|Table of Contents|

The investigation of the mechanism of high-intensity focused ultrasound in the treatment of adenomyosis based on JAK2/STAT3 signal pathway

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

Issue:
2023 20
Page:
3722-3729
Research Field:
Publishing date:

Info

Title:
The investigation of the mechanism of high-intensity focused ultrasound in the treatment of adenomyosis based on JAK2/STAT3 signal pathway
Author(s):
QI Yingying; HE Yueming; MING Fanghua; ZHANG Ting
Department of Gynecology,the Fifth Affiliated Hospital of Guangzhou Medical University,Guangdong Guangzhou 510700,China.
Keywords:
JAK2/STAT3 signaling pathway; high-intensity focused ultrasound; GnRH-a; adenomyosis
PACS:
R737.3
DOI:
10.3969/j.issn.1672-4992.2023.20.002
Abstract:
Objective:To explore the mechanism of high-intensity focused ultrasound (HIFU) in the treatment of adenomyosis (AM) based on the JAK2/STAT3 signaling pathway.Methods:Endometrial cells in different groups of AM patients (GnRH-a+HIFU group,GnRH-a group,HIFU group and control group) were used to construct an in vitro model,and a countercurrent method was used to establish a rat AM model.qRT-PCR was used to detect the relative mRNA expression levels of JAK2,STAT3,IL-6,estrogen receptor,VEGF,MMP-2 and HOXA10.Western Blot was used to detect the protein expression levels of JAK2,STAT3,LIF.Transwell experiment and MTT experiment were used to detect the invasion and proliferation of cells.The pathological changes of mouse uterus were detected by HE staining.Uterine adenomyocytes were transfected with JAK2 overexpression plasmid to construct different animal models in order to verify the effect of JAK2/STAT3 pathway on HIFU therapy.Results:Results of qRT-PCR of different in vitro cell models groups showed that the mRNA relative expression levels of JAK2,STAT3,IL-6,estrogen receptor,VEGF and MMP-2 were down-regulated in GnRH-a group,HIFU group and their combined treatment group than that in the control group,and the differences were statistically significant (P＜0.05).The proliferation ability of adenomyocytes was most significantly inhibited in the combined treatment group (P＜0.05),and the relative expression level of HOXA10 mRNA in GnRH-a group,HIFU group and the combined treatment group was higher than that in control group (P＜0.05).The cell proliferation and invasion ability of the GnRH-a+HIFU group was significantly lower than that of the GnRH-a group,HIFU group,and control group (P<0.05).Western Blot results of JAK2 and STAT3 also found similar differences among different groups,but GnRH-a+HIFU group had a higher expression level of LIF protein than GnRH-a group,HIFU group and control group (P＜0.05).qRT-PCR test of animal models showed that the mRNA relative expression levels of JAK2,STAT3,IL-6,estrogen receptor,VEGF and MMP-2 in GnRH-a+HIFU group,HIFU group and GnRH-a group were lower than those in the model group,and the decreased level of GnRH-a+HIFU group was the most significant (all P＜0.05).The relative expression levels of HOXA10 mRNA in GnRH-a+HIFU group,HIFU group and GnRH-a group were higher than that in model group (P＜0.05).Western Blot results showed that the differences of JAK2 and STAT3 protein relative expression levels were consistent with the differences of mRNA expression levels among different groups (P＜0.05),and GnRH-a+HIFU group had higher LIF protein expression level than GnRH-a group,HIFU group and model group (P＜0.05).The mRNA expression levels of JAK2,STAT3,estrogen receptor,VEGF and MMP-2 in JAK2 over-expression+HIUF group were lower than those in JAK2 over-expression group,and still higher than those in HIFU group alone (all P＜0.05).The differences in protein expression levels of JAK2,STAT3,estrogen receptor,VEGF and MMP-2 in different groups of tissues were consistent with the differences in mRNA expression levels.Conclusion:GnRH-a combined with HIFU treatment can alleviate the proliferation and invasion of endometrial cells and block the progression of AM,improve endometrial receptivity.The expression of JAK2/STAT3 signaling pathway related factors is closely related to the therapeutic effect.

