Department of Traditional Chinese Medicine, the Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China.
Traditional Chinese Medicine Gynecology, Maternal and Child Health Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, 830011, PR China.
Cancer Gene Ther. 2021 Jun;28(6):719-736. doi: 10.1038/s41417-020-00269-2. Epub 2021 Jan 7.
Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. While exosomal LINC00161 has been identified as a potential biomarker for HCC, its regulatory function and clinical values remain largely unknown. LINC00161 expressions in serum-derived exosomes from HCC patients and HCC cells were determined by qRT-PCR. The ability of proliferation, migration, and angiogenesis in HUVECs was assessed by MTT, Transwell, and tube formation. Luciferase reporter assay and AGO2-RIP assay were conducted to explore the interactions among LINC00161, miR-590-3p, and ROCK2. The level of ROCK signal-related proteins was examined by Western blotting and immunohistochemistry (IHC) assay. Subcutaneous tumor growth was observed in nude mice, in which in vivo metastasis was observed following tail vein injection of HCC cells. High levels of LINC00161 were detected in both serum-derived exosomes from HCC patients and the supernatants of HCC cell lines and were significantly associated with poor survival. Functional study demonstrated that exosomal LINC00161 derived from HCC-cells were significantly associated with enhanced proliferation, migration, and angiogenesis in HUVECs in vitro, all of which were effectively inhibited when LINC00161 was sliced with shRNA in HCC-cells. In vivo experiment showed that LINC00161 loss inhibited tumorigenesis and metastasis of HCC. Mechanistic study revealed that exosome-carried LINC00161 directly targeted miR-590-3p and induced its downstream target ROCK2, finally activating growth/metastasis-related signals in HCC. Exosome-carried LINC00161 promotes HCC tumorigenesis through inhibiting miR-590-3p to activate the ROCK2 signaling pathway, suggesting that LINC00161 may be used as potential targets to improve HCC treatment efficiency.
肝细胞癌（HCC）是一种致命的恶性肿瘤，在晚期阶段治疗选择有限。虽然外泌体 LINC00161 已被确定为 HCC 的潜在生物标志物，但它的调节功能和临床价值在很大程度上仍不清楚。通过 qRT-PCR 测定 HCC 患者和 HCC 细胞来源的血清衍生外泌体中的 LINC00161 表达。通过 MTT、Transwell 和管形成实验评估 HUVECs 的增殖、迁移和血管生成能力。通过荧光素酶报告基因检测和 AGO2-RIP assay 探索 LINC00161、miR-590-3p 和 ROCK2 之间的相互作用。通过 Western blot 和免疫组化（IHC）检测 ROCK 信号相关蛋白的水平。在裸鼠中观察皮下肿瘤生长，在 HCC 细胞尾静脉注射后观察体内转移。在 HCC 患者的血清衍生外泌体和 HCC 细胞系的上清液中均检测到高表达的 LINC00161，且与不良预后显著相关。功能研究表明，来自 HCC 细胞的外泌体 LINC00161 与体外 HUVECs 的增殖、迁移和血管生成显著相关，当在 HCC 细胞中用 shRNA 切割 LINC00161 时，所有这些都得到了有效抑制。体内实验表明，LINC00161 缺失抑制 HCC 的发生和转移。机制研究表明，外泌体携带的 LINC00161 直接靶向 miR-590-3p 并诱导其下游靶标 ROCK2，最终激活 HCC 中的生长/转移相关信号。外泌体携带的 LINC00161 通过抑制 miR-590-3p 激活 ROCK2 信号通路促进 HCC 肿瘤发生，提示 LINC00161 可作为提高 HCC 治疗效率的潜在靶点。
