Ma Sen-Lin, Li Ai-Jun, Hu Zhao-Yang, Shang Fu-Sheng, Wu Meng-Chao
Department of Second Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China.
Tumor Research Institute, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China.
Mol Med Rep. 2015 Dec;12(6):7915-26. doi: 10.3892/mmr.2015.4435. Epub 2015 Oct 13.
The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non‑coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl‑phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1‑IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1‑IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1‑IT1 on the proliferation and apoptosis of the ICC‑9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1‑IT1 were co‑upregulated in ICC tissues compared with non‑cancerous tissues. Knockdown of CPS1 andor CPS1‑IT1 reduced the proliferation and increased the apoptosis of ICC‑9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1‑IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease‑free survival (P=0.034). In addition, there were differential trends in CA19‑9 (P=0.068), globulin (P=0.052) and total bilirubin (P=0.066). The comparisons between the high CPS1‑IT1 expression group and the low expression group indicated significant differences in lymphatic invasion (P=0.045), carbohydrate antigen 19‑9 (P=0.044), disease‑free survival (P=0.026), and non‑significant differential trends in alkaline phosphatase were observed (P=0.085). In conclusion, CPS1 and CPS1‑IT1 may serve an important role in ICC development by promoting the proliferation of ICC cells. Furthermore, CPS1 and CPS1‑IT1 were associated with poor liver function and reduced survival rates. Thus, CPS1 and CPS1‑IT1 may be potential prognostic indicators for patients with ICC.
导致人类肝内胆管癌（ICC）高恶性率和复发率的机制仍不清楚。由于缺乏特异性生物标志物，临床上难以诊断和评估ICC患者的预后。此外，长链非编码RNA（lncRNAs）已被报道在某些类型的肿瘤发生中起重要作用，然而其在ICC中的作用仍有待报道。本研究的目的是筛选在ICC中异常表达的基因和lncRNAs，并研究它们在ICC中的生物学和临床病理意义。使用生物信息学分析测量ICC中的全局基因和lncRNA表达谱。观察到氨甲酰磷酸合酶1（CPS1）及其lncRNA CPS1内含子转录本1（CPS1-IT1）在ICC中上调。在31例ICC患者的组织样本和一些细胞系中测量了CPS1和CPS1-IT1的表达。测量了CPS1和CPS1-IT1对ICC-9810细胞系增殖和凋亡的影响。此外，分析了ICC患者关于基因和lncRNA表达状态的临床病理特征和生存率。与非癌组织相比，CPS1和CPS1-IT1在ICC组织中共同上调。敲低CPS1和/或CPS1-IT1可降低ICC-9810细胞的增殖并增加其凋亡。此外，临床分析表明，当癌组织中相对表达值大于4时，CPS1和CPS1-IT1与肝功能差和生存率降低相关。高CPS1表达组与低表达组之间的比较表明，国际标准化比值（P = 0.048）、总蛋白（P = 0.049）、间接胆红素（P = 0.025）、碱性磷酸酶（P = 0.003）和无病生存期（P = 0.034）存在显著差异。此外，CA19-9（P = 0.068）、球蛋白（P = 0.052）和总胆红素（P = 0.066）存在差异趋势。高CPS1-IT1表达组与低表达组之间的比较表明，在淋巴浸润（P = 0.045）、糖类抗原19-9（P = 0.044）、无病生存期（P = 0.026）方面存在显著差异，并且观察到碱性磷酸酶存在非显著差异趋势（P = 0.085）。总之，CPS1和CPS1-IT1可能通过促进ICC细胞的增殖在ICC发展中起重要作用。此外，CPS1和CPS1-IT1与肝功能差和生存率降低相关。因此，CPS1和CPS1-IT1可能是ICC患者潜在的预后指标。
