【作者】 陈旭；

【导师】 赵永福；

【作者基本信息】 郑州大学 ， 普通外科学， 2014， 硕士

【摘要】 背景肝细胞肝癌是恶性程度与转移率很高的消化道恶性肿瘤之一，随着慢性肝炎和肝硬化发病率的上升，肝癌的发病率也逐年呈现升高趋势，肝癌的复发与转移是影响其治疗效果的主要原因。趋化因子是调节细胞定向移动的一类细胞因子，由趋化因子受体介导发挥其生物学功能；趋化因子根据其半胱氨酸相对位置不同,可将趋化因子分为C、CC、CXC和CX3C四类；CCL22是巨噬细胞衍生因子，为CC类趋化因子亚家族成员,CCL22的受体为CC类趋化因子受体4(CCR4)。近年的研究表明，CCL22通过与其受体CCR4的特异性结合参与细胞的生长、分化、凋亡、炎症反应及过敏反应等细胞行为，与肿瘤的转移调控、肿瘤血管的形成、调控宿主对肿瘤的免疫应答、直接影响肿瘤细胞的生存、增殖和凋亡等密切相关，因此推测CCL22与CCR4的特异性结合可能在肝癌肿瘤的生长及转移侵袭的分子生物学机制中发挥着重要作用。目的本研究通过检测CCL22及其受体CCR4于肝细胞肝癌、癌旁组织和正常肝脏中的表达情况,分析CCL22与CCR4的相关蛋白表达与临床病理特征之间的关系,探讨CCL22与CCR4的表达在肝细胞肝癌发生及转移侵袭过程中的作用,评价其在肝细胞肝癌诊疗及预后中的价值，并为肝癌的进一步研究提供新思路。方法收集手术切除、病理证实、且临床资料完整的60例肝细胞肝癌组织、46例癌旁组织和30例正常肝脏组织（24例来自肝血管瘤旁正常肝脏组织、6例为外伤性肝脏部分切除组织）；所有患者术前均未给予放疗、化疗、生物治疗、介入栓塞。通过检测肝细胞肝癌组织、癌旁组织和正常肝脏组织切片标本中CCL22与CCR4蛋白的表达情况，分析其表达程度与肝细胞肝癌临床病理特征的关系。结果正常肝脏组织既无CCL22蛋白的表达,也无CCR4的表达,癌旁组织中CCL22蛋白阳性率为19.6%(9/46),CCR4蛋白阳性率为28.2%(13/46),在60例肝细胞肝癌标本中,CCL22的阳性表达为56.7%(34/60),CCR4的阳性表达88.3%(53/60)。正常肝脏、癌旁肝组织与肝细胞肝癌组织中CCL22、CCR4阳性率比较,差异性具有统计学意义(P<0.05)。肿瘤组织中CCL22和CCR4的蛋白表达与年龄、性别、肿瘤的大小、有无腹水等因素无明显相关性。CCL22与肿瘤的分化程度、是否有转移侵袭及管道侵犯无明显相关性,而CCR4与中低分化瘤体、转移侵袭及管道侵犯存在相关性(P<0.05)。Spearman等级相关分析显示CCL22和CCR4蛋白表达呈正相关（r=0.297,P<0.05)。结论1. CCL22、CCR4在肝细胞肝癌组织中的表达水平明显高于正常肝组织及癌旁组织；CCL22与CCR4蛋白表达在HCC中呈正相关。2. CCR4的高表达可能与肝癌的分化程度和侵袭能力有一定联系；通过抑制CCR4蛋白的表达有可能降低肝癌生长、浸润、转移的能力，从而提高肝癌患者的生存率。对CCL22和CCR4的研究，有可能为肝癌的诊疗提供新的思路。更多还原

【Abstract】 BackgroundHepatocellular carcinoma is one of the digestive cancers having the highestmalignant degree and metastasis rate. With the rise in the incidence of chronichepatitis and liver cirrhosis, liver cancer incidence also showed a trend of increaseyear by year, Relapse and metastasis are the main causes for failure of treatmenteffect. Chemokines is the group of cytokines that control cell directional movement.All of these biological effects are performed by binding of ligands to Chemokinereceptors. Depending on the relative location of cysteine, chemokines can be dividedinto four classes: C, CC, CXC and CX3C. CCL22is a macrophage derived factor andits receptor is chemokine receptor4(CCR4). Recent data indicated that CCL22binding with its receptor CCR4leads to cell growth and promotes apoptosisinflammation and allergic reactions. Various tumor cells expressed chemotactic factorCCL22and its receptor CCR4, which was closely related to tumor metastasis,angiogenesis, improving organism immunity and inducing tumor cell proliferation, apoptosis. Thus speculate CCL22combined with CCR4specificity may be themolecular mechanism of tumor growth and metastasis of liver cancer plays animportant role.Objective：By detecting chemokine CCL22and its receptor CCR4expression betweenhepatocellular carcinoma, adjacent tissues and normal liver tissues, the study is toanalyze the relationship between CCL22and CCR4protein expression andclinicopathological features, discuss its expression in hepatocellular carcinomaoccurrence and development role, and evaluate its value in hepatocellular carcinomaprognosis, which may provide new ideas for the study of liver cancer.Methods:By immunohistochemical SP in paraffin section specimen, expression of CCL22and CCR4were detected in60cases of hepatocellular carcinoma,46cases of theadjacent tissues and30cases of normal liver tissue. And then we ananlyzed therelationship between CCL22and CCR4protein expression and clinical pathologicfeatures.Results:Neither CCL22nor CCR4was expressed in normal liver tissue and the positiverate of CCL22protein was19.6%(9/46) and CCR4was28.2%(13/46) in theadjacent tissues. In hepatocellular carcinoma tissues, the positive rate of CCL22was56.7%(34/60) and CCR4was88.3%(53/60). The positive rate of CCL22and CCR4protein expression were statistically significant between epatocellular carcinoma,carcinoma of adjacent tissues and normal liver tissues(P<0.05).There was nosignificant relationship between CCL22and CCR4protein expression and gender,age, tumor size, ascites, etc. Tumor metastasis and pipeline violation had no relationwith CCL22but they do have a relation with CCR4(P<0.05).Spearman rankcorrelation analysis showed that CCL22and CCR4protein expression was positivelycorrelated (r=0.297, P <0.05).Conclusion:1. CCL22and CCR4had a high expression in human hepatocellular carcinoma butlow in carcinoma of adjacent tissues and normal liver tissues. CCL22and CCR4 protein expression were positively correlated.2. The expression of CCR4protein in hepatocellular carcinoma is related to theirhistological differentiation and invasive capacity. By inhibiting the expression ofCCR4protein may reduces liver cancer growth, invasion and metastasis ability toimprove the survival rate of liver cancer patients. The study of CCL22and CCR4may provide new ideas for the treatment of liver cancer.更多还原