目的: 本研究旨在系统评估长链非编码RNA 微小RNA205宿主基因（long non-coding RNA microRNA 205 host gene,lncRNA MIR205HG）在非小细胞肺癌（non-small cell lung cancer,NSCLC）患者中的表达水平及其与临床特征的关联,进一步探讨MIR205HG是否通过调控Kruppel样转录因子5（Kruppel-like factor 5,KLF5）影响肺癌细胞对吉西他滨的耐药性,从而为克服化疗耐药提供潜在的分子靶点。方法: 回顾我院胸外科2019年10月—2021年5月收治的81例NSCLC患者资料,比较患者肿瘤组织及癌旁组织的MIR205HG表达水平,比较不同MIR205HG表达水平患者的预后,并进行生存分析。体外检测肺癌细胞系中MIR205HG表达水平,构建MIR205HG过表达和敲低的肺癌细胞,CCK-8检测细胞增殖,克隆形成实验检测细胞克隆形成能力,qRT-PCR和Western blot检测MIR205HG和KLF5 mRNA 蛋白表达。比较SK-MES-1和吉西他滨耐药细胞（SK-MES-1/GR）的吉西他滨药物敏感性,检测SK-MES-1和SK-MES-1/GR中MIR205HG和KLF5 mRNA 蛋白表达水平。采用SK-MES-1/GR细胞转染MIR205HG干扰质粒检测吉西他滨药物敏感性和KLF5 mRNA 蛋白表达水平。结果: 肿瘤组织的MIR205HG表达水平高于癌旁组织。MIR205HG高表达与患者肿瘤分期高、发生淋巴结转移有关。MIR205HG高表达组预后更差。MIR205HG在肺癌细胞系SK-MES-1、NCI-H1703、NCI-H2170、NCI-H226中的表达均高于BEAS-2B细胞。抑制MIR205HG抑制细胞的增殖和克隆形成能力,并下调KLF5的表达水平。SK-MES-1/GR中MIR205HG和KLF5表达水平上调,抑制MIR205HG后增加细胞的吉西他滨的敏感性。结论: MIR205HG在NSCLC中高表达并与不良预后相关,可能成为NSCLC不良预后生物标志物;MIR205HG/KLF5信号轴是介导NSCLC吉西他滨耐药的关键通路,靶向该轴有望成为克服NSCLC吉西他滨耐药的新策略。
Abstract
Objective The aim of this study is to systematically evaluate the expression level of lncRNA MIR205HG in non-small cell lung cancer (NSCLC) patients and its association with clinical features, and further explore whether MIR205HG affects the resistance of lung cancer cells to gemcitabine by regulating KLF5, thereby providing potential molecular targets for overcoming chemotherapy resistance. Methods Data from 81 NSCLC patients admitted to our thoracic surgery department from October 2019 to May 2021 were reviewed. The expression levels were compared in tumor tissue and adjacent tissues, and the prognosis of patients with different levels of expression of expression of expression of MIR205HG was compared. Survival analysis was also conducted. In vitro detection of MIR205HG expression levels in lung cancer cell lines, construction of MIR205HG overexpression and knockdown lung cancer cells, CCK-8 detection of cell proliferation, clone formation assay to detect cell clone formation ability, qRT PCR and Western blot detection of MIR205HG and KLF5 mRNA and protein expression. Compare the sensitivity of in in gemcitabine drug in SK-MES-1 and gemcitabine resistant cells (SK-MES-1/GR) and detect MIR205HG and KLF5 mRNA and protein expression levels in SK-MES-1 and SK-MES-1/GR. Using SK-MES-1/GR cells transfected with MIR205HG interference plasmid to detect gemcitabine drug sensitivity and KLF5 mRNA and protein expression levels. Results The expression level of MIR205HG in tumor tissue was higher than that of adjacent tissues. High expression of MIR205HG is associated with increased tumor staging and lymph node metastasis in patients. The prognosis of the MIR205HG high expression group was worse. The expression of MIR205HG in lung cancer cell lines SK-MES-1, NCI-H1703, NCI-H2170 and NCI-H226 was higher than in BEAS-2B cells. Inhibition of MIR205HG suppresses cell proliferation and colony formation ability of cells, and down-regulates the expression level of KLF5. The expression levels of MIR205HG and KLF5 were up-regulated in SK-MES-1/GR, and inhibition of MIR205HG increased cell sensitivity to gemcitabine. Conclusion MIR205HG is highly expressed in NSCLC and is associated with poor prognosis, suggesting its potential as a prognostic biomarker for adverse outcomes in NSCLC. The MIR205HG/KLF5 signaling axis serves as a key pathway mediating gemcitabine resistance in NSCLC. Targeting this axis holds promise as a novel strategy to overcome gemcitabine resistance in NSCLC.