References:

[1] MOLDASSARINA RS.Modern view on the diagnostics and treatment of adenomyosis［J］.Arch Gynecol Obstet,2023,308(1):171-181.
[2] MISHRA I,MELO P,EASTER C,et al.Prevalence of adenomyosis in women with subfertility:systematic review and meta-analysis［J］.Ultrasound Obstet Gynecol,2023,62(1):23-41.
[3] PENG Y,DAI Y,YU G,et al.Clinical evaluation of HIFU combined with GnRH-a and LNG-IUS for adenomyosis patients who failed to respond to drug therapies:two-year follow-up results［J］.Int J Hyperthermia,2021,38(1):1271-1275.
[4] YUAN Y,XU W,SHEN H,et al.Long-term outcomes of ultrasound guided high intensity focused ultrasound ablation for patients with uterine fibroids classified by T2WI:a multicenter retrospective study［J］.Int J Hyperthermia,2023,40(1):2212887.
[5] LI Y,ZHANG D,JIN B,et al.Proteomic analysis of uterine tissues during peri-implantation period in mice with experimentally induced adenomyosis that Treated with anti-Ngf:implications for cell-cell adhesion and metabolic processes［J］.Reproductive Sciences,2021,28(1):207-217.
[6] HIRAOKA T,HIROTA Y,AIKAWAS,et al.Constant activation of STAT3 contributes to the development of adenomyosis in females［J］.Endocrinology,2022,163(5):bqac044.
[7] PANG LL,MEI J,FAN LX,et al.Efficacy of high-intensity focused ultrasound combined with GnRH-a for adenomyosis:a systematic review and meta-analysis［J］.Front Public Health,2021,16(9):688264.
[8] ANVARI AR,GHASEMZADEH A,HAMDI K,et al.Investigating the efficacy of ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on pro-inflammatory cytokine levels:A single-arm clinical trial［J］.Clinics (Sao Paulo),2023,78:100224.
[9] PASCAL P,D STEPHANIE,NELLY P,et al.In the mouse,prostaglandin D2 signalling protects the endometrium against adenomyosis［J］.Molecular Human Reproduction,2021,7(5):5-8.
[10] KOTIPALLI RSS,PATNAIK SS,KUMAR,et al.Biochanin-A attenuates DHEA-induced polycystic ovary syndrome via upregulation of GDF9 and BMP15 signaling in vivo［J］.Life Sci,2023,326:121795.
[11] KOTLYAR AM,MAMILLAPALLI R,FLORES VA,et al.Tofacitinib alters STAT3 signaling and leads to endometriosis lesion regression［J］.Mol Hum Reprod,2021,27(4):gaab016.
[12] SEO J,PARK M,KO D,et al.Ebastine impairs metastatic spread in triple-negative breast cancer by targeting focal adhesion kinase［J］.Cell Mol Life Sci,2023,80(5):132.
[13] GUO S,ZHANG D,LU X,et al.Hypoxia and its possible relationship with endometrial receptivity in adenomyosis:a preliminary study［J］.Reproductive Biology and Endocrinology,2021,19(1):93-100.
[14] NIE S,ZHANG L,LIU J,et al.ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer［J］.J Exp Clin Cancer Res,2021,40(1):284.
[15] 戚莹莹,潘礼洁,张婷.高强度聚焦超声促进子宫腺肌症子宫内膜表达LIF、HOXA-10对子宫容受性的调节作用分析［J］.山西卫生健康职业学院学报,2022,32(05):2-6. QI YY,PAN LJ,ZHANG T.Analysis of regulating effects of high-intensity focused ultrasound on expression of LIF and HOXA-10 regulating uterine receptivity in adenomyosis［J］.Journal of Shanxi Health Vocational College,2022,32(05):2-6.
[16] ERBAS E,GEDIKLI S.Investigation of the endometrial receptivity status in experimental hypothyroid-induced female rats［J］.Iran J Basic Med Sci,2022,25(9):1077-1083.
