|Table of Contents|

miR-590 enhances the immune function of NK cells against bladder cancer by targeting STAT3

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2023 21
Page:
3914-3920
Research Field:
Publishing date:

Info

Title:
miR-590 enhances the immune function of NK cells against bladder cancer by targeting STAT3
Author(s):
LIU Jun; DU Heng; MA Bin
Department of Urology,the Second Affiliated Hospital of Xinjiang Medical University,Xinjiang Urumqi 830063,China.
Keywords:
bladder cancer; miR-590; STAT3; NK cells
PACS:
R737.14
DOI:
10.3969/j.issn.1672-4992.2023.21.003
Abstract:
Objective:To investigate the expression of miR-590 in peripheral blood natural killer(NK) cells of patients with bladder cancer and its regulatory mechanism on the immune function of NK cells.Methods:Peripheral blood samples of 31 patients with bladder cancer(Tumor group) and the same number of healthy subjects(Normal group)were collected as the research objects.Primary NK cells were isolated from peripheral blood mononuclear cells of patients in both groups using the NK cell isolation kit.The expressions of miR-590 and signal transduction and transcription activator 3(STAT3) in primary NK cells were detected by qRT-PCR.Pearson correlation coefficient was used to analyze the correlation between miR-590 and STAT3 mRNA expression in NK cells of bladder cancer patients.Bioinformatics technology was used to analyze the targeting binding sites of miR-590 and STAT3,and double luciferase gene reporting assay was used for detection.Human NK cell line NK-92 was transfected with miR-590 mimics,miR-590 inhibitor and negative control miR-NC,and activated with interleukin-2(IL-2).NK-92 cells were divided into Control group,IL-2 group,IL-2+miR-NC group,IL-2+miR-590 mimics group and IL-2+miR-590 inhibitor group according to different treatments.The contents of interferon γ(IFN-γ) and tumor cell necrosis factor-α(TNF-α) in the supernatant of cells in each group were detected by ELISA,and the killing effect of NK-92 cells on bladder cancer cell line T24 cells was detected by cytotoxicity assay.To investigate the effect of STAT3 on the immune function of NK cells mediated by miR-590,NK-92 cells were divided into IL-2+miR-590 mimic+pcDNA-NC group and IL-2+miR-590 mimic+pcDNA-STAT3 group.The secretion of IFN-γ and TNF-α and the killing effect of NK-92 cells on T24 cells in each group were detected by ELISA and cytotoxicity assay.Results:Compared with Normal group,the expression of miR-590 in Tumor group was significantly decreased(P<0.05),while the expression of STAT3 was increased(P<0.05),and there was a negative correlation between the two expressions in bladder cancer patients' NK cells(r=-0.641,P<0.05).Bioinformatics analysis showed that the 3' UTR region of STAT3 had a sequence region recognized by miR-590,and dual luciferase gene reporting assay showed that miR-590 could target the inhibition of STAT3 expression.Compared with Control group,the secretion levels of NK-92 on IFN-γ and TNF-α and the killing effect on T24 cells in IL-2 group,IL-2+miR-NC group,IL-2+miR-590 mimics group and IL-2+miR-590 inhibitor group were significantly increased(P<0.05).Compared with IL-2 group,the secretion levels of NK-92 on IFN-γ and TNF-α and the killing effect on T24 cells in IL-2+miR-590 mimics group were significantly increased(P<0.05),while those in IL-2+miR-590 inhibitor group were significantly decreased(P<0.05).There were no significant changes in IL-2+miR-NC group(P>0.05).In addition,compared with the IL-2+miR-NC group,the levels of IFN-γ and TNF-α secreted by NK-92 and the killing effect on T24 cells in the IL-2+miR-590 mimics group and the IL-2+miR-590 mimics+pcDNA-NC group were significantly increased(P<0.05).And IL-2+miR-590 mimics+pcDNA-STAT3 group had no significant changes(P>0.05).Compared with the IL-2+miR-590 mimics group,the levels of IFN-γ and TNF-α secreted by NK-92 and the killing effect on T24 cells in IL-2+miR-590 mimics+pcDNA-STAT3 group were significantly decreased(P<0.05),while the IL-2+miR-590 mimics+pcDNA-NC group had no significant changes(P>0.05).Conclusion:The expression of miR-590 is decreased in peripheral blood NK cells of bladder cancer,and the up-regulation of miR-590 expression can enhance the immunotoxic effect of NK cells on tumor cells by inhibition STAT3.

