Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients with Hepatocellular Carcinoma
Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients with Hepatocellular Carcinoma
复制标题
进行 EMT 的循环肿瘤细胞为肝细胞癌患者的诊断和预后提供了衡量标准。
DOI：
10.1158/0008-5472.can-17-2459
复制
发表时间：
2018-08-15
期刊：
影响因子：
11.2
通讯作者：
Li, Le-Qun
中科院分区：
文献类型：
--
作者：
Qi, Lu-Nan;Xiang, Bang-De;Li, Le-Qun
为了阐明循环肿瘤细胞（CTC）在肝细胞癌（HCC）患者中经历上皮间质转化（EMT）的意义，我们使用先进的CanPatrol CTC富集技术和原位杂交来富集和分类来自血液样品的CTC。112例HCC患者中有101例（90.18%）CTC阳性，即使是早期疾病。在12名携带B型肝炎病毒（HBV）的患者中，也有2名检测到CTC，这两名患者均在5个月内检测到小肝癌肿瘤。术前CTC计数≥16和间质-CTC（M-CTC）百分比≥2%与早期复发、多次肝内复发和肺转移显著相关。10名患者的术后CTC监测发现，大多数患者在出现临床可检测到的复发结节之前，CTC计数和M-CTC百分比均增加。对具有高CTC计数和高M-CTC百分比的HCC的分析鉴定了67个参与癌症相关生物学途径的差异表达的癌症相关基因（例如，细胞粘附和迁移、肿瘤血管生成和凋亡）。其中一个已鉴定的基因BCAT 1显著上调，在Hepg 2、Hep 3B和Huh 7细胞中敲低BCAT 1可降低细胞增殖、迁移和侵袭，同时促进细胞凋亡。上皮标志物表达（EpCAM和E-cadherin）的同时增加和间充质标志物表达（波形蛋白和Twist）的减少表明BCAT 1可能触发EMT过程。总的来说，CTC与HCC特征高度相关，代表了早期诊断的新标志物和早期复发的预后因素。BCAT 1过表达可能通过触发EMT诱导CTC释放，可能是HCC转移的重要生物标志物。意义：在肝癌中，CTC检查可能代表重要的“液体活检”工具，以检测早期疾病和复发或转移性疾病，为早期干预或辅助治疗提供线索。Cancer Res; 78（16）; 4731-44.©2018 AACR.
To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in patients with hepatocellular carcinoma (HCC), we used an advanced CanPatrol CTC-enrichment technique and in situ hybridization to enrich and classify CTC from blood samples. One hundred and one of 112 (90.18%) patients with HCC were CTC positive, even with early-stage disease. CTCs were also detected in 2 of 12 patients with hepatitis B virus (HBV), both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal-CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g., cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggest that BCAT1 may trigger the EMT process. Overall, CTCs were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis.Significance: In liver cancer, CTC examination may represent an important "liquid biopsy" tool to detect both early disease and recurrent or metastatic disease, providing cues for early intervention or adjuvant therapy. Cancer Res; 78(16); 4731-44. ©2018 AACR.