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

Issue:

2023 07

Page:

1195-1201

Research Field:

Publishing date:

Info

Title:

circ-ERBB2 promotes trastuzumab resistance by inhibiting miR-136-5p to maintain HER2 downstream signal in breast cancer

Author(s):

WANG Lan¹; DONG Jiangmeng²; LEI Yong¹; QI Yixin³

1.The First of Department of General Surgery;2.Department of Glandular Vascular Surgery,Hengshui People's Hospital,Hebei Hengshui 053099，China;3.Department of Oncology,the Fourth Hospital of Hebei Medical University,Hebei Shijiazhuang 053011，China.

Keywords:

HER2-positive breast cancer; trastuzumab resistance; circ-ERBB2; miR-136-5p

PACS:

R73-3

DOI:

10.3969/j.issn.1672-4992.2023.07.003

Abstract:

Objective:To explore whether the circ-ERBB2/miR-136-5p axis is involved in the molecular mechanism of drug resistance in trastuzumab-resistant breast cancer.Methods:The expression levels of circ-ERBB2 and miR-136-5p in trastuzumab-sensitive and resistant breast cancer tissues,as well as in HER2- and HER2+ breast cancer tissues were detected by qPCR.Xenograft mouse model was established to evaluate the effects of knockdown/overexpression of circ-ERBB2 combined with overexpression/knockdown of miR-136-5p on tumorigenicity and trastuzumab resistance of breast cancer cells.Bioinformatics and dual-luciferase reporter analysis were used to analyze the interaction site between circ-ERBB2 and miR-136-5p.CCK-8 cell proliferation assay was used to analyze the proliferation ability of BT-474 or BT-474(Trast-resist) cells,when knockdown/overexpressed circ-ERBB2 was combined with overexpressed/knockdown miR-136-5p and cells were administered with Trastuzumab.Western blot was used to detect the expression levels of HER2,p-Akt and p-ERK1/2 in BT-474 or BT-474(Trast-resist) cells after knockdown/overexpression of circ-ERBB2 was combined with overexpression/knockdown of miR-136-5p.Results:Compared with trastuzumab-sensitive breast cancer tissues,the expression level of circ-ERBB2 in trastuzumab-resistant breast cancer tissues was significantly increased,and the expression level of miR-136-5p was significantly decreased(P<0.01).Regardless of whether hormone receptor expression was positive or negative,compared with HER2- breast cancer tissues,the expression of circ-ERBB2 was significantly up-regulated and the expression level of miR-136-5p was significantly inhibited(P<0.01) in HER2+ breast cancer tissues.Knockdown of circ-ERBB2 expression or overexpression of miR-136-5p could inhibit the proliferation of BT-474(Trast-resist) cells and the expression levels of HER2,p-Akt and p-ERK1/2 in cells(P<0.01).Conclusion：circ-ERBB2 can maintain HER2 downstream signaling in breast cancer and promote trastuzumab resistance by inhibiting miR-136-5p.

References:

