Zhang Yong, Liu Wen-Shuai, Zhang Xiang-Yu, Tong Han-Xing, Yang Hua, Liu Wei-Feng, Fan Jia, Zhou Jian, Hu Jie
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Carcinogenesis. 2022 Nov 23;43(10):930-940. doi: 10.1093/carcin/bgac059.
Liver metastasis is a leading indicator of poor prognosis in patients with colorectal cancer (CRC). Exosomal intercellular communication has been reported to play an important role in cancer invasion and metastasis. Here, we characterized exosomal miRNAs underlying liver metastasis in CRC patients (Cohort 1, n = 30) using miRNA arrays. Exosomal miR-150 was found to be downregulated in CRC patients with liver metastases compared to those without (P = 0.025, fold change [FC] = 2.01). These results were then validated using another independent cohort of CRC patients (Cohort 2, n = 64). Patients with low expression of exosomal miR-150 had significantly shorter overall survival (OS) time (33.3 months versus 43.3 months, P = 0.002). In addition, the low expression of exosomal miR-150 was significantly correlated with advanced tumor node metastasis staging (P = 0.013), higher CA199 level (P = 0.018), and the presence of liver metastasis (P = 0.048). Multivariate analysis showed that low expression of exosomal miR-150 (P = 0.035) and liver metastasis (P < 0.001) were independent prognostic factors for overall survival. In vivo and in vitro studies showed that the viability and invasion of CRC cells were both significantly suppressed by ExomiR-150. Target-prediction assessment and dual-luciferase reporter assay indicated that FTO (the fat mass and obesity-associated gene) was a direct target for miR-150. This study first demonstrated that exosomal miR-150 may be a potential prognostic factor and treatment target for CRC.
肝转移是结直肠癌（CRC）患者预后不良的主要指标。据报道，外泌体介导的细胞间通讯在癌症侵袭和转移中起重要作用。在此，我们使用miRNA阵列对CRC患者（队列1，n = 30）肝转移相关的外泌体miRNA进行了表征。发现与无肝转移的CRC患者相比，有肝转移的CRC患者中外泌体miR-150表达下调（P = 0.025，倍数变化[FC] = 2.01）。然后使用另一组独立的CRC患者（队列2，n = 64）对这些结果进行了验证。外泌体miR-150低表达的患者总生存（OS）时间显著缩短（33.3个月对43.3个月，P = 0.002）。此外，外泌体miR-150的低表达与肿瘤淋巴结转移晚期分期（P = 0.013）、较高的CA199水平（P = 0.018）以及肝转移的存在（P = 0.048）显著相关。多变量分析表明，外泌体miR-150低表达（P = 0.035）和肝转移（P < 0.001）是总生存的独立预后因素。体内和体外研究表明，ExomiR-150可显著抑制CRC细胞的活力和侵袭。靶标预测评估和双荧光素酶报告基因检测表明，FTO（脂肪量和肥胖相关基因）是miR-150的直接靶标。本研究首次证明外泌体miR-150可能是CRC的潜在预后因素和治疗靶点。
