|
|
IL-33、MVD及LVD在肝细胞癌癌组织与癌旁组织中的表达及临床意义
|
Abstract:
背景：白细胞介素33 (Interleukin-33, IL-33)是1种具有双重作用的细胞因子，属于IL-1细胞因子家族。IL-33既可以与ST2受体结合，激活丝裂原活化蛋白激酶(Mitogen-activated protein kinase, MAPK)和核因子(Nuclear factor, NF, NF-κB)的信号传导通路，增加Th2细胞因子(如IL-4、IL-5和IL-13)的表达，又在细胞核中起着染色质相关因子的作用，通过表现出转录抑制因子的特性来调节基因转录，在炎症性疾病及多种恶性肿瘤的发生发展过程中起重要作用。然而IL-33在肝细胞癌(Hepatocellular car-cinoma, HCC)的发生发展及预后中是否具有临床意义尚不明确。目的：本文通过研究淋巴管密度(Lymphatic vessel density, LVD)，IL-33和微血管密度(Microvessel density, MVD)等在HCC癌组织及癌旁组织中的不同表达情况，结合患者的临床及病理学参数分析和研究IL-33、MVD、LVD与HCC的相关性及临床意义。方法：本研究收集了62例HCC患者的临床资料及手术病理样本，将符合要求的临床资料纳入进行回顾性的分析。通过免疫组织化学染色方法(SP法)检测患者癌组织及癌旁组织中IL-33蛋白、MVD及LVD的表达情况，分析三者与入组HCC患者临床病理参数之间的可能相关性，随访患者疾病进展状况，分析与HCC患者无进展生存期(PFS)的相关关系。结果：结合免疫组化染色结果及统计学分析数据，IL-33在HCC癌旁组织中的表达高于癌组织，差异有统计学意义(P < 0.01)。HCC癌组织中的MVD表达高于癌旁组织(P < 0.01)，LVD表达无明显差异(P > 0.05)。IL-33的表达强度与MVD表达有关(P < 0.01)而与LVD无关(P > 0.05)。IL-33的表达强度还与肿瘤的病理组织学分级(P < 0.01)、肿瘤T分期(P < 0.05)及淋巴结转移(P < 0.01)呈正相关，但与年龄、性别、饮酒史、肝炎和肝硬化背景无明显相关性(P > 0.05)。单因素及多因素Cox回归分析获得的IL-33表达、MVD表达、淋巴结转移情况、临床T分期及肿瘤病理组织学分级与PFS有关。结论：HCC患者癌旁组织IL-33的高表达与患者不良预后有关。IL-33高表达、MVD高表达、淋巴结有转移、临床T分期晚及肿瘤的病理组织学分级差是患者PFS预后不良的危险因素，除肿瘤病理组织学分级外，其余4项为影响PFS时间的独立危险因素。IL-33或可作为预后预测因子为HCC的诊断和治疗提供新的方向和策略。
Background: Interleukin-33 (IL-33) is a dual-acting cytokine that belongs to the IL-1 family of cyto-kines. IL-33 binds to the ST2 receptor and activates Mitogen-activated protein kinase (MAPK) and nuclear factor (NF, NF-κB) signaling pathways, increasing the expression of Th2 cytokines (e.g. IL-4, IL-5 and IL-13). It also acts as a chromatin-associated factor in the nucleus, regulates gene tran-scription by exhibiting transcriptional repressor properties, and plays an important role in the de-velopment of inflammatory diseases and various malignancies. However, the clinical significance of IL-33 in the development and prognosis of hepatocellular carcinoma (HCC) is unclear. Objective: In this paper, we studied the different expression of lymphatic vessel density (LVD), IL-33 and mi-crovessel density (MVD) in HCC cancer tissues and paracancerous tissues, and analyzed and studied the correlation and clinical significance of IL-33, MVD, LVD and HCC with the clinical and pathological parameters of patients. The correlation between IL-33, MVD, LVD and HCC and their clinical signifi-cance were analyzed and studied in the context of the patients’ clinical and pathological parame-ters. Methods: In this study, clinical data and surgical pathology samples of 62 HCC patients were collected, and those that met the requirements were included for retrospective analysis. The ex-pression of IL-33 protein, MVD and LVD in the
| [1] | Jin, Z., Lei, L., Lin, D., et al. (2018) IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4(+) and CD8(+) T Cell Responses in Hepatocellular Carcinoma. The Journal of Immunology, 201, 3770-3779.
https://doi.org/10.4049/jimmunol.1800627 |
| [2] | Brunner, S.M., Rubner, C., Kesselring, R., et al. (2015) Tu-mor-Infiltrating, Interleukin-33-Producing Effector-Memory CD8(+) T Cells in Resected Hepatocellular Carcinoma Pro-long Patient Survival. Hepatology, 61, 1957-1967.
https://doi.org/10.1002/hep.27728 |
| [3] | Wang, Z., Wu, L., Pan, B., et al. (2021) Interleukin 33 Mediates Hepatocyte Autophagy and Innate Immune Response in the Early Phase of Acetaminophen-Induced Acute Liver Injury. Toxicology, 456, Article ID: 152788.
https://doi.org/10.1016/j.tox.2021.152788 |
| [4] | Wang, W., Wu, J., Ji, M., et al. (2020) Exogenous Interleukin-33 Promotes Hepatocellular Carcinoma Growth by Remodelling the Tumour Microenvironment. Journal of Translational Medicine, 18, 477.
