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The Role of ARHGAP9: Clinical Implication and Potential Function In Han et al. J Transl Med (2021) 19:65 https://doi.org/10.1186/s12967-021-02733-5 Journal of Translational Medicine RESEARCH Open Access The role of ARHGAP9: clinical implication and potential function in acute myeloid leukemia Caixia Han1, Shujiao He1, Ruiqi Wang2, Xuefeng Gao1, Hong Wang2, Jingqiao Qiao1, Xiangyu Meng1, Yonghui Li1* and Li Yu1* Abstract Background: Rho GTPase activating protein 9 (ARHGAP9) is expressed in various types of cancers and can inactivate Rho GTPases that mainly regulate cytoskeletal dynamics. However, the exact role of ARHGAP9 in acute myeloid leuke- mia (AML) has yet to be clarifed. Methods: We compared the transcriptional expression, prognosis, diferentially expressed genes, functional enrich- ment, and hub genes in AML patients on the basis of the data published in the following databases: UALCAN, GEPIA, Gene Expression Omnibus, the Human Protein Atlas, Cancer Cell Line Encyclopedia, LinkedOmics, Metascape, and String. Data from the Cancer Genome Atlas database was used to evaluate the correlations between ARHGAP9 expression and various clinicopathological parameters, as well as the signifcantly diferent genes associated with ARHGAP9 expression. Results: We found that ARHGAP9 expression was higher in the tissues and cell lines extracted from patients with AML than corresponding control tissues and other cancer types. ARHGAP9 overexpression was associated with decreased overall survival (OS) in AML. Compared with the ARHGAP9low group, the ARHGAP9high group, which received only chemotherapy, showed signifcantly worse OS and event-free survival (EFS); however, no signifcant diference was observed after treatment with autologous or allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT). The ARHGAP9high patients undergoing auto/allo-HSCT also had a signifcantly better prognosis with respect to OS and EFS than those receiving only chemotherapy. Most overlapping genes of the signifcantly diferent genes and co-expression genes exhibited enriched immune functions, suggesting the immune regulation potential of ARHGAP9 in AML. A total of 32 hub genes were identifed from the diferentially expressed genes, within which the KIF20A had a signifcant prognostic value for AML. Conclusions: ARHGAP9 overexpression was associated with poor OS in AML patients and can be used as a prognostic biomarker. AML patients with ARHGAP9 overexpression can beneft from auto/allo-HSCT rather than chemotherapy. Keywords: ARHGAP9, AML, t(15;17), Prognosis, Auto/allo-HSCT, Chemotherapy Background Acute myeloid leukemia (AML), which is caused by the *Correspondence: [email protected]; [email protected] malignant transformation of myeloid primordial cells, is 1 Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health the second most common type of leukemia diagnosed Science Center, 1098 Xueyuan Ave, Shenzhen 518060, China in adults and children. Despite the signifcant progress Full list of author information is available at the end of the article made in risk stratifcation, supportive care, multiagent © 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. Han et al. J Transl Med (2021) 19:65 Page 2 of 13 chemotherapy intensifcation, and autologous or allo- the prognostic signifcance of ARHGAP9. We also inves- geneic hematopoietic stem cell transplantation (auto/ tigated the diferentially expressed genes associated with allo-HSCT), the outcome for AML patients remains ARHGAP9 expression and discussed their potential discouraging because of recurrence and refractory [1, functions in AML. 2]. Approximately 10% to 40% of younger patients and a larger percentage of patients aged 60 and above have Materials and methods refractory after standard chemotherapy (40%–60%) [3]. Analysis of The Human Protein Atlas (HPA) database Terefore, identifying robust prognostic markers is cru- Te HPA (https ://www.prote inatl as.org/) is user-friendly cial to provide optimal care for AML patients. online server, which contains the human transcriptomic Te Rho family of GTPases is a family of small and proteomic data in cells, tissues, and organs from (~ 21 kDa) signaling G proteins, which act as molecular human normal or pathological tissues via RNA sequenc- switches