[17] SHOJI-KATO K,CHISHIMA F,NAKAJIMA T,et al.Changes of platelet indices patients with adenomyosis during menstrual cycle［J］.Journal of Reproductive Immunology,2020,142(8):103226-103229.
[18] OTGONTUA A,JENG CJ,WU TN,et al.Comparison of the treatment efficacies of HIFU,HIFU combined with GnRH-a,and HIFU combined with GnRH-a and LNG-IUS for adenomyosis:A systematic review and meta-analysis［J］.Taiwan J Obstet Gynecol,2023,62(2):226-238.
[19] ZHONG Q,YANG MJ,HU Y,et al.Factors influencing treatment decisions in HIFU treatment of adenomyosis:A retrospective study［J］.Front Surg,2022,12(9):941368.
[20] HE B,TENG XM,HAO F,et al.Decreased intracellular IL-33 impairs endometrial receptivity in women with adenomyosis［J］.Front Endocrinol (Lausanne),2022,13:928024.
[21] WANG X,WEI Z,TANG Z,et al.IL-37bΔ1-45 suppresses the migration and invasion of endometrial cancer cells by targeting the Rac1/NF-κB/MMP2 signal pathway［J］.Lab Invest,2021,101(6):760-774.
[22] BIAN Y,YUAN L,YANG X,et al.SMURF1-mediated ubiquitylation of SHP-1 promotes cell proliferation and invasion of endometrial stromal cells in endometriosis［J］.Ann Transl Med,2021,9(5):362.
[23] RIZNER TL,ROMANO A.Targeting the formation of estrogens for treatment of hormone dependent diseases-current status［J］.Front Pharmacol,2023,14:1155558.
[24] SIERSBAEK R,SCABIA V,NAGARAJAN S,et al.IL6/STAT3 signaling hijacks estrogen receptor α enhancers to drive breast cancer metastasis［J］.Cancer Cell,2020,38(3):412-423.
[25] XUE W,WEN S,SHEN W.Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis［J］.Journal of Hepatology,2016,64(6):1283-1294.
[26] MACLEAN A,BARZILOVA V,PATEL S,et al.Characterising the immune cell phenotype of ectopic adenomyosis lesions compared with eutopic endometrium:A systematic review［J］.J Reprod Immunol,2023,157:103925.
[27] MAKABE T,KOGA K,NAGABUKURO H,et al.Use of selective PGE2 receptor antagonists on human endometriotic stromal cells and peritoneal macrophages［J］.Mol Hum Reprod,2021,27(1):gaaa077.
[28] ELIAS MH,LAZIM N,SUTAJI A,et al.HOXA10 DNA methylation level in the endometrium women with endometriosis:A systematic review［J］.Biology (Basel),2023,12(3):474.
[29] SHI Y,ZHANG C,WANG X,et al.Analysis of the mechanism of guizhifuling wan in treating adenomyosis based on network pharmacology combined with molecular docking and experimental verification［J］.Evid Based Complement Alternat Med,2022,2022:6350257.
[30] 李雁,张绍芬,夏贤,等.口服他莫昔芬法建立ICR小鼠子宫腺肌病模型［J］.中国实验动物学报,2009,17(5):7-10. LI Y,ZHANG SF,XIA X,et al.Establishment of an ICR mouse model of adenomyosis by oral administration of tamoxifen［J］.Acta Laboratorium Animalis Scientia Sinica,2009,17(5):7-10.
[31]MELKOZEROVA O,SHCHEDRINA I,GRYSHKINA A,et al.How noninvasive treatment of uterine fibroids affects endometrial receptivity:a prospective cohort study［J］.Gynecol Endocrinol,2020,36(sup1):28-32.

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广东省医学科学技术研究基金项目(编号：A2020536）；广东省广州市基础研究计划基础与应用基础研究项目（编号：2021-02-08-12-3017-0002）；广东省广州市基础研究计划市校（院）企联合资助项目（编号：2023A03J0821）
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