https://doi.org/10.1186/s12967-020-02661-w |
| [5] | Askoura, M., Abbas, H.A., Al, S.H., et al. (2022) Elevated Levels of IL-33, IL-17 and IL-25 Indicate the Progression from Chronicity to Hepatocellular Carcinoma in Hepatitis C Virus Patients. Pathogens, 11, 57.
https://doi.org/10.3390/pathogens11010057 |
| [6] | Saranchova, I., Han, J., Huang, H., et al. (2016) Discovery of a Metastatic Immune Escape Mechanism Initiated by the Loss of Expression of the Tumour Biomarker Interleukin-33. Sci-entific Reports, 6, Article No. 30555.
https://doi.org/10.1038/srep30555 |
| [7] | Zhao, R., Yu, Z., Li, M., et al. (2019) Interleukin-33/ST2 Signaling Pro-motes Hepatocellular Carcinoma Cell Stemness Expansion through Activating c-Jun N-terminal Kinase Pathway. The American Journal of the Medical Sciences, 358, 279-288. https://doi.org/10.1016/j.amjms.2019.07.008 |
| [8] | Wei, Z.H., Li, Y.Y., Huang, S.Q., et al. (2019) Genetic Variants in IL-33/ST2 Pathway with the Susceptibility to Hepatocellu-lar Carcinoma in a Chinese Population. Cytokine, 118, 124-129. https://doi.org/10.1016/j.cyto.2018.03.036 |
| [9] | Bergis, D., Kassis, V., Ranglack, A., et al. (2013) High Serum Levels of the Interleukin-33 Receptor Soluble ST2 as a Negative Prognostic Factor in Hepatocellular Carcinoma. Trans-lational Oncology, 6, 311-318.
https://doi.org/10.1593/tlo.12418 |
| [10] | Pisani, L.F., Tontini, G.E., Gentile, C., et al. (2021) Proinflammatory Inter-leukin-33 Induces Dichotomic Effects on Cell Proliferation in Normal Gastric Epithelium and Gastric Cancer. Interna-tional Journal of Molecular Sciences, 22, 5792. https://doi.org/10.3390/ijms22115792 |
| [11] | Zhou, Q., Wu, X., Wang, X., et al. (2020) The Reciprocal Interaction between Tumor Cells and Activated Fibroblasts Mediated by TNF-alpha/IL-33/ST2L Signaling Promotes Gastric Cancer Metastasis. Oncogene, 39, 1414-1428.
https://doi.org/10.1038/s41388-019-1078-x |
| [12] | Xu, L., Zheng, Y., Wang, J., et al. (2020) IL33 Activates CD8+T and NK Cells through MyD88 Pathway to Suppress the Lung Cancer Cell Growth in Mice. Biotechnology Letters, 42, 1113-1121.
https://doi.org/10.1007/s10529-020-02815-2 |
| [13] | Casciaro, M., Cardia, R., Di Salvo, E., et al. (2019) Interleu-kin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update. Biomolecules, 9, 203. https://doi.org/10.3390/biom9050203 |
| [14] | Qi, L., Zhang, Q., Miao, Y., et al. (2020) Interleukin-33 Activates and Recruits Natural Killer Cells to Inhibit Pulmonary Metastatic Cancer Development. International Journal of Cancer, 146, 1421-1434.
https://doi.org/10.1002/ijc.32779 |
| [15] | Jovanovic, I.P., Pejnovic, N.N., Radosavljevic, G.D., et al. (2014) Interleu-kin-33/ST2 Axis Promotes Breast Cancer Growth and Metastases by Facilitating Intratumoral Accumulation of Immu-nosuppressive and Innate Lymphoid Cells. International Journal of Cancer, 134, 1669-1682. https://doi.org/10.1002/ijc.28481 |
| [16] | Zeng, X., Zhang, Z., Gao, Q.Q., et al. (2016) Clinical Significance of Serum Interleukin-31 and Interleukin-33 Levels in Patients of Endometrial Cancer: A Case Control Study. Disease Markers, 2016, Article ID: 9262919.
https://doi.org/10.1155/2016/9262919 |
| [17] | Zhang, X., Bi, K., Tu, X., et al. (2021) Interleukin-33 as an Early Pre-dictor of Cetuximab Treatment Efficacy in Patients with Colorectal Cancer. Cancer Medicine, 10, 8338-8351. https://doi.org/10.1002/cam4.4331 |
| [18] | Chatrabnous, N., Jafarzadeh, A., Ghaderi, A., et al. (2019) Association of Elevated Interleukin-33 Serum Levels with Tumorstages in Patients with Prostate Cancer. European Cytokine Network, 30, 144-150. |
| [19] | Jiang, S.W., Wang, P., Xiang, X.G., et al. (2017) Serum Soluble ST2 Is a Promising Prognostic Bi-omarker in HBV- Related Acute-on-Chronic Liver Failure. Hepatobiliary & Pancreatic Diseases International, 16, 181-188.
https://doi.org/10.1016/S1499-3872(16)60185-6 |
| [20] | Hong, J., Kim, S. and Lin, P.C. (2019) Interleukin-33 and ST2 Signaling in Tumor Microenvironment. Journal of Interferon & Cytokine Research, 39, 61-71. https://doi.org/10.1089/jir.2018.0044 |
| [21] | Hammerich, L. and Tacke, F. (2014) Interleukins in Chronic Liver Dis-ease: Lessons Learned from Experimental Mouse Models. Clinical and Experimental Gastroenterology, 7, 297-306. https://doi.org/10.2147/CEG.S43737 |