References:

［1］ SUNG H,FERLAY J,SIEGEL RL,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］.CA Cancer J Clin,2021,71(3):209-249.
［2］ CAO W,CHEN HD,YU YW,et al.Changing profiles of cancer burden worldwide and in China:a secondary analysis of the global cancer statistics 2020［J］.Chin Med J(Engl),2021,134(7):783-791.
［3］ WITJES JA,BRUINS HM,CATHOMAS R,et al.European association of urology guidelines on muscle-invasive and metastatic bladder cancer:summary of the 2020 guidelines［J］.Eur Urol，2021,79(1):82-104.
［4］ WU SY,FU T,JIANG YZ,et al.Natural killer cells in cancer biology and therapy［J］.Mol Cancer,2020,19(1):120.
［5］ HE B,ZHAO Z,CAI Q,et al.miRNA-based biomarkers,therapies,and resistance in Cancer［J］.Int J Biol Sci,2020,16(14):2628-2647.
［6］ LI Y,LI G,GUO X,et al.Non-coding RNA in bladder cancer［J］.Cancer Lett,2020,485(13):38-44.
［7］ MO M,PENG F,WANG L,et al.Roles of mitochondrial transcription factor A and microRNA-590-3p in the development of bladder cancer［J］.Oncol Lett,2013,6(2):617-623.
［8］ WU CC,WANG YH,HU SW,et al.MED10 Drives the oncogenicity and refractory phenotype of bladder urothelial carcinoma through the upregulation of hsa-miR-590［J］.Front Oncol,2022,11(21):744937.
［9］ MIAO L,LIU HY,ZHOU C,et al.LINC00612 enhances the proliferation and invasion ability of bladder cancer cells as ceRNA by sponging miR-590 to elevate expression of PHF14［J］.J Exp Clin Cancer Res,2019,38(1):143.
［10］ LONG X,LI Y,QIU S,et al.miR-582-5p/miR-590-5p targeted CREB1/CREB5-NF-κB signaling and caused opioid-induced immunosuppression in human monocytes［J］.Transl Psychiatry,2016,6(3):e757.
［11］ HUANG J,XU X,WANG X,et al.MicroRNA-590-3p inhibits T helper 17 cells and ameliorates inflammation in lupus mice［J］.Immunology,2022,165(2):260-273.
［12］ DENG F,YAN J,LU J,et al.M2 macrophage-derived exosomal miR-590-3p Attenuates DSS-induced mucosal damage and promotes epithelial repair via the LATS1/YAP/ β-Catenin signalling axis［J］.J Crohns Colitis,2021,15(4):665-677.
［13］ YU H,LEE H,HERRMANNN A,et al.Revisiting STAT3 signalling in cancer:new and unexpected biological functions［J］.Nat Rev Cancer,2014,14(11):736-746.
［14］ FERGUSON SD,SRINIVASAN VM,HEIMBERGER AB.The role of STAT3 in tumor-mediated immune suppression［J］.J Neurooncol,2015,123(3):385-394.
［15］ CACALANO NA.Regulation of natural killer cell function by STAT3［J］.Front Immunol,2016,11(7):128-134.
［16］ SUMI D,TSUYAMA H,OGAWA T,et al.Arsenite suppresses IL-2-dependent tumoricidal activities of natural killer cells［J］.Toxicol Appl Pharmacol,2021,17(412):e115353.
［17］ 杨莹,刘卓刚,王洪涛.NK细胞治疗多发性骨髓瘤的研究进展［J］.现代肿瘤医学,2020,28(19):3430-3433. YANG Y,LIU ZG,WANG HT.The progression of NK cells' function in the treatment of multiple myeloma［J］.Modern Oncology,2020,28(19):3430-3433.
［18］ BREUNIG C,PAHL J,KUBLBECK M,et al.MicroRNA-519a-3p mediates apoptosis resistance in breast cancer cells and their escape from recognition by natural killer cells［J］.Cell Death Dis,2017,8(8):e2973.
［19］ LI X,ZHANG Y,HE F,et al.miR-582 suppresses the proliferation of B-cell precursor acute lymphoblastic leukemia(BCP-ALL) cells and protects them from natural killer cell-mediated cytotoxicity［J］.Front Immunol,2022,13(9):e853094.
［20］ RAMAKRISHNAN S,GRANGER V,RAK M,et al.Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer［J］.Cell Death Differ,2019,26(10):2100-2114.
［21］张梅,崔新厂,刘烨.miR-590靶向SIP1抑制胆管癌细胞上皮间充质转化的实验研究［J］.临床肿瘤学杂志,2018,23(9):785-789. ZHANG M,CUI XC,LIU Y.miR-590 targeting SIP1 inhibition epithelial-mesenchymal transition in cholangiocarcinoma cells［J］.Journal of Clinical Oncology,2018,23(9):785-789.
［22］ HAO X,SU A.MiR-590 suppresses the progression of non-small cell lung cancer by regulating YAP1 and Wnt/β-catenin signaling［J］.Clin Transl Oncol,2022,24(3):546-555.
［23］ SHI S,JIN L,ZHANG S,et al.MicroRNA-590-5p represses proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3［J］.Arch Med Sci,2018,14(5):1093-1101.
［24］ WAN Z,LI X,LUO X,et al.The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma［J］.Aging(Albany NY),2022,14(14):5783-5799.
［25］ ZHENG QW,NI QZ,ZHU B,et al.PPDPF promotes lung adenocarcinoma progression via inhibiting apoptosis and NK cell-mediated cytotoxicity through STAT3［J］.Oncogene,2022,41(36):4244-4256.

Memo

Memo:
新疆维吾尔自治区自然科学基金项目（编号：2021D01C364）
Last Update: 2023-09-28