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Cancer Cell International Gao et al. Cancer Cell Int (2021) 21:366 https://doi.org/10.1186/s12935-021-02064-x Cancer Cell International PRIMARY RESEARCH Open Access Integrative analysis the characterization of peroxiredoxins in pan-cancer Lei Gao1†, Jialin Meng2†, Chuang Yue3†, Xingyu Wu3, Quanxin Su3, Hao Wu3, Ze Zhang3, Qinzhou Yu2, Shenglin Gao3* , Song Fan2* and Li Zuo3* Abstract Background: Peroxiredoxins (PRDXs) are an antioxidant enzymes protein family involved in several biological functions such as diferentiation, cell growth. In addition, previous studies report that PRDXs play critical roles in the occurrence and development of carcinomas. However, few studies have conducted systematic analysis of PRDXs in cancers. Therefore, the present study sought to explore the molecular characteristics and potential clinical signifcance of PRDX family members in pan cancer and further validate the function of PRDX6 in bladder urothelial carcinoma (BLCA). Methods: A comprehensive analysis of PRDXs in 33 types of cancer was performed based on the TCGA database. This involved an analysis of mRNA expression profles, genetic alterations, methylation, prognostic values, potential biological pathways and target drugs. Moreover, both the gain and loss of function strategies were used to assess the importance and mechanism of PRDX6 in the cell cycle of BLCA. Result: Analysis showed abnormal expression of PRDX1-6 in several types of cancer compared to normal tissues. Uni- variate Cox proportional hazard regression analysis showed that expression levels of PRDX1, PRDX4 and PRDX6 were mostly associated with poor survival of OS, DSS and PFI, and PRDX2 and PRDX3 with favorable survival. In addition, the expression of PRDX genes were positively correlated with CNV and negatively with methylation. Moreover, analysis based on PharmacoDB dataset showed that the augmented levels of PRDX1, PRDX3 and PRDX6 were signifcantly correlated with EGFR/VEGFR inhibitor drugs. Furthermore, knocking down of PRDX6 inhibited growth of cancer cells through the JAK2-STAT3 in bladder cell lines. Conclusions: PRDXs are potential biomarkers and therapeutic targets for several carcinomas, especially for BLCA. In addition, PRDX6 could regulate proliferation of cancer cell via JAK2-STAT3 pathway and involve into the process of cell cycle in BLCA. Keywords: Peroxiredoxins, Pan-cancer, PRDX6, JAK2-STAT3, Bladder cancer Background Peroxiredoxin (PRDX) belongs to a large group of antiox- *Correspondence: [email protected]; [email protected]; zuoli@njmu. idant enzymes protein family which includes more than edu.cn †Lei Gao, Jialin Meng and Chuang Yue contributed equally to the study 3500 members [1]. Members of this family are character- 2 Department of Urology, The First Afliated Hospital of Anhui Medical ized by a cysteine residue that is involved in reduction of University, Institute of Urology, Anhui Medical University, Anhui Province peroxides [2], which are ubiquitously expressed in most Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China organisms [3]. PRDXs can be classifed into three sub- 3 Department of Urology, The Afliated Changzhou No. 2 People’s families based on the number and location of the active Hospital of Nanjing Medical University, Changzhou, China cysteine residues and other factors. Tese subfamilies Full list of author information is available at the end of the article include: typical 2-Cys, atypical 2-Cys, and 1-Cys [4, 5]. © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gao et al. Cancer Cell Int (2021) 21:366 Page 2 of 17 Moreover, PRDXs can also be divided into six subfami- Materials and methods lies based on the structural information around the active TCGA pan‑cancer data sites including AhpC-Prx1, BCP-PrxQ, Tpx, Prx5, Prx6, RNA-seq, clinical information, stemness scores based and AhpE [6]. Currently, there are 6 known mamma- on mRNA (mRNAsi) and immune subtypes data for 33 lian PRDX members, namely PRDX1, PRDX2, PRDX3, cancer types were obtained from Xena browser (https:// PRDX4, PRDX5, PRDX6 [7]. Te family members are xenab rowser. net/ datap ages/). Out of the samples, only 18 involved in several biological processes, such as cell dif- cancer types had adjacent normal tissue samples. Tese ferentiation, metabolism [8], infammation [9], cellular samples were used to explore gene expression profles protection against reactive oxygen species (ROS) [10], in tumors compared with normal tissues. In addition, in embryonic development and cellular homeostasis [11]. order to analyze the correlation between gene expression Although the cardio- and neuroprotective efects have (as continuous variable) and patient prognosis, patients been fully established [12, 13], studies report that PRDXs with corresponding survival information were included. play critical roles in the process of carcinogenesis and Te OS, DFI, PFI and DSS data of PRDXs were analyzed the development of drug resistance. Notably, PRDX1 based on HIPLOT dataset (https:// hiplot. com. cn/ advan was originally reported to act as an antioxidant enzyme ce/ ucsc- xena- shiny). because of its high susceptibility to oxidative stress [14], which plays important roles in cell growth, diferentia- Tumor immune subtypes analysis tion and apoptosis [15]. On the other hand, PRDX2 is Six immune subtypes were used to explore immune infl- associated with the proliferative, migratory and meta- tration in tumor environment [31]. Immune subtype static activities of melanoma [16]. Additionally, PRDX3 was used to determine the relationship between PRDXs is highly expressed in tumor tissues of breast cancer, cer- expression and immune infltrate types in tumor micro- vical cancer, liver cancer and prostate cancer [17–20]. environment using ANOVA methods. Tumor stemness Moreover, PRDX4 increases the proliferation rate of data obtained from TCGA dataset were performed to prostate cancer cell and promotes the metastasis of ovar- assess the stem-cell-like levels of tumor cells [32]. Te ian cancer, breast cancer, lung cancer and oral squamous association between cancer stemness and PRDXs expres- cell carcinoma [21–24]. In addition, high expression of sion profles was examined using Spearman correlation PRDX5 is associated with short overall survival (OS) in method. ovarian cancer [25]. Furthermore, high levels of PRDX6 have been reported with an invasive phenotype in breast Genetic alteration and DNA methylation cancer. Oncogenic role of PRDX6 was also reported in Genetic alterations, including mutation and copy num- prostate cancer [26, 27]. Previous studies report that the ber variation (CNV) data of diferent cancer types were augmented levels of PRDX1, PRDX3 and PRDX6 were retrieved from cBioPortal (http:// www. cbiop ortal. org/). associated with cisplatin resistance status for erythro- Te association of CNV, methylation and tumor types leukemia, breast cancer and ovarian carcinoma [28, 29]. were analyzed using GSCALite tool (http:// bioin fo. However, the comprehensive function of PRDXs in pan- life. hust. edu. cn/ web/ GSCAL ite/). Correlation analyses cancer has not been explored. between mRNA expression levels of PRDXs and CNV In the present study, the mRNA expression profles of levels, and methylation in BLCA were released from cBi- PRDXs and their relationship with overall survival (OS), oPortal. Data on methylation levels between tumor and disease free interval (DFI), progression free interval normal tissues in BLCA were obtained from UALCAN (PFI), and disease specifc survival (DSS) among 33 can- (http:// ualcan. path. uab. edu). cer types based on the TCGA database were explored. In addition, the association of expression levels of PRDXs Drug and pathway analysis with tumor microenvironment, genetic alteration and Global proportion plot and heatmap of PRDXs genes drug response activity were evaluated. ROS are criti- in 10 tumor-associated pathways were generated using cal mediators of tissue damage in patients with (BLCA) GSCALite (http:// bioin fo. life. hust. edu. cn/ web/ GSCAL [30] are limited. Terefore, a comprehensive analysis of ite/). Data on PRDXs-related drugs were from Pharma- PRDXs was conducted. Moreover, efects of expression coDB (https:// pharm acodb. pmgen omics. ca/). Te cut- levels of PRDX6 in cell growth, apoptosis and the poten- of was absolute value of correlation more than 0.1 and tial mechanisms were explored in T24 and TCCSUP cells. P < 0.05 (Additional fle 1: Table S3). Gao et al. Cancer Cell Int (2021) 21:366 Page 3 of 17 Fig. 1 Expression levels of
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