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Upregulation of ARNTL2 Is Associated with Poor Survival and Immune

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Upregulation of ARNTL2 Is Associated with Poor Survival and Immune Wang et al. Cancer Cell Int (2021) 21:341 https://doi.org/10.1186/s12935-021-02046-z Cancer Cell International PRIMARY RESEARCH Open Access Upregulation of ARNTL2 is associated with poor survival and immune infltration in clear cell renal cell carcinoma Song Wang†, Xueyou Ma†, Yufan Ying†, Jiazhu Sun, Zitong Yang, Jiangfeng Li, Ke Jin, Xiao Wang, Bo Xie, Xiangyi Zheng, Ben Liu* and Liping Xie* Abstract Background: Aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2) is a member of the PAS superfamily. Previous studies explored the carcinogenic roles of transcription factor ARNTL2 in human malignancies. However, its roles in ccRCC have not been elucidated. This study sought to explore the roles of ARNTL2 in ccRCC and determine its correlations with tumor immunity. Methods: The expression of ARNTL2 was analyzed using the GEO, TCGA and GTEx database, and verifed in ccRCC tissue samples and cell lines by qRT-PCR and western blot analysis. Kaplan–Meier survival curve analysis, Cox regres- sion analysis (including univariate and multivariate analysis) was utilized to evaluate the prognostic values of ARNTL2. Potential biological mechanisms of ARNTL2 were explored using GSEA method. Colony formation and wound healing assays were conducted to explore the oncogenic role of ARNTL2 in ccRCC. ssGSEA and xCell algorithm were used to explore the correlation between ARNTL2 expression and tumor immune microenvironment (TIME). Results: ARNTL2 was signifcantly upregulated in ccRCC tissues and cell lines compared to normal kidney tissues and cell line. Enhanced expression of ARNTL2 was strongly linked to advanced clinical stage and unfavorable overall survival in ccRCC. ARNTL2 was determined as an independent prognostic marker through cox regression analysis. A prognostic nomogram was constructed to predict 1-, 3- and 5-year overall survival of ccRCC patients by integrating ARNTL2 expression with other clinicopathologic variables. GSEA analysis showed that focal adhesion, T cell receptor, cell cycle, and JAK-STAT signaling pathway were signifcantly enriched in high ARNTL2 samples. Silencing of ARNTL2 suppressed the colony formation ability and wound healing efcacy of ccRCC cell lines. xCell analysis showed that high expression level of ARNTL2 exhibited an immune infltration status similar to CD8 infamed ccRCC subtype, which was characterized by high infltration level of CD8 T cell and high expression level+ of the immune escape biomarkers such as PD-L1, PD-L2, PD1 and CTLA4. + Conclusion: ARNTL2 is an independent adverse predictor of ccRCC patient survival. High expression level of ARNTL2 is associated with immune infltration, and may be a novel therapeutic target in ccRCC. Keywords: ARNTL2, Clear cell renal cell carcinoma, Unfavorable survival, Immune infltration, xCell Background *Correspondence: [email protected]; [email protected] †Song Wang, Xueyou Ma, Yufan Ying authors have contributed equally to Kidney cancer is among the top ten cause of cancer- this work and share frst authorship related deaths worldwide. Kidney cancer results in Department of Urology, School of Medicine, The First Afliated Hospital, more than 431,000 new cases and 179,000 deaths annu- Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang, China ally. Clear cell renal cell carcinoma (ccRCC) is the most © 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. Wang et al. Cancer Cell Int (2021) 21:341 Page 2 of 13 common subtype of kidney cancer [1, 2]. Despite signif- roles of ARNTL2 in ccRCC and explore correlation cant advances in modalities of diagnosis and treatment between ARNTL2 expression and tumor immunity. in the recent decades, ccRCC is a major threat to health and signifcantly afects the quality of life of patients Materials and methods worldwide, mainly metastatic patients that beneft few Data acquisition and analysis from currently available therapies [3]. Studies reported Transcriptome and clinical data of ccRCC (also namely that interactions between cancer cells and immune sys- KIRC) patients were retrieved through the Genomic Data tem play a vital role in carcinogenesis of ccRCC [4, 5]. Commons (GDC) data portal of TCGA database (https:// Meanwhile, current immunotherapies, such as mono- portal. gdc. cancer. gov/), including 539 ccRCC tissues and clonal antibodies targeting PD-L1 and/or CTLA4, have 72 normal kidney tissues (in remote kidney parenchyma). become the main therapy for advanced ccRCC treatment Te data of GSE15641, GSE46699 and GSE53757 