analyze the expression changes, clinical features, and prognostic values of PTCD1. A nomogram was built to predict the prognostic outcomes of BLCA cases. The potential genes interacting with PTCD1 were explored by Weighted Gene Coexpression Network Analysis (WGCNA). The estimation of associations between PTCD1 and tumor mutations, tumor immunities, and m6A methylations was performed. The study found that the gradual decrease of PTCD1 expression was observed with the increase of stage and grade. Low PTCD1 expression was greatly correlated with higher pathological stage, N stage, and poor prognosis in TCGA cohorts; interestingly, low-grade BLCA cases all exhibited high expression of PTCD1. HPA database analysis implied that the expression of PTCD1 protein in BLCA was lower than that in normal bladder tissue, and the protein expression of PTCD1 in high-grade BLCA was lower than that in low-grade BLCA. Multivariate Cox regression analysis indicated that PTCD1 may serve as an independent factor influencing prognosis of BLCA. Mechanistically, PTCD1 played a regulatory role in BLCA progression through multiple tumor-related pathways containing PI3K-Akt signaling, ECM-receptor interaction, oxidative phosphorylation, and extracellular matrix organization. WGCNA reported that PTCD1 had a strong positive correlation with POLR2J, ZNHT1, ATP5MF, PDAP1, BUD31, and COPS6. Besides, the mRNA expression of PTCD1 was negatively associated with immune cells’ infiltrations, immune functions, and checkpoints, especially with some m6A methylation regulators in BLCA. In sum, downregulation of PTCD1 expression may be involved in the development of BLCA and remarkably correlated with poor prognosis. Meantime, it showed an influence in immune cell infiltration and may serve as an agreeable prognostic indicator in BLCA.

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LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis

Cited by 35 publications

References 57 publications

Updates on the Pivotal Roles of Mitochondria in Urothelial Carcinoma

Updates on the Pivotal Roles of Mitochondria in Urothelial Carcinoma

M6A-Mediated Upregulation of CircMDK Promotes Tumorigenesis and Acts as a Nanotherapeutic Target in Hepatocellular Carcinoma

Downregulation of PTCD1 in Bladder Urothelial Carcinoma Predicts Poor Prognosis and Levels of Immune Infiltration

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