关键词
微小RNA205宿主基因 /
Kruppel样转录因子5 /
非小细胞肺癌 /
吉西他滨 /
耐药性
Key words
MIR205HG /
KLF5 /
non-small cell lung cancer /
gemcitabine /
drug resistance
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参考文献
[1] CAO W, QIN K, LI F, et al.Socioeconomic inequalities in cancer incidence and mortality: An analysis of GLOBOCAN 2022[J]. Chin Med J (Engl), 2024, 137(12): 1407-1413.
[2] ADAMS SJ, STONE E, BALDWIN DR, et al.Lung cancer screening[J]. Lancet, 2023, 401(10374): 390-408.
[3] LV P, LIU M.Meta-analysis of the clinical effect of Kanglaite injection-assisted gemcitabine plus cisplatin regimen on non-small cell lung cancer[J]. Am J Transl Res, 2023, 15(5): 2999-3012.
[4] LI D, QIAN X, XU P, et al.Identification of lncRNAs and Their Functional Network Associated with Chemoresistance in SW1990/GZ Pancreatic Cancer Cells by RNA Sequencing[J]. DNA Cell Biol, 2018, 37(10): 839-849.
[5] ASBERGER J, GE I, SCHMIDT B, et al.Long non-coding RNA signatures in breast cancer: Properties as biomarkers?[J]. Exp Ther Med, 2025, 29(3): 54.
[6] HSU XR, WU JE, WU YY, et al.Exosomal long noncoding RNA MLETA1 promotes tumor progression and metastasis by regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R axes in non-small cell lung cancer[J]. J Exp Clin Cancer Res, 2023, 42(1): 283.
[7] DI AGOSTINO S, VALENTI F, SACCONI A, et al.Long Non-coding MIR205HG Depletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma[J]. Theranostics, 2018, 8(7): 1850-1868.
[8] CHANG Y, XUE X, LI C, et al.MIR205HG facilitates carcinogenesis of lung squamous cell carcinoma in vitro revealed by long noncoding RNA profiling[J]. Acta Biochim Biophys Sin (Shanghai), 2020, 52(4): 371-381.
[9] AZWAR S, NG CT, ZAHARI SHAM SY, et al.Possible Involvement of Long Non-Coding RNAs GNAS-AS1 and MIR205HG in the Modulation of 5-Fluorouracil Chemosensitivity in Colon Cancer Cells through Increased Extracellular Release of Exosomes[J]. Noncoding RNA, 2024, 10(2): 25.
[10] ZENG L, ZHU Y, MORENO CS, et al.New insights into KLFs and SOXs in cancer pathogenesis, stemness, and therapy[J]. Semin Cancer Biol, 2023, 90: 29-44.
[11] ZENG X, WANG Y, LIU B, et al.multi-omics data reveals novel impacts of human papillomavirus integration on the epigenomic and transcriptomic signatures of cervical tumorigenesis[J]. J Med Virol, 2023, 95(5): e28789.
[12] WEI F, MA C, ZHOU T, et al.Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p[J]. Mol Cancer, 2021, 20(1): 35.
[13] WANG G, DONG Y, LIU H, et al.Loss of miR-873 contributes to gemcitabine resistance in triple-negative breast cancer via targeting ZEB1[J]. Oncol Lett, 2019, 18(4): 3837-3844.
[14] ZHANG H, SHAO F, GUO W, et al.Knockdown of KLF5 promotes cisplatin-induced cell apoptosis via regulating DNA damage checkpoint proteins in non-small cell lung cancer[J]. Thorac Cancer, 2019, 10(5): 1069-1077.
[15] TAO L, ZHOU K, ZHAO Y, et al.Betulinic acid, a major therapeutic triterpene of Celastrus orbiculatus Thunb. , acts as a chemosensitizer of gemcitabine by promoting Chk1 degradation[J]. J Ethnopharmacol, 2023, 309: 116295.
基金
2022年珠海市社会发展领域科技计划项目“Lnc RNA MIR205HG靶向KLF5增强肺癌细胞吉西他滨化疗敏感性的相关研究”（2220004000099）
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