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AMOT Suppresses Tumor Progression Via Regulating DNA Damage Response Signaling in Diffuse Large B-Cell Lymphoma

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AMOT Suppresses Tumor Progression Via Regulating DNA Damage Response Signaling in Diffuse Large B-Cell Lymphoma Cancer Gene Therapy https://doi.org/10.1038/s41417-020-00258-5 ARTICLE AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma 1,2,3 1,2 1,2 1,2 1,2 1,2,4,5,6 1,2,4,5,6 Tan Sang ● Juan Yang ● Jiarui Liu ● Yang Han ● Ying Li ● Xiangxiang Zhou ● Xin Wang Received: 7 June 2020 / Revised: 22 October 2020 / Accepted: 4 November 2020 © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 Abstract Angiomotin (AMOT) is a membrane protein that is aberrantly expressed in a variety of solid tumors. Accumulating evidence support that AMOT is involved in the pathological processes of tumor proliferation, apoptosis, and invasion. However, the potential role of AMOT in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains elusive. In the present study, we investigated the expression level and biological function of AMOT in DLBCL. AMOT expression was significantly reduced in DLBCL biopsy section, and low AMOT expression was associated with poor clinical prognosis. Overexpression of AMOT by lentivirus in human DLBCL cells induced cell viability inhibition concomitant with an increased percentage of cells in G1 phase and decreased percentage in S phase. Moreover, AMOT upregulation increased the 1234567890();,: 1234567890();,: sensitivity of DLBCL cells to doxorubicin. Furthermore, overexpression of AMOT led to reduced activation of key kinases for the DNA damage response (DDR). The above results indicated that AMOT acts as a tumor suppressor via inhibition of the DDR, thus reducing the viability while increasing the chemosensitivity in DLBCL. In summary, AMOT may be a novel potential target for DLBCL therapeutic intervention. Introduction These authors contributed equally: Xiangxiang Zhou, Xin Wang Diffuse large B-cell lymphoma (DLBCL) is the most Supplementary information The online version of this article (https:// common type of highly aggressive non-Hodgkin’s lym- doi.org/10.1038/s41417-020-00258-5) contains supplementary phoma. Though the long-term survival rate of DLBCL is material, which is available to authorized users. ~60% after immunochemotherapy with R-CHOP [1], * Xiangxiang Zhou 30–40% of patients will present refractory or relapsed [email protected] process after an initial response to therapy [2, 3]. Gene * Xin Wang heterogeneity accounts for different clinical outcomes [4], [email protected] therefore, the research of individualized treatment schemes based on new molecular targets and oncogenic pathways is 1 Department of Hematology, Shandong Provincial Hospital, the main research strategy at current. Cheeloo College of Medicine, Shandong University, Angiomotin (AMOT) was initially identified in 2001 as a Jinan, Shandong 250021, China medium that binding to angiostatin and regulating angio- 2 School of Medicine, Shandong University, Jinan, Shandong genesis or endothelial cell migration [5–7]. Human AMOT 250012, China gene is located in chromosome Xq23 with a 2025-bp open 3 Department of Hematology, Jinan Central Hospital, Cheeloo reading frame. AMOT-p130 and AMOT-p80 are two clas- College of Medicine, Shandong University, Jinan, Shandong 250012, China sic isoforms which are nearly identical at the C-terminal, while there is an extended glutamine-rich domain at the N- 4 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong terminal of AMOT-p130 [7]. These two splicing formations 250021, China have different functions in regulating polarity rearrange- – 5 Shandong Provincial Engineering Research Center of Lymphoma, ments related to cell shaping and migration [8 10]. In Jinan, Shandong 250021, China murine, inactivation of AMOT led to failure in cell growth 6 National Clinical Research Center for Hematologic Diseases, and migration in the anterior visceral endoderm, causing Jinan, Shandong 250021, China early embryonic lethal [11]. Consistently, knockout of T. Sang et al. AMOT in zebrafish inhibited the proliferation rate of epi- (TBD Science, Tianjin, China). The study was approved by thelial cells [12, 13] and led to defects in endothelial the Medical Ethics Committee of Jinan Central Hospital migration [14]. affiliated to Shandong University. In accordance with the At present, the role of AMOT in several solid tumors is Declaration of Helsinki, the informed consent was obtained still controversial. AMOT expression was decreased in lung before all samples were collected. cancer, breast cancer, undifferentiated pleomorphic sar- coma, ovarian serous carcinoma, and clear cell renal cell Cell lines carcinoma [15–19], and was related to poor prognosis of these diseases. Nevertheless, in