Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China.
Mol Oncol. 2012 Aug;6(4):445-57. doi: 10.1016/j.molonc.2012.04.001. Epub 2012 Apr 17.
Tumor recurrence-related microRNAs (miRNAs) in hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT) are not clear yet. This study was designed to determine whether altered miRNA expression is associated with HCC recurrence and prognosis following OLT. 18 miRNAs, including 6 up-regulated and 12 down-regulated miRNAs were identified by microarray in primary HCC samples of patients who had developed HCC recurrence (n = 5) compared to those with non-recurrence (n = 5) following OLT by using p < 0.05 as cutoff value. The six most significantly altered miRNAs (fold change ≥ 2: miR-19a, miR-886-5p, miR-126, miR-223, miR-24 and miR-147) were further confirmed by qRT-PCR in the remaining 105 HCC samples. In receiver-operating characteristic curve analysis, this six miRNAs were of high sensitivity and specificity in predicting HCC recurrence. Using Cox regression and risk score analysis, we built a six-miRNA signature based on their qRT-PCR readings for the prediction of outcome of HCC following OLT. Kaplan-Meier and Cox proportional regression revealed this six-miRNA signature was a significant independent predictor of overall survival (log-rank p = 0.020) and recurrence-free survival (log-rank p < 0.001). Finally, the data were further reconfirmed in an independent cohort of 50 patients from another transplant center. In addition, bioinformatics Gene Ontology and pathway analysis were also performed to better understand the critical roles of these miRNAs in HCC recurrence. Our study, in addition to suggesting a different miRNA expression pattern between HCC samples of patients with recurrence and those with non-recurrence, proposes that this six-miRNA signature may serve as biomarker for prognosis of HCC patients following OLT.
肝移植（OLT）后肝癌（HCC）肿瘤复发相关的 microRNAs（miRNAs）尚不清楚。本研究旨在确定 miRNA 表达的改变是否与 OLT 后 HCC 复发和预后相关。通过微阵列分析，在发生 HCC 复发（n = 5）的 OLT 后原发性 HCC 样本中鉴定了 18 个 miRNA，包括 6 个上调和 12 个下调 miRNA，以 p < 0.05 作为截值值。使用 qRT-PCR 在其余 105 个 HCC 样本中进一步验证了六个最显著改变的 miRNA（倍数变化≥2：miR-19a、miR-886-5p、miR-126、miR-223、miR-24 和 miR-147）。在接受者操作特征曲线分析中，这六个 miRNA 在预测 HCC 复发方面具有较高的灵敏度和特异性。使用 Cox 回归和风险评分分析，我们根据 qRT-PCR 读数构建了一个基于六个 miRNA 的特征，用于预测 OLT 后 HCC 的结果。Kaplan-Meier 和 Cox 比例回归表明，该六个 miRNA 特征是总生存（log-rank p = 0.020）和无复发生存（log-rank p < 0.001）的显著独立预测因子。最后，在另一个移植中心的 50 例患者的独立队列中进一步重新确认了这些数据。此外，还进行了生物信息学基因本体论和途径分析，以更好地理解这些 miRNA 在 HCC 复发中的关键作用。我们的研究不仅表明复发和非复发患者的 HCC 样本之间存在不同的 miRNA 表达模式，还提出该六个 miRNA 特征可能作为 OLT 后 HCC 患者预后的生物标志物。
