Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
Hepatology. 2021 Jul;74(1):214-232. doi: 10.1002/hep.31673. Epub 2021 May 9.
Bone is the second most frequent site of metastasis for HCC, which leads to an extremely poor prognosis. HCC bone metastasis is typically osteolytic, involving the activation of osteoclasts. Long noncoding RNA H19 plays an important role in the pathogenesis of human cancers. Nonetheless, the mechanism underlying the participation of H19 in HCC bone metastasis remains unclear.
The current study established a mouse HCC bone metastasis model by using serial intracardiac injection and cell isolation to obtain cells with distinct bone metastasis ability. H19 was highly expressed in these cells and in clinical HCC bone metastasis specimens. Both osteoclastogenesis in vitro and HCC bone metastasis in vivo were promoted by H19 overexpression, whereas these processes were suppressed by H19 knockdown. H19 overexpression attenuated p38 phosphorylation and further down-regulated the expression of osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor. However, up-regulated OPG expression as well as suppressed osteoclastogenesis caused by H19 knockdown were recovered by p38 interference, indicating that p38 mitogen-activated protein kinase (MAPK)-OPG contributed to H19-promoted HCC bone metastasis. Furthermore, we demonstrated that H19 inhibited the expression of OPG by binding with protein phosphatase 1 catalytic subunit alpha (PPP1CA), which dephosphorylates p38. SB-203580-mediated inactivation of p38MAPK reversed the down-regulation of HCC bone metastasis caused by H19 knockdown in vivo. Additionally, H19 enhanced cell migration and invasion by up-regulating zinc finger E-box binding homeobox 1 through the sequestration of microRNA (miR) 200b-3p.
H19 plays a critical role in HCC bone metastasis by reducing OPG expression, which is mediated by the PPP1CA-induced inactivation of the p38MAPK pathway; and H19 also functions as a sponge for miR-200b-3p.
骨是 HCC 转移的第二大常见部位，导致预后极差。HCC 骨转移通常为溶骨性，涉及破骨细胞的激活。长链非编码 RNA H19 在人类癌症的发病机制中发挥重要作用。然而，H19 参与 HCC 骨转移的机制尚不清楚。
本研究通过连续心脏内注射和细胞分离建立了小鼠 HCC 骨转移模型，以获得具有明显骨转移能力的细胞。这些细胞中 H19 高表达，且在临床 HCC 骨转移标本中高表达。H19 过表达促进体外破骨细胞生成和体内 HCC 骨转移，而 H19 敲低则抑制这些过程。H19 过表达减弱了 p38 的磷酸化，并进一步下调了骨保护素（OPG）的表达，也称为破骨细胞生成抑制因子。然而，H19 敲低引起的 OPG 表达上调以及破骨细胞生成被 p38 干扰所恢复，表明 p38 丝裂原活化蛋白激酶（MAPK）-OPG 参与了 H19 促进的 HCC 骨转移。此外，我们证明 H19 通过与蛋白磷酸酶 1 催化亚单位α（PPP1CA）结合来抑制 OPG 的表达，PPP1CA 使 p38 去磷酸化。SB-203580 介导的 p38MAPK 失活逆转了 H19 敲低在体内引起的 HCC 骨转移下调。此外，H19 通过结合锌指 E 盒结合同源盒 1（ZEB1）上调 miR-200b-3p 的表达来增强细胞迁移和侵袭。
H19 通过降低 OPG 表达在 HCC 骨转移中起关键作用，该作用是由 PPP1CA 诱导的 p38MAPK 通路失活介导的；H19 还作为 miR-200b-3p 的海绵发挥作用。