epithelial ovarian cancer, Human DLBCL cell lines LY1 and LY8 were obtained prostate cancer, liver cancer, osteosarcoma, and sinonasal from Dr. B. Hilda Ye (Albert Einstein College of Medicine, tumors, AMOT was overexpressed and promoted tumor cell NY, USA), and human DLBCL cell line Val was provided proliferation or invasion [10, 20–23]. AMOT participated in by Pro. Wing C. Chan (City of Hope National Medical the regulation of several signaling pathways, including Center, CA, USA). Cells were maintained in IMDM med- Hippo, Wnt, ERK1/2, and VEGFR-2 pathways [12, 24–29]. ium (Gibco, Carlsbad, USA) containing 10% fetal bovine However, the effect of AMOT in hematopoietic malig- serum (HyClone, Logan, USA) and 1% penicillin/strepto- nancies has not been reported. mycin mixture. All cells were incubated at 37 °C in a Increased replication pressure and alteration of the DNA humidified atmosphere with 5% CO2. All human cell lines damage response (DDR) are crucial features of genetic were examined for mycoplasma infection periodically and instability and are closely related to tumorigenesis [30]. authenticated using small tandem repeat profiling conducted DDR senses different types of damage and initiates DNA by LGC standards and ATCC. repair, involving transcriptional activation, cell cycle, senescence, and apoptosis [31]. The ataxia-telangiectasia Immunohistochemistry (IHC) mutated (ATM) and ATM and RAD3-related (ATR) protein kinases are the main regulators of the DDR program. Formalin-fixed and paraffin-embedded tissue sections Despite their functional similarity, ATM is activated pri- obtained from DLBCL and RLH patients were used to marily during DNA double-strand breaks, phosphorylates perform IHC. The RLH tissues were used as control, as checkpoint kinases 1 (Chk1) at S317 and S345, while ATR previously described [34, 35]. After deparaffinized and primarily regulates damaged replication forks, phosphor- hydrated, the antigen was retrieved in 10 mM sodium citrate ylates checkpoint kinases 2 (Chk2) at Thr68 [32, 33]. In buffer (pH = 6.0) under high-pressure for 10 min. Three some cases, AMOT was considered a substrate for ATM percent solution of H2O2 was used at 37 °C for 30 min to and ATR, but this finding has not been confirmed by further block the samples from endogenous peroxidases. After that, experiments [31]. sections were incubated with primary anti-AMOT (1:200, In this study, we evaluated the expression level of Abcam, 85143, Cambridge, UK) at 4 °C overnight, then AMOT in DLBCL. AMOT expression was upregulated to rinsed by 1× PBS for 15 min, and treated with second assess its effect on cell growth with or without doxorubicin antibody from (Golden Bridge, Beijing, China) at 37 °C for treatment. The results showed that AMOT could act as a 30 min. After incubation with SABC from SP reagent kit, negative regulator of DDR signaling in DLBCL. As far as the sections were stained with DAB (Golden Bridge, Beij- we know, this is the first report to confirm the regulatory ing, China), counterstained with hematoxylin and mounted effect of AMOT on the key enzymes of DDR in DLBCL. with neutral gum. The criterion for a positive result is that the positive cells rate exceeds 10%. Two independent researchers scored the IHC staining at different time points. Materials and methods Real-time quantitative polymerase chain reaction Patients and samples (qRT-PCR) Fifty-two specimens of newly diagnosed DLBCL and Total RNA was isolated from peripheral blood mononuclear twenty-five specimens of reactive lymphoid hyperplasia cells (PBMCs) and cultured cells by RNAiso Plus (TaKaRa, (RLH) were collected at Jinan Central Hospital affiliated to Dalian, China) and assessed by UV spectrophotometry for Shandong University. According to the WHO classification, the concentrations and purity. After reverse transcription of all patients were independently diagnosed by two experi- total RNA into cDNA using the reagents kit (TaKaRa, enced pathologists. Peripheral venous blood was collected Dalian, China), the amplification reactions were carried out from three healthy volunteers (N1, N2, and N3) and with specific primers by means of SYBR Green Premix Ex mononuclear cells were isolated by Ficoll centrifugation Taq II kit (Takara, Dalian, China) on a Light Cycler 480 AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell. real-time PCR system (Roche, Basel, CH). AMOT-specific efficiencies were evaluated by GFP and then validated by primers were the following: forward, 5′-AGCTCCAGG qRT-PCR and western blot assays. CAGCATGTGAA-3′; reverse, 5′-CTGAAACGTTGGT GGGCTGA-3′. Primers of GAPDH and DDR members are Cell viability assay listed in Table S1. GAPDH was used as an endogenous control. The relative quantification was calculated by the LY1 and LY8 cells with designed treatment were seeded at 2−ΔΔCt
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