［1］SIEGEL RL,MILLER KD,FUCHS HE,et al.Cancer statistics, 2022［J］.CA:A Cancer Journal for Clinicians,2022,72(1):7-33.
［2］BREDIN P,WALSHE JM,DENDULURI N,et al.Systemic therapy for metastatic HER2-positive breast cancer［J］.Seminars in Oncology,2020,47(5):259-269.
［3］CHAN WL,LAM TC,LAM KO,et al.Local and systemic treatment for HER2-positive breast cancer with brain metastases:a comprehensive review［J］.Therapeutic Advances in Medical Oncology,2020,12:1758835920953729.
［4］KREUTZFELDT J,ROZEBOOM B,DEY N,et al.The trastuzumab era:current and upcoming targeted HER2+breast cancer therapies［J］.American Journal of Cancer Research,2020,10(4):1045-1067.
［5］李蒙蒙，周晓艳.曲妥珠单抗联合TP化疗对HER2阳性乳腺癌的疗效［J］.河南医学研究,2021,30(8):1474-1476. LI MM,ZHOU XY.Curative effect of trastuzumab combined with TP chemotherapy on HER2 positive breast cancer［J］.Henan Medical Research,2021,30(8):1474-1476.
［6］朱逸慜，徐兵河.Her2阳性乳腺癌的精准治疗及研究进展［J］.中国肿瘤外科杂志,2020,12(4):294-300. ZHU YQ,XU BH.Precision therapy and research progress of Her2 positive breast cancer［J］.Chinese Journal of Surgical Oncology,2020,12(4):294-300.
［7］AHN S,WOO JW,LEE K,et al.HER2 status in breast cancer:changes in guidelines and complicating factors for interpretation［J］.Journal of Pathology and Translational Medicine,2020,54(1):34-44.
［8］VO JN,CIESLIK M,ZHANG Y,et al.The landscape of circular RNA in cancer［J］.Cell,2019,176(4):869-881.e13.
［9］ZHONG Y,DU Y,YANG X,et al.Circular RNAs function as ceRNAs to regulate and control human cancer progression［J］.Molecular Cancer,2018,17(1):79.
［10］徐彩鹏，陈小花，赵大鹏，等.环状RNA及其在肿瘤中的作用［J］.生理科学进展，2022，53(1):39-44. XU CP,CHEN XH,ZHAO DP,et al.Cyclic RNA and its role in tumor［J］.Progress in Physiological Sciences，2022，53(1):39-44.
［11］何啸，胡为杰，吕文昌，等.环状RNA在乳腺癌中作用的研究进展［J］.基础医学与临床，2022，42(3):507-511. HE X,HU WJ,LYU WC,et al.Research progress on the role of cyclic RNA in breast cancer［J］.Basic & Clinical Medicine，2022，42(3):507-511.
［12］MEMCZAK S,JENS M,ELEFSINIOTI A,et al.Circular RNAs are a large class of animal RNAs with regulatory potency［J］.Nature,2013,495(7441):333-338.
［13］HAN ML,HU JG,LU PW,et al.Exosome-transmitted miR-567 reverses trastuzumab resistance by inhibiting ATG5 in breast cancer［J］.Cell Death & Disease,2020,11(1):43.
［14］REN XF,DIAO ZZ,XI YM,et al.Adeno-associated virus-mediated BMP-7 and SOX9 in vitro co-transfection of human degenerative intervertebral disc cells［J］.Genetics and Molecular Research,2015,14(2):3736-3744.
［15］黄红莉，董桂玉，牛立志.曲妥珠单抗联合微波热疗治疗HER-2阳性晚期乳腺癌的临床疗效分析［J］.现代肿瘤医学，2020,28（17）:2985-2989. HUANG HL,DONG GY,NIU LZ.Clinical efficacy of trastuzumab combined with microwave hyperthermia in treatment of HER-2 positive advanced breast cancer［J］.Modern Oncology，2020,28（17）:2985-2989.
［16］XU JJ,JI L,LIANG YL,et al.CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1［J］.Signal Transduction and Targeted Therapy,2020,5(1):298.
［17］HONG WJ,XUE M,JIANG J,et al.Circular RNA circ-CPA4/ let-7 miRNA/PD-L1 axis regulates cell growth,stemness,drug resistance and immune evasion in non-small cell lung cancer(NSCLC)［J］.Journal of Experimental & Clinical Cancer Research,2020,39(1):149.
［18］PENG L,SANG HM,WEI SC,et al.circCUL2 regulates gastric cancer malignant transformation and cisplatin resistance by modulating autophagy activation via miR-142-3p/ROCK2［J］.Molecular Cancer,2020,19(1):156.
［19］SANG YT,CHEN B,SONG XJ,et al.circRNA_0025202 regulates tamoxifen sensitivity and tumor progression via regulating the miR-182-5p/FOXO3a axis in breast cancer［J］.Molecular Therapy,2019,27(9):1638-1652.
［20］ZHONG JX,KONG YY,LUO RG,et al.Circular RNA circ-ERBB2 promotes HER2-positive breast cancer progression and metastasis via sponging miR-136-5p and miR-198［J］.Joural of Translational Medicine,2021,19(1):455.
［21］GAO J,DING CZ,ZHOU JH,et al.Propofol suppresses lung cancer tumorigenesis by modulating the circ-ERBB2/miR-7-5p/FOXM1 axis［J］.Thoracic Cancer,2021,12(6):824-834.
［22］LI XS,HE M,GUO JJ,et al.Upregulation of circular RNA circ-ERBB2 predicts unfavorable prognosis and facilitates the progression of gastric cancer via miR-503/CACUL1 and miR-637/MMP-19 signaling［J］.Biochemical Biophysical Research Communications,2019,511(4):926-930.
［23］HUANG YH,ZHENG S,LIN Y,et al.Circular RNA circ-ERBB2 elevates the Warburg effect and facilitates triple-negative breast cancer growth by the microRNA 136-5p/pyruvate dehydrogenase kinase 4 axis［J］.Molecular and Cellular Biology,2021,41(10):e0060920.
［24］LI JF,HUANG CC,ZOU YF,et al.CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p［J］.Molecular Cancer,2020,19(1):103.
［25］ZHANG Q,FENG YF,FENG JG,et al.Circ_0013359 facilitates the tumorigenicity of melanoma by regulating miR-136-5p/RAB9A axis［J］.Open Life Science,2021,16(1):482-494.
［26］YANG B,ZANG J,YUAN WL,et al.The miR-136-5p/ROCK1 axis suppresses invasion and migration,and enhances cisplatin sensitivity in head and neck cancer cells［J］.Experimental and Therapeutic Medicine,2021,21(4):317.

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河北省重点研发计划项目（编号：19277799D）；河北省衡水市科技计划项目（编号：2021014088Z）

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Last Update: 2023-02-28