高迁移率族蛋白1在肝内胆管癌中的作用及其与肿瘤微血管形成的关系

Function of high mobility group protein 1 in intrahepatic cholangiocarcinoma and its relationship with tumor microangiogenesis

背景与目的:肝内胆管癌(ICC)是源于二级及以上胆管上皮细胞的高度恶性肿瘤,其不良的预后源于对其发病机制认识不足、早期诊断方法匮乏和治疗手段有限。对ICC分子标志物的研究有助于早期诊断、预后判断和指导治疗。本研究旨在探讨促炎症因子高迁移率族蛋白1(HMGB1)在ICC组织中的表达与其临床意义及其与肿瘤微血管生成的关系。方法:用免疫组化法检测65例ICC患者手术标本(ICC组织与癌旁组织)以及30例正常肝内胆管组织标本中HMGB1的表达及肿瘤微血管密度(MVD)计数(CD31的表达),分析HMGB1表达与MVD与ICC患者临床病理特征的关系,两者在ICC组织中的相关性,及两者对ICC患者预后的影响。结果:HMGB1的表达与MVD计数均表现为在ICC组织、癌旁组织、正常胆管组织明显依次降低(均P<0.05)。HMGB1的表达与肿瘤组织分化程度、淋巴结转移、血管浸润与HMGB1有关(均P<0.05);MVD计数与肿瘤血管浸润明显有关(P<0.05);在ICC组织中,HMGB1的表达量与MVD计数呈明显正相关(r=0.330,P=0.008)。全组ICC患者术后的1、3、5年生存率分别为55.4%、36.9%、7.7%。HMGB1阳性ICC患者的生存率明显低于HMGB1阴性ICC患者(χ~2=6.278,P=0.012),高MVD计数ICC患者的生存率明显低于低MVD计数ICC患者(χ~2=5.101,P=0.024);具有HMGB1阳性与高MVD计数两种特征的患者生存率明显低于只具有其中一种特征或两种特征均无的患者(均P<0.05)。结论:HMGB1在ICC组织中表达升高,且与ICC的侵袭转移以及预后情况关系密切,作用机制可能与HMGB1通过各种信号通路系统诱导肿瘤微血管生成,从而促进肿瘤的生长和侵袭转移有关。HMGB1可作为ICC患者预后评估、治疗方案选择的参考指标,以及提供了靶向药物开发的新方向。

Background and Aims:Intrahepatic cholangiocarcinoma (ICC) is an extremely malignant tumor arising from the epithelial cells of the second-order or more proximal bile ducts.The poor prognosis of this disease is mainly due to the insufficient understanding of the pathogenesis,lack of early diagnosis methods and limited treatment modalities.The investigations on molecular biomarkers of ICC may help the early diagnosis,prognostic estimation and treatment recommendations.The aim of this study was to investigated the expression of the pro-inflammatory factor,high mobility group protein 1 (HMGB1) in ICC tissue and its clinical significance as well as its relationship with tumor microangiogenesis.Methods:The HMGB1 expressions and tumor microvascular density (MVD) counts (CD31 expressions) in surgical specimens of ICC tissue and tumor adjacent tissue from 65 ICC patients and 30 specimens of normal bile duct tissues were detected by immunohistochemical staining.The relations of HMGB1 expression and MVD count with the clinicopathologic factors of ICC patients and their correlation in ICC tissue were determined,and their influences on prognosis of ICC patients were also analyzed.Results:Both HMGB1 expression and MVD count presented a significant decreasing order in ICC tissue,tumor adjacent tissue and normal bile duct tissue (all P<0.05).The HMGB1 expression was significantly associated with the degree of tumor differentiation,vascular invasion and lymph node metastasis (all P<0.05),while the MVD count was significantly associated with vascular invasion of the tumor (P<0.05);there was a significant positive correlation between HMGB1 expression and MVD count in ICC tissue (r=0.330,P=0.008).In the whole group of ICC patients,the postoperative 1-,3-and 5-year survival rates of patients were 55.4%,36.9% and 7.7%.The survival rate in patients with positive HMGB1 expression was significantly lower than that in patients with negative HMGB1 expression (χ~2=6.278,P=0.012),and in those with high MVD count was significantly lower than that in cases with low MVD count (χ~2=5.101,P=0.024);the survival rate in patients with characteristics of both positive HMGB1 expression and high MVD count was significantly lower than those with only one or none of the characteristics (all P<0.05).Conclusion:The HMG1 expression is elevated in ICC tissue and is closely related to the invasion,metastasis and prognosis of ICC.The action mechanism may be probably associated with HMG1 inducing tumor microangiogenesis through various signaling pathways and then promoting growth and progression of the tumor.HMG1 can be potentially used as an indicator for prognostic assessment and decision-making,and also provides a new direction for the targeted drug development.