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Silencing of Microrna-135B Inhibits Invasion

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Silencing of Microrna-135B Inhibits Invasion Zhou et al. Cancer Cell Int (2020) 20:134 https://doi.org/10.1186/s12935-020-01210-1 Cancer Cell International PRIMARY RESEARCH Open Access Silencing of microRNA-135b inhibits invasion, migration, and stemness of CD24+CD44+ pancreatic cancer stem cells through JADE-1-dependent AKT/mTOR pathway Jingyang Zhou1, Haihong Wang2, Jinhui Che2, Lu Xu2, Weizhong Yang2, Yunjiu Li2 and Wuyuan Zhou2* Abstract Background: Recent studies have emphasized determining the ability of microRNAs (miRNAs) as crucial regulators in the occurrence and development of pancreatic cancer (PC), which continues to be one of the deadliest malignancies with few efective therapies. The study aimed to investigate the functional role of miR-135b and its associated mecha- nism to unravel the biological characteristics of tumor growth in pancreatic cancer stem cells (PCSCs). Methods: Microarray analyses were initially performed to identify the PC-related miRNAs and genes. The expression of miR-135b and PCSC markers in PC tissues and cells was determined by RT-qPCR and western blot analysis, respec- tively. The potential gene (JADE-1) that could bind to miR-135b was confrmed by the dual-luciferase reporter assay. To investigate the tumorigenicity, migration, invasion, and stemness of PC cells, several gain-of-function and loss-of- function genetic experiments were conducted. Finally, tumor formation in nude mice was conducted to confrm the results in vivo. Results: miR-135b was highly-expressed in PC tissues and PCSCs, which was identifed to specifcally target JADE-1. The overexpression of miR-135b promoted proliferation, migration, and invasion of PCSC, inhibited cell apoptosis and increased the expression of stemness-related factors (Sox-2, Oct-4, Nanog, Aldh1, and Slug). Moreover, miR-135b could promote the expression of phosphorylated AKT and phosphorylated mTOR in the AKT/mTOR pathway. Addi- tionally, miR-135b overexpression accelerated tumor growth in nude mice. Conclusions: Taken together, the silencing of miR-135b promotes the JADE-1 expression, which inactivates the AKT/mTOR pathway and ultimately results in inhibition of self-renewal and tumor growth of PCSCs. Hence, this study contributes to understanding the role of miR-135 in PCSCs and its underlying molecular mechanisms to aid in the development of efective PC therapeutics. Keywords: microRNA-135b, Jade family PHD fnger 1, Protein kinase B/mammalian target of rapamycin pathway, Pancreatic cancer, Stemness Background Pancreatic cancer (PC) is a devastating malignancy *Correspondence: [email protected] aficting the digestive system [1] with a 5-year survival 2 Department of Hepatopancreatobillary Surgery, Xuzhou City Cancer rate of less than 10% over the past decades [2]. According Hospital, No. 131 Huancheng Rd., Gulou District, Xuzhou 221000, Jiangsu, to GLOBOCAN 2018, PC remains one of the most lethal People’s Republic of China Full list of author information is available at the end of the article malignancies leading to 432,242 new deaths in 2018, as © The Author(s) 2020. 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://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhou et al. Cancer Cell Int (2020) 20:134 Page 2 of 16 patients rarely present symptoms before the advanced of Xuzhou City Cancer Hospital. Extensive eforts were stage of the disease [3, 4]. Currently, it was reported that made to minimize the pain and sufering of the experi- there is a subpopulation of cells in tumors, cancer stem mental animal. cells (CSCs), which are capable of self-renewal and gen- erating unique progeny that form the main tumor cell Bioinformatics prediction of PC related miRNA/gene component of tumors [5]. Tus, the possible reason for PC-related datasets were obtained from the Gene the high incidence of PC can be associated with the high Expression Omnibus (GEO) database (https ://www.ncbi. oncogenic ability of pancreatic CSCs (PCSCs) which can nlm.nih.gov/geo/) for diferential expression analysis. not only boast self-renewal ability but also produce later One miRNA expression dataset (GSE41369) and three generation with ability to diferentiate [6]. Intriguingly, coding gene expression datasets (GSE16515, GSE32676, the functional role of PSCSs in promoting the metastasis and GSE71989) were used to screen out diferentially of PC could be related to the resistance of PC to stand- expressed miRNAs/genes. Details of the datasets are ard chemotherapy and radiation