具核梭杆菌诱导缺氧诱导因子及血管生成因子高表达对食管鳞癌患者生存预后的影响

doi:10.6040/j.issn.1671-7554.0.2023.0655

摘要/Abstract

摘要： 目的分析食管鳞癌(ESCC)中具核梭杆菌(Fn)对缺氧诱导因子(HIF-1α)及血管生成因子(VEGF)的诱导效应,并探讨3个指标对ESCC患者生存预后的影响。方法将ESCC细胞(KYSE30和KYSE150)分为对照组和Fn感染组。采用Western blotting法、CCK8法及平板克隆法检测各组细胞的HIF-1α与VEGF表达量、紫杉醇(PTX)与顺铂(CDDP)应答效力及体外增殖能力。采用RNA scope法及免疫组化法检测309例ESCC组织中Fn感染、HIF-1α及VEGF的表达。采用Kaplan-Meier生存法分析比较Fn+HIF-1α+VEGF高风险组与低风险组生存时间差异。结果与对照组相比,Fn感染组细胞的HIF-1α与VEGF表达量、PTX与CDDP半数抑制浓度及体外增殖能力均增高(P<0.05)。ESCC组织中Fn感染率、HIF-1α及VEGF阳性率分别为43.04%、65.37%及60.52%,三者具有显著一致性(P<0.05)。与Fn+HIF-1α+VEGF低风险组相比,Fn+HIF-1α+VEGF高风险组术后5年生存时间显著缩短(P<0.05)。结论 Fn感染可诱导HIF-1α与VEGF高表达,降低ESCC细胞对化疗药物的敏感性,促进其恶性增殖,导致ESCC患者生存预后差。

关键词: 食管鳞癌, 具核梭杆菌, 缺氧诱导因子, 血管生成因子, 预后

Abstract: Objective To investigate the induction effect of Fusobacterium nucleatum(Fn)on hypoxia inducible factor-1(HIF-1α)and vascular endothelial growth factor(VEGF)in esophageal squamous cell carcinoma(ESCC), and to explore the influence of the above three indexes on the survival and prognosis of ESCC patients. Methods ESCC cells(KYSE30 and KYSE150)were divided into control and Fn infection groups. The expressions of HIF-1α and VEGF, the response efficacy of paclitaxel(PTX)and cisplatin(CDDP), and the in vitro proliferation ability of cells were detected with Western blotting, CCK8 and plate cloning, respectively. The Fn infection and expressions of HIF-1α and VEGF in 309 ESCC tissues were determined with RNA scope and immunohistochemistry. The difference in survival between Fn+HIF-1α+VEGF high-risk and low-risk groups were compared with Kaplan-Meier survival analysis. Results Compared with the control group, the Fn infection group had increased expressions of HIF-1α and VEGF, the 50% inhibitory concentration of PTX and CDDP, and the proliferation capacity(P<0.05). The Fn infection rate, HIF-1α and positive rate of VEGF in ESCC tissues were 43.04%, 65.37% and 60.52%, respectively, with significant consistency(P<0.05). Compared with Fn+HIF-1α+VEGF low-risk group, the high-risk group had significantly shortened 5-year survival(P<0.05). Conclusion Fn infection can induce the high expression of HIF-1α and VEGF, reduce the sensitivity of ESCC cells to chemotherapy drugs, promote their malignant proliferation, and lead to poor prognosis of ESCC patients.

Key words: Esophageal squamous cell carcinoma, Fusobacterium nucleatum, Hypoxia inducible factor-1, Vascular endothelial growth factor, Prognosis

中图分类号:

R735.1

华月帆,何珂瑶,张家豪,钱梦凡,刘怡文,孔金玉,杨海军,周福有. 具核梭杆菌诱导缺氧诱导因子及血管生成因子高表达对食管鳞癌患者生存预后的影响[J]. 山东大学学报 (医学版), 2023, 61(11): 59-67.

HUA Yuefan, HE Keyao, ZHANG Jiahao, QIAN Mengfan, LIU Yiwen, KONG Jinyu, YANG Haijun, ZHOU Fuyou. Effects of high expressions of hypoxia inducible factor-1 and vascular endothelial growth factor induced by Fusobacterium nucleatum on survival and prognosis of patients with esophageal squamous cell carcinoma[J]. Journal of Shandong University (Health Sciences), 2023, 61(11): 59-67.

