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

Expression and Clinical Significance of IL-33, MVD and LVD in Carcinoma and Paraneoplastic Tissues of Hepatocellular Carcinoma

摘要: 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。

Abstract: 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 patients’ cancer and paraneoplastic tissues was de-tected by immunohistochemical staining method (SP method), and the possible correlation be-tween the three and the clinicopathological parameters of the enrolled HCC patients was analysed. The patients were followed up for disease progression and the correlation with the progression-free survival (PFS) of HCC patients was analysed. Results: Combined with the immunohistochemical staining results and statistical analysis, the expression of IL-33 was higher in HCC paraneoplastic tissues than in cancer tissues, and the difference was statistically significant (P < 0.01). The expres-sion of MVD was higher in HCC cancer tissues than in paracancerous tissues (P < 0.01), while LVD expression was not significantly different (P > 0.05). The intensity of IL-33 expression was associat-ed with MVD expression (P < 0.01) but not with LVD (P > 0.05). The intensity of IL-33 expression was also positively correlated with the pathological histological grade of the tumour (P < 0.01), the T-stage of the tumour (P < 0.05) and lymph node metastasis (P < 0.01), but not with age, gender, history of alcohol consumption, hepatitis and cirrhosis background (P > 0.05). IL-33 expression, MVD expression, lymph node metastasis status, clinical T-stage and tumour pathological histological grade obtained by univariate and multifactorial Cox regression analysis were associated with PFS. Conclusion: High expression of IL-33 in paracancerous tissues of HCC patients is associated with poor prognosis of patients. High expression of IL-33, high expression of MVD, presence of metastasis in lymph nodes, late clinical T-stage and poor pathological histological grading of tumour are risk fac-tors for poor prognosis of patients with PFS, except for pathological histological grading of tumour, the other four are independent risk factors affecting the time to PFS. IL-33 may be used as IL-33 may provide a new direction and strategy for the diagnosis and treatment of HCC as a prognostic predictor.