treatment [7]. Tere is shown in Additional fle 1: Table S1. Te R-language afy a well-defned requirement to investigate more potential installation package (http://www.bioco nduct or.org/packa therapeutic approaches for the treatment of PC. ges/relea se/bioc/html/afy.html) was applied to carry Located on 1q32.1, miR-135b is encoded in the frst out standardized pre-processing of datasets. Te limma intron of the LEMD1 gene, cancer/testis antigen [8]. package (http://maste r.bioco nduct or.org/packa ges/relea Specifcally, miR-135b is a well-documented oncogene, se/bioc/html/limma .html) was used to screen out dif- possesses the ability to adjust the growth of various ferentially expressed miRNAs/genes between tumor tumors [9]. Moreover, several studies have illustrated the tissues and normal tissues and the corrected p-value aberrant expression of miR-135b in various malignant was expressed by adj. p. Val. Te miRNAs/genes with tumors, which highlights the crucial role of miR-135b in |log2FC| > 1.0 and adj. p. Val < 0.05 were considered multiple tumors [10, 11]. Of note, a Global microRNA signifcantly diferentially expressed whereas the heat expression profling of microdissected tissues has indi- map of diferentially expressed genes was drawn with cated the potential role of miR-135b might act as a novel heatmap package (https ://cran.r-proje ct.org/web/packa biomarker for pancreatic ductal adenocarcinoma [12]. ges/pheat map/index .html). Te target genes of diferen- Additionally, another study by Jiang et al. has confrmed tially expressed miRNAs were predicted in the DIANA, the involvement of miR-135b in tumourigenesis and miRDB, miRWalk, and mirDIP. Ten, miRNA-gene pairs chemoresistance of PC [13]. diferentially expressed in PC and regulatory interac- Nevertheless, due to its high expression in renal proxi- tions were screened in connection with the Venn online mal tubules, JADE-1 has been suggested as a promising analysis tools-Calculate and custom Venn diagrams were candidate for renal tumor inhibitor [14] that accelerates drawn (http://bioin forma tics.psb.ugent .be/webto ols/ the apoptosis of renal cancer [15]. Importantly, the AKT/ Venn/). mammalian target of rapamycin (mTOR) is known as one of the most critical pathways in regulating cell develop- Cell culture ment, proliferation, and survival [16]. A further study has Human PCSCs (CD44 +/CD24+/ESA+) were isolated indicated that the activation of the AKT/mTOR pathway from human PC cell line PANC-1 (cell bank of Chinese could enhance cell proliferation in PC cells [17]. Besides, Academy of Sciences, Shanghai, China) (source bank: another study suggested that the AKT/mTOR pathway https ://www.fengh bio.cn) according to the method could also impact the survival ability and proliferation of described by Jun Sheng Fu et al. [20]. Te isolated PCSCs prostate cancer cells [18]. Additionally, the AKT pathway were cultured in the PCSC culture medium (Celprogen) could be regulated by miR-135b in colorectal cancer cells containing 1% N2, 2% B27, 100 ng/mL epidermal growth [19]. However, scarce data is determining the relationship factor, and 1% antifungal agent (Invitrogen, Shanghai, between miR-135b and JADE-1 and the efect of this cor- China), as well as 20 ng/mL human platelet, derived relation on PC progression. Considering these limitations growth factor (Sigma-Aldrich, Shanghai, China). Te here we aimed to investigate whether miR-135b target cells were cultured in a 37°C incubator with 5% CO2 and JADE-1 to regulate the AKT/mTOR pathway, thus modu- 95% saturated humidity [21]. lating the invasion, migration, and stemness of PCSCs. Cell grouping and transfection Materials and methods CD24+CD44+ESA+ cells were assigned into the ago- Ethics statement mir-negative control (NC) group, the agomir-miR-135b All the animal study was carried out by following the group, the antagomir-NC group, the antagomir-miR- Institutional Animal Ethics Care and Use Committee 135b group, the sh-NC group, the sh-JADE-1 group, the Zhou et al. Cancer Cell Int (2020) 20:134 Page 3 of 16 dimethyl sulphoxide (DMSO) group (10 μmol/mL, St. synthesized by Shanghai GeneCore BioTechnologies Co., Louis, MO, USA), the perifosine (AKT/mTOR inhibitor) Ltd. (Shanghai, China) as illustrated in Table 1. Te fold group (10 μmol/mL, Selleck Chemicals, CA, USA), the changes were calculated using relative quantifcation -ΔΔCt agomir-miR-135b + DMSO (10 μmol/mL) group, and the (2 method). agomir-miR-135b + perifosine (10 μmol/mL) group. Te antagomirs and agomirs were designed and synthesized Western blot analysis by Dharmacon Inc.
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