参考文献

[1] Waters JK, Reznik SI. Update on management of squamous cell esophageal cancer[J]. Curr Oncol Rep, 2022, 24(3): 375-385.
[2] Zhang N, Liu YW, Yang H, et al. Clinical significance of Fusobacterium nucleatum infection and regulatory T cell enrichment in esophageal squamous cell carcinoma[J]. Pathol Oncol Res, 2021, 27: 1609846. doi:10.3389/pore.2021.1609846.
[3] Liang MX, Liu YW, Zhang ZY, et al. Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance[J]. Ann Med, 2022, 54(1): 989-1003.
[4] Wang X, Liu Y, Lu Y, et al. Clinical impact of Fn-induced high expression of KIR2DL1 in CD8 T lymphocytes in oesophageal squamous cell carcinoma[J]. Ann Med, 2022, 54(1): 51-62.
[5] Liu X, Chen Y, Zhang S, et al. Gut microbiota-mediated immunomodulation in tumor[J]. J Exp Clin Cancer Res, 2021, 40(1): 221.
[6] Nakashima M, Watanabe M, Nakano K, et al. Differentiation of Hodgkin lymphoma cells by reactive oxygen species and regulation by heme oxygenase-1 through HIF-1α[J]. Cancer Sci, 2021, 112(6): 2542-2555.
[7] Wei J, Li R, Lu Y, et al. Salivary microbiota may predict the presence of esophageal squamous cell carcinoma[J]. Genes Dis, 2022, 9(4): 1143-1151.
[8] 刘新亚, 刘英敏, 范志勤, 等. 缺氧诱导因子-1α和血管内皮生长因子在食管鳞癌组织中的表达及临床意义[J]. 新疆医科大学学报, 2022, 45(10): 1099-1103. LIU Xinya, LIU Yingmin, FAN Zhiqin, et al. Expression and clinical significance of hypoxia-inducible factor-1α and vascular endothelial growth factor in esophageal squamous cell carcinoma[J]. Journal of Xinjiang Medical University, 2022, 45(10): 1099-1103.
[9] Jin ML, Zou ZH, Tao T, et al. Effect of the recombinant adenovirus-mediated HIF-1 alpha on the expression of VEGF in the hypoxic brain microvascular endothelial cells of rats[J]. Neuropsychiatr Dis Treat, 2020, 16: 397-406. doi:10.2147/NDT.S238616.
[10] 王文然, 郭瑞, 张华. HIF-1α靶向SP1促进食管鳞状细胞癌转移及血管生成的机制研究[J]. 现代肿瘤医学, 2022, 30(10): 1734-1741. WANG Wenran, GUO Rui, ZHANG Hua. Mechanism of HIF-1α targeting SP1 to promote metastasis and angiogenesis of esophageal squamous cell carcinoma[J]. Modern oncology, 2022, 30(10): 1734-1741.
[11] 张哲源, 刘怡文, 付臻, 等. 具核梭杆菌对炎症小体NLRP3的诱导作用对食管鳞状细胞癌患者生存期的影响[J]. 郑州大学学报(医学版), 2022, 57(2): 170-175. ZHANG Zheyuan, LIU Yiwen, FU Zhen, et al. Effects of induction of NLRP3 by Fusobacterium nucleatum on survival of patients with esophageal squamous cell carcinoma[J]. Journal of Zhengzhou University(Medical Sciences), 2022, 57(2): 170-175.
[12] 柏效治, 原翔, 刘怡文, 等. 组蛋白赖氨酸去甲基化酶4C对卵巢癌SKOV3细胞恶性生物学行为的影响[J]. 实用医学杂志, 2020, 36(2): 141-146. BAI Xiaozhi, YUAN Xiang, LIU Yiwen, et al. Effect of recombinant lysine specific demethylase 4C on malignant biological behavior of SKOV3 cells in ovarian cancer[J]. The Journal of Practical Medicine, 2020, 36(2): 141-146.
[13] Shao N, Han Y, Song L, et al. Clinical significance of hypoxia-inducible factor 1α, and its correlation with p53 and vascular endothelial growth factor expression in resectable esophageal squamous cell carcinoma[J]. J Cancer Res Ther, 2020, 16(2): 269-275.
[14] Ahmad A, Nawaz MI. Molecular mechanism of VEGF and its role in pathological angiogenesis[J]. J Cell Biochem, 2022, 123(12): 1938-1965.
[15] López-Cortés A, Prathap L, Ortiz-Prado E, et al. The close interaction between hypoxia-related proteins and metastasis in pancarcinomas[J]. Sci Rep, 2022, 12(1): 11100.
[16] Jiang X, Wang J, Deng X, et al. The role of microenvironment in tumor angiogenesis[J]. J Exp Clin Cancer Res, 2020, 39(1): 204.
[17] Al-Ostoot FH, Salah S, Khamees HA, et al. Tumor angiogenesis: current challenges and therapeutic opportunities[J]. Cancer Treat Res Commun, 2021, 28: 100422. doi: 10.1016/j.ctarc.2021.100422.
