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Increased Expression of CELSR3 Indicates a Poor Prognostic Factor

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Increased Expression of CELSR3 Indicates a Poor Prognostic Factor Journal of Cancer 2021, Vol. 12 1115 Ivyspring International Publisher Journal of Cancer 2021; 12(4): 1115-1124. doi: 10.7150/jca.49567 Research Paper Increased expression of CELSR3 indicates a poor prognostic factor for Prostate Cancer Xuanrong Chen*, Qianwang Ma*, Yixi Liu*, Hanling Li, Zihao Liu, Zheng Zhang, Yuanjie Niu, Zhiqun Shang Department of Urology, Tianjin Institute of Urology, The second hospital of Tianjin Medical University, Tianjin, 300211, China. *These authors contributed equally to this work. Corresponding authors: Zhiqun Shang: [email protected] or Yuanjie Niu: [email protected] © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.06.16; Accepted: 2020.11.19; Published: 2021.01.01 Abstract Background: Cadherin EGF LAG Seven-Pass G-Type Receptor 3 (CELSR3) gene was reported to be overexpressed in various human cancers and involved in the regulation of neurite-dependent neurite outgrowth and may play a role in tumor formation. However, the clinical significance of CELSR3 in prostate cancer (PCa) has not been fully studied. Methods: The expression of CELSR3 was detected by crossover analysis of the public datasets and cell lines. MTT assay and migration assay were performed to evaluate the cells’ physiological functioning. Co-expressed genes and enrichment analysis was performed to investigate the biological significance of CELSR3 in PCa. Quantitative real-time polymerase chain reaction was used to detect the expression levels of hub genes (CENPE, CENPA, CDC20, NUF2, ESPL1, PLK1) related to CELSR3. Results: We found a significant increase in CELSR3 expression in PCa patients and cell lines. Furthermore, immunohistochemical analysis showed that CELSR3 protein expression was significantly more highly expressed in the PCa tissues compared to the non-cancerous PCa tissues. CELSR3 downregulation significantly suppressed cell proliferation and migration potential. CELSR3-related hub genes (CENPE, CENPA, CDC20, NUF2, ESPL1, PLK1) were selected and the functions of these hub genes showed that the function of CELSR3 was closely related to the cell cycle-related signaling pathways. The upregulation of CELSR3 mRNA expression in the PCa tissues significantly correlated with the presence of high serum PSA levels, high pathological stage, high Gleason score, short overall survival time and short disease-free survival time. Conclusion: Our data suggest that CELSR3 may play an important role in the progression of PCa. More importantly, an increase in CELSR3 expression may be indicative of poor disease-free survival and poor prognosis in PCa patients. Key words: Prostate cancer; flamingo subfamily; prognostic factor; Bioinformatics Introduction Prostate cancer (PCa) has become the second gene expression databases and profiles for prostate most common cancer in men, and both morbidity and cancer established using microarray and sequencing mortality are on the rise in recent years[1]. As a technology[3]. Cumulative evidence suggests that heterogeneous disease, the occurrence of PCa may be multiple genes and signalling pathways are involved affected by multiple factors such as genes, cellular in the carcinogenesis, progression, and recurrence of context, and environment[2]. Gene expression PCa. However, its tumor-related mechanisms have profiling using high-throughput platforms is not been fully clarified. Therefore, it is crucial to increasingly used as an effective tool for analysing identify efficient biomarkers to better predict the tumor progression mechanisms. There are a variety of diagnosis and prognosis of PCa. http://www.jcancer.org Journal of Cancer 2021, Vol. 12 1116 Cadherin EGF LAG seven-pass G-type receptors datasets and used to conduct the analysis[3, 15, 16]. 1, 2 and 3 (CELSR1-3) constitute three atypical The main parameters of the public datasets were cadherin families with multiple functions in epithelial summarized in Table 1. For prostate cancer specimen, cells and the nervous system[4, 5]. As we know, CELSR3 antibody (Atlas Antibodies, Cat#HPA062866, cadherin is a calcium-dependent transmembrane RRID: AB_2684886) was used. Immunohistochemical glycoprotein that is typically characterized by an staining of human PCa cells shows moderate extracellular calcium binding domain that plays an cytoplasmic or membranous positivity in the luminal important role in embryonic development and cancer cells in the Human Protein Atlas database [17, synapse formation[6]. CELSR3 is an important 18]. signaling molecule in the INT-1/planar cell polarity (WNT/PCP) pathway, and this pathway is involved Table 1. The main