from [6]. Based on the CheckMate025 study [7], Nivolumab GEO database (https:// www. ncbi. nlm. nih. gov/ geo/) were was identifed as the frst PD-1 monoclonal antibody downloaded and used to further validate the expression approved for the treatment of advanced ccRCC, which level of ARNTL2. Genetic mutation data were retrieved signifcantly prolonged the overall survival of ccRCC from TCGA database and visualization was performed patients. Subsequently, a series of clinical trials dem- using the package “maftools” in R software [15]. Te onstrated that Nivolumab in combination with Ipilil- RNA-seq of ccRCC cell lines were obtained from the mumab was superior to targeted therapy in patients with Cancer Cell Line Encyclopedia (CCLE) database (https:// advanced ccRCC [8, 9], ushering in a new era of frst-line porta ls. broad insti tute. org/ ccle). IHC staining images of treatment for advanced kidney cancer. However, there are normal kidney tissue sample and kidney cancer tissue still many patients who beneft less from immunotherapy sample were downloaded and analyzed from the human as they are not sensitive to these immunotherapy agents. protein atlas (HPA) (http:// www. prote inatl as. org/) data- Terefore, there is need to discover efective prognostic base. All samples were treated with same anti-ARNTL2 biomarkers and highly specifc tumor immune related antibody (ID: HPA059074). therapeutic targets to improve treatment of ccRCC patients. Human tissue samples and qRT‑PCR analysis Aryl hydrocarbon receptor nuclear translocator like 2 Twenty pairs of ccRCC and adjacent nontumorous tis- (ARNTL2) belongs to the PAS superfamily. It encodes sue samples were gathered from patients who had a transcription factor, whose protein structure is highly undergone radical nephrectomy (from 2011 to 2013) homologous to hypoxia-inducible factors, such as at First Afliated Hospital of Zhejiang University. Te HIF1alpha. ARNTL2 plays important roles in circadian adjacent nontumorous tissues were at least 3 cm away and hypoxia process [10]. Previous studies have explored from the tumor tissues of ccRCC patients. Informed carcinogenesis roles of ARNTL2 in human malignancies consent was acquired from every patient and this study such as breast carcinoma and colorectal adenocarcinoma was approved by Institutional Ethics Committee in the [11, 12]. In addition, recent researches reported that hospital. All patients’ clinical information was shown ARNTL2 is correlated with poor survival and immune in Additional fle 1: Table S1. Total RNA was extracted infltration level of lung adenocarcinoma [13, 14]. How- using TRIzol agentia (Takara) and PrimeScript RT Rea- ever, the potential roles of ARNTL2 in ccRCC have not gent Kit (Takara), RNA was then reverse transcribed been investigated so far. into cDNA. Te relative ARNTL2 mRNA expression In the current study, analysis showed signifcantly high was detected using RT-qPCR, with the help of the ABI expression level of ARNTL2 in ccRCC through integrated 7500 fast real-time PCR System (Applied Biosystems) analyses using RNA-seq data from TCGA and GEO data- and SYBR Premix Ex Taq (Takara). GAPDH was used base. Te fndings were verifed in human ccRCC tissue as endogenous normalization reference to quantify the samples and cell lines, highly expressed ARNTL2 was relative mRNA expression of ARNTL2. All primers were correlated with advanced clinical tumor stage and poor listed as follows: ARNTL2 F 5’-ACT TGG TGC TGG TAG OS. ARNTL2 can also serve as an independent predic- TAT TGGA-3’; ARNTL2 R 5’-TGT TGG ACT CGA ATC tor of ccRCC patient survival. Potential biological func- ATC AAGG-3’; GAPDH F 5’-CTG GGC TAC ACT GAG tions and mechanisms of ARNTL2 were determined CAC C-3’; GAPDH R 5’- AAG TGG TCG TTG AGG GCA through GSEA analysis. A series of in vitro assays were ATG-3’. also applied to explore the oncogenic role of ARNTL2 in ccRCC cells. ssGSEA and xCell algorithm were combined Cell lines and cell transfection and used to analyze the associations between ARNTL2 Human ccRCC cell lines 786-O, Caki-1, and normal renal and TIME in ccRCC. Tis study sought to explore the cell line HK-2 were obtained from the Shanghai Institute Wang et al. Cancer Cell Int (2021) 21:341 Page 3 of 13 of Cell Biology, Shanghai, China. Cells were cultured in by using the ssGSEA algorithm of the GSVA package RPMI 1640 medium with 10% fetal bovine serum (FBS) [19]. xCell algorithm [20] was used to calculate the rela- under a humidifed atmosphere of 5% CO2 at 37℃. Te tive proportions of diverse tumor-infltrating immune RNA duplexes were chemically synthesized by TsingKe cells in every cancer sample, and the results were (Hangzhou, China).
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