[18] Korbecki J, Simińska D, Gssowska-Dobrowolska M, et al. Chronic and cycling hypoxia: drivers of cancer chronic inflammation through HIF-1 and NF-κB activation: a review of the molecular mechanisms[J]. Int J Mol Sci, 2021, 22(19): 10701.
[19] Wing PAC, Liu PJ, Harris JM, et al. Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter[J]. J Hepatol, 2021, 75(1): 64-73.
[20] 张黎明, 朱彩霞, 蔡启良. 人类肿瘤病毒介导缺氧信号致病机制的研究进展[J].微生物与感染, 2014, 9(3): 131-138. ZHANG Liming, ZHU Caixia, CAI Qiliang. Advances in the pathogenesis of hypoxic signaling mediated by human tumor virus[J]. Microbes and Infection, 2014, 9(3): 131-138.
[21] 吴桐桐, 王志莲. HPV16相关宫颈癌中PI3K/Akt自噬通路与HIF-1α的关系[J]. 国际生殖健康/计划生育杂志, 2022, 41(2): 172-176. WU Tongtong, WANG Zhilian. The relationship between PI3K/Akt autophagy pathway and HIF-1α in HPV16 related cervical cancer[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(2): 172-176.
[22] 芦慧, 朱凌云, 刘登洋, 等. Hp感染慢性胃炎患者VEGF基因多态性及血清水平与胃癌前病变的关联[J]. 中华医院感染学杂志, 2022, 32(14): 2116-2121. LU Hui, ZHU Lingyun, LIU Dengyang, et al. Correlation between VEGF gene polymorphisms, serum VEGF of chronic gastritis patients with Hp infection and gastric precancerous lesions[J]. Chinese Journal of Nosocomiology, 2022, 32(14): 2116-2121.
[23] 李文茜, 王学红, 朱思雨, 等. 缺氧诱导因子-1α和幽门螺杆菌在胃癌中的研究进展[J]. 癌症进展, 2022, 20(21): 2181-2185. LI Wenqian, WANG Xuehong, ZHU Siyu, et al. Research progress of hypoxia inducible factor-1α and Helicobacter pylori in gastric cancer[J]. Oncology Progress, 2022, 20(21): 2181-2185.
[24] 陈斯默, 张哲源, 张家豪, 等. 具核梭杆菌诱导内质网应激相关蛋白GRP78及XBP1高表达在食管鳞癌中的临床意义[J]. 中山大学学报(医学科学版), 2023, 44(3): 403-415. CHEN Simo, ZHANG Zheyuan, ZHANG Jiahao, et al. Clinical significance of endoplasmic reticulum stress-related proteins GRP78 and XBP1 induced by Fusobacterium nucleatum in esophageal squamous cell carcinoma[J]. Journal of Sun Yat-sen University(Medical Science Edition), 2023, 44(3): 403-415.
[25] Korbecki J, Siminska D, Gassowska-dobowolska M, et al. Chronic and cycling hypoxia: drivers of cancer chronic inflammation through HIF-1 and NF-κB activation: a review of the molecular mechanisms[J]. Int J Mol Sci, 2021, 22(19): 10701.
[26] 张永刚, 张作峰, 王刚平. HIF-1α、VEGF在乳腺癌中的表达及其与化疗敏感性的关系[J]. 青岛医药卫生, 2014, 46(3): 161-163. ZHANG Yonggang, ZHANG Zuofeng, WANG Gangping. Expression of HIF-1α and VEGF in breast cancer and their relationship with chemotherapy sensitivity[J]. Qingdao Medicine and Health, 2014, 46(3): 161-163.
[27] 唐静, 张湘燕, 夏婧. HIF-1α、MMP-2、VEGF与肿瘤的侵袭和转移[J]. 贵州医药, 2017, 41(9): 995-996. TANG Jing, ZHANG Xiangyan, XIA Jing. HIF-1α, MMP-2, VEGF and tumor invasion and metastasis[J]. Guizhou Medicine, 2017, 41(9): 995-996.
[28] 卢明华, 陶功财, 方亚男, 等. 缺氧导致胃癌化疗耐药的研究进展[J].中国肿瘤临床, 2019, 46(13): 700-703. LU Minghua, TAO Gongcai, FANG Yanan, et al. Research progress on chemotherapy resistance of gastric cancer caused by hypoxia[J]. Chinese Oncology Clinic, 2019, 46(13): 700-703.
[29] Tang K, Toyozumi T, Murakami K, et al. HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway[J]. Br J Cancer, 2022, 127(3): 474-487.
[30] 李东辉, 李杰, 王艳伟. 食管鳞状细胞癌患者miRNA-210、缺氧诱导因子-1表达及其与放疗疗效关系[J]. 现代消化及介入诊疗, 2022, 27(7): 906-909. LI Donghui, LI Jie, WANG Yanwei. Expression of miRNA-210 and hypoxia-inducible factor-1 in patients with esophageal squamous cell carcinoma and their relationship with radiotherapy efficacy[J]. Modern Digestion & Intervention, 2022, 27(7): 906-909.

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