parameters of the public datasets. in controlling tissue polarity and cell migration[7]. According to reports, the CELSR3 gene is Dataset Characteristic Reference the MSKCC 218 prostate tumors with 181 primaries tumors and 37 [3] overexpressed in various human cancers, including dataset metastases tumors brain tumors, ovarian cancer, pancreatic cancer, liver the PRAD 497 primary prostate cancer samples with mRNA and [16] dataset clinicopathological characteristics* cancer, colorectal cancer and cervical cancer[8-11]. the PCTA 1,321 clinical specimens from 38 PCa cohorts [15] CELSR3 was specifically expressed in adult brain dataset *, the PRAD dataset refers to the Prostate Adenocarcinoma (TCGA, TCGA tumors. Erkan et al. showed that CELSR3 was Provisional) dataset. selectively up-regulated in the stellate cells of liver and pancreas cancer[11]. Asad et al. found that CELSR3 was expressed more strongly in Stem-A than Cell culture and transfection non-Stem-A ovarian cancer and that CELSR3 might The BPH1, LNCaP, C42, 22RV1 cell lines were promote Stem-A ovarian cancer invasiveness by obtained from the American Type Culture Collection regulating cell proliferation and cell cycle progression (ATCC) and grown in RPMI 1640 (Gibco, through a non-canonical Wnt/PCP pathway[8]. ThermoFisher, USA) supplemented with 10% Fetal Through ceRNA network analysis, Pan et al. bovine serum (FBS) (Gibco, ThermoFisher, USA) in demonstrated that CELSR3 was a prognostic gene for 5% CO2 at 37°C. CELSR3 silencing was performed the overall survival of head and neck squamous cell using two custom made siRNAs targeting CELSR3 carcinoma[12]. Gu et al. showed that CELSR3 mRNA mRNA region (siCELSR3 #1 sense: GCAAUAGCC was an independent prognostic factor for the overall GUGGACACUUTT, siCELSR3 #1 antisense: survival of hepatocellular carcinoma patients[13]. AAGUGUCCACGGCUAUUGCTT and siCELSR3 #2 Gene set enrichment analysis revealed that a high sense: CCAGUACACUUUCCAGAAUTT, siCELSR3 CELSR3 mRNA expression phenotype related to #2 antisense: AUUCUGGAAAGUGUACUGGTT) somatic diversification of immune receptors, and one scramble control siRNA (Genepharma, endonuclease activity, DNA repair complex, and China) and transfected by Lipofectamine™ 3000 somatic cell DNA recombination[13, 14]. In all, Transfection Reagent followed the manufacturer’s CELSR3 was found to be an oncogene that promoted instructions. malignant progression of the tumor. However, the RNA extraction and Quantitative RT-PCR clinical value and role of CELSR3 in PCa has not been analysis fully elucidated. In this study, we found that high expression of Total RNA was isolated from cells using TRIzol CELSR3 may be a potentially effective biomarker for reagent (Invitrogen, USA) according to the PCa. Cox proportional hazards regression model manufacturer's instructions. Quantitative RT-PCR analysis showed that increased expression of CELSR3 (qRT-PCR) was performed on an ABI 7900 96 HT is closely related to the clinical pathology of PCa. This Series PCR Instrument (Applied Biosystem, expression pattern of CELSR3 can be used as a ThermoFisher, USA) using FastStart Universal SYBR prognostic biomarker and is associated with poor Green Master (ROX) (Roche, Sigma-Aldrich). Gene prognosis in patients with prostate cancer. expression levels were determined by the Ct method and further normalized to GAPDH levels. The Materials and Methods sequences of the primers used were listed in Table S1. Public datasets and immunohistochemistry Cell growth assay analysis Cell growth was monitored by the The clinical information and expression profiles 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium were obtained from the MSKCC, PRAD, and PCTA bromide proliferation assay. 22RV1 cells were seeded http://www.jcancer.org Journal of Cancer 2021, Vol. 12 1117 into a 96-well plate at a density of 2000 cells per well. Results After for 24 hours of incubation, cell proliferation ability was evaluated every 24 hours for three Increased expression of CELSR3 in human PCa consecutive days. Each experiment was performed in tissues triplicate and repeated at least three times. Previous studies have reported that the atypical cadherin family was critical in the development and Transwell migration assay progression of tumors [7]. First, we investigated the For migration detection, 100 ul of 1640 medium CELSR3 gene expression profiles in the PCTA dataset containing 2 × 104 cells were added to the upper (Figure 1A and 1B). We confirmed that CELSR3 was chamber of a 24-well plate, and 500 μl of 1640 medium significantly upregulated in PCa (primary PCa and containing 20% FBS was supplemented in the lower metastatic castration-resistant prostate cancer) when chamber. After incubating for 48 hours in a 37 ° C compared to benign
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