原发性肝细胞癌中干细胞标志物的表达与上皮细胞-间质转化的关系

Relationship of liver cancer stem cell markers and epithelial mesenchymal transition in hepatocellular carcinoma

目的探讨原发性肝细胞癌(hepatocellular carcinoma,HCC)中肝干细胞标志物的表达及其与上皮细胞-间质转化(epithelial-mesenchymal transition,EMT)的关系。方法采用免疫组化法检测72例HCC中肝干细胞标志物CK19、EpCAM、CD133、CD90的表达及其与EMT相关蛋白E-cadherin、vimentin和Snail的关系。结果 HCC组织中CK19、EpCAM、CD133、CD90阳性率分别为31.9%(23/72)、40.3%(29/72)、51.4%(37/72)、41.7%(30/72),有镜下癌栓和门静脉癌栓组中CK19、EpCAM、CD133、CD90阳性率均高于无镜下癌栓和无门静脉癌栓组,Ⅲ+Ⅳ期、肿瘤数目多发的HCC中EpCAM、CD133、CD90阳性率高于Ⅰ+Ⅱ期和单发的HCC;<46岁、组织学Ⅲ+Ⅳ级、血清AFP≥350 ng/ml的HCC中CK19阳性率高于其相应对照组。E-cadherin与其余两种EMT标志物均呈负相关(vimentin:r=-0.572,P=0.004;Snail:r=-0.597,P=0.003),CK19、EpCAM、CD90阳性HCC组中vimentin阳性强度均高于阴性组,CD133阳性HCC组中E-cadherin阳性强度低于CD133阴性组,vimentin、Snail阳性强度均高于CD133阴性组。结论与CK19、EpCAM、CD90相比,CD133阳性的肝癌干细胞与EMT的关系更加密切,CD133可作为同时针对HCC肝干细胞和EMT的治疗靶点。

Purpose To investigate the relationship of liver cancer stem cell markers and epithelial-mesenchymal transition （EMT） in hepatncellular carcinoma （HCC）. Methods The expression status of liver cancer stem cell markers （CK19, EpCAM, CD133, and CD90） and EMT-related markers （E-cadherin, vimentin and Snail） were detected by immunohistochemistry in 72 patients with primary HCCs. The relations between liver cancer stem cell markers and EMT-related markers were also analyzed. Results 31.9% （23/72）, 40. 3% （29/72）, 51.4% （37/72）, and 41.7% （30/72） tumor cells were immunoreactive with CK19, EpCAM, CD133 and CD90. The expression of these four stem cell markers in this study was positively correlated with portal vein tumor thrombus and microvascular invasion. The positive rate of EpCAM, CD133, and CD90 in patients with multiple tumors and UICC stage Ⅲ＋ Ⅳ was significantly higher than those with solitary tumor and UICC stage Ⅰ ＋ Ⅱ. CK19-positive HCCs was demonstrated more frequently in young ages, poor differentiation, high values of serum alpha fetoprotein, compared to CK19-negative HCCs. There was a significant negative correlation between E-cadherin and other EMT-related markers （ vimentin： r = - 0. 572, P = 0. 004, Snail ： r = - 0. 597, P = 0. 003 ） ; vimentin was more frequently expressed in HCCs positive for four stemness-related proteins in this study. Furthermore, CD133-positive HCCs were characterized by increased expression of EMT-related proteins （vimentin, Snail） and loss of E-cadherin expression. Conclusions CD133 is more closely related to EMT in HCCs, compared to CK19, EpCAM and CD90, CD133 is an excellent therapeutic target against liver cancer stem cells and EMT in liver cancer patients.