Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Radiotherapy, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, China; WuHan University, Wuhan, China.
Cancer Lett. 2021 Apr 10;503:19-31. doi: 10.1016/j.canlet.2021.01.011. Epub 2021 Jan 17.
Tumor-associated mesenchymal stem cells (MSCs) play a critical role in the growth and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the crosstalk between MSCs and HCC cells is not completely understood. Here, HCC cells were treated with or without conditioned medium of MSCs (CM-MSC), and examined for differential expression of long non-coding RNAs (lncRNAs). Knockdown and overexpression experiments were conducted to explore the function of the lncRNA DNM3OS in MSC-induced HCC growth and metastasis. CM-MSC treatment led to a concentration-dependent induction of DNM3OS in HCC cells. DNM3OS was significantly upregulated in HCC compared to adjacent liver tissues. High DNM3OS expression was associated with TNM stage, vascular invasion, and poor prognosis of HCC patients. Silencing of DNM3OS inhibited HCC cell proliferation and invasion in vitro and tumorigenesis and metastasis in vivo. Overexpression of DNM3OS enhanced HCC cell proliferation, invasion, and metastasis. Biochemically, DNM3OS was mainly localized in the nucleus and physically interacted with KDM6B. The association of DNM3OS with KDM6B induced the expression of TIAM1 through reduction of H3K27me3 at the TIAM1 promoter. TIAM1 overexpression restored the proliferation and invasion of DNM3OS-depleted HCC cells. Our data delineate a mechanism by which MSCs accelerate HCC growth and metastasis through a DNM3OS/KDM6B/TIAM1 axis.
肿瘤相关间充质干细胞（MSCs）在肝细胞癌（HCC）的生长和转移中起着关键作用。然而，MSCs 与 HCC 细胞之间相互作用的机制尚不完全清楚。在这里，用或不用 MSC 条件培养基（CM-MSC）处理 HCC 细胞，并检测长链非编码 RNA（lncRNA）的差异表达。进行敲低和过表达实验，以探讨 lncRNA DNM3OS 在 MSC 诱导的 HCC 生长和转移中的功能。CM-MSC 处理导致 HCC 细胞中 DNM3OS 的浓度依赖性诱导。与相邻肝组织相比，DNM3OS 在 HCC 中显著上调。高 DNM3OS 表达与 HCC 患者的 TNM 分期、血管侵犯和预后不良相关。DNM3OS 的沉默抑制 HCC 细胞在体外的增殖和侵袭以及体内的致瘤性和转移。DNM3OS 的过表达增强了 HCC 细胞的增殖、侵袭和转移。从生物化学角度来看，DNM3OS 主要定位于细胞核内，并与 KDM6B 发生物理相互作用。DNM3OS 与 KDM6B 的结合通过降低 TIAM1 启动子上的 H3K27me3 来诱导 TIAM1 的表达。TIAM1 的过表达恢复了 DNM3OS 耗尽的 HCC 细胞的增殖和侵袭能力。我们的数据描绘了一种机制，即 MSCs 通过 DNM3OS/KDM6B/TIAM1 轴加速 HCC 的生长和转移。