and are tightly controlled by guanine nucleotide ing (RNA-Seq) analysis and immunohistochemistry exchange factors (GEFs) and GTPase activating proteins (IHC) [20]. Tus, ARHGAP9 expression was analyzed (GAPs) by generating active GTP-binding and inactive in multiple cell lines, such as various leukemia cell lines, GDP-binding proteins, respectively [4, 5]. Activated Rho lung cell lines, breast cell lines, and brain cell lines in GTPases interact with their downstream efectors to HPA by using the search term “ARHGAP9”. regulate the cytoskeleton of the cell membrane or other cellular compartments [6, 7]. Considerable research has The Cancer Cell Line Encyclopedia (CCLE) database analysis supported the importance of Rho GTPases in hemat- Te CCLE project (https ://porta ls.broad insti tute.org/ opoiesis and confrmed that Rho GTPases are related to ccle) is an efort to conduct comprehensive genetic char- cytoskeleton rearrangement including adhesion, cytoki- acterization of a large panel of human cancer cell lines nesis, diferentiation, migration, engraftment, aging, and from individuals of various lineages and ethnicities [21]. self-renewal in the cellular process [8–14]. Te reor- It provides public access to analysis and visualization ganization of the actin and microtubuleb cytoskeleton is of mRNA expression, mutation data, DNA methyla- essential for platelet adhesion and thrombus formation to tion, DNA copy number, and histone H3 modifcation avoid excessive bleeding. for > 1100 cancer cell lines, such as breast cell lines, gas- A total of 80 Rho family GAPs have thus far been tric cancer cell lines, and AML cell lines. RNA-Seq of identifed, but fewer than half of them in cancer have RNA expression was used to verify ARHGAP9 expres- been clearly investigated. Rho GTPase activating pro- sion in various cell lines. tein 9 (ARHGAP9) containing RhoGAP, SH3, WW, and PH domains, is a member of the Rho GAPs family. UALCAN database analysis Research indicates that ARHGAP9 suppresses the adhe- Te UALCAN database (http://ualca n.path.uab.edu/) sion of KG-1 (a human leukemia cell line) to fbronec- contains level-3 RNA-seq and clinical data from 31 can- tin and collagen via the activation of Cdc42 and Rac1 cer types selected by the Cancer Genome Atlas (TCGA) rather than RhoA [15]. ARHGAP9 is also considered as [22]. It is an interactive web resource for the in-depth a MAP kinase docking protein, and the WW domain of analysis of RNA-Seq expression. Te function module of ARHGAP9 interacts with the CD domains of Erk2 and TCGA analysis in the UALCAN database was used in the p38alpha, leading to the inactivation of MAP kinases pan-cancer analysis of ARHGAP9 expression. [16]. ARHGAP9 inhibits the migration and invasion of hepatocellular carcinoma cell by increasing FOXJ2/E- GEPIA database analysis cadherin expression [17]. By contrast, silencing ARH- Te GEPIA database (http://gepia .cance r-pku.cn) is a GAP9 reduces the proliferation, migration, and invasion comprehensive resource for the systematic analysis of of breast and gastric cancer cells in vitro [18, 19]. Tese gene expression [23]. Tis database includes 9736 tumor occurrences suggest that ARHGAP9 plays distinct roles and 8587 normal tissue samples from the TCGA and in various physiological conditions or various tissues and the Genotype-Tissue Expression (GTEx) projects. In the cells. function module, single-gene analysis was used to create No studies have thus far been conducted to access the plots for ARHGAP9 expression in various cancers and expression profle and functions of ARHGAP9 in AML, normal tissues. Te threshold was selected as the default although ARHGAP9 expression in peripheral blood leu- value. kocytes has been demonstrated [15]. In the present study, we investigated ARHGAP9 expression in human AML The Gene Expression Omnibus (GEO) database analysis samples and cell lines, as well as explored its associations ARHGAP9 expression profles in various chromosome with clinicopathological factors. We then we evaluated abnormalities were acquired from the GEO (https :// Han et al. J Transl Med (2021) 19:65 Page 3 of 13 www.ncbi.nlm.nih.gov/geo) database. Data on ARH- Table 1 Correlations between ARHGAP9 expression GAP9 expression of GSE14468 and GSE13159
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