H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen-Activated Protein Kinase-Dependent Manner and Sponging microRNA 200b-3p
H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen-Activated Protein Kinase-Dependent Manner and Sponging microRNA 200b-3p
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DOI：
10.1002/hep.31673
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发表时间：
2021-05-09
期刊：
影响因子：
13.5
通讯作者：
Zhang, Bixiang
中科院分区：
文献类型：
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作者：
Huang, Zhao;Chu, Liang;Zhang, Bixiang
背景与目的骨是HCC第二常见的转移部位，预后极差。HCC骨转移是典型的溶骨，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起着重要作用。然而，H19参与HCC骨转移的机制尚不清楚。方法与结果本研究通过连续心内注射和细胞分离，建立小鼠肝癌骨转移模型，获得具有明显骨转移能力的细胞。H19在这些细胞和临床HCC骨转移标本中高度表达。H19过表达可促进体外破骨细胞形成和体内HCC骨转移，而H19敲低可抑制这些过程。H19过表达可减弱p38磷酸化，进一步下调破骨细胞生成抑制因子（osteoprotegerin， OPG）的表达。然而，p38干扰可恢复H19敲低导致的OPG表达上调和破骨细胞生成抑制，提示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催化亚基α (PPP1CA)结合抑制OPG的表达，从而使p38去磷酸化。sb -203580介导的p38MAPK失活在体内逆转了H19敲低引起的HCC骨转移的下调。此外，H19通过隔离microRNA (miR) 200b-3p，上调锌指E-box结合同源盒1，从而增强细胞的迁移和侵袭。结论H19通过ppp1ca诱导的p38MAPK通路失活介导OPG表达降低，在HCC骨转移中起关键作用；H19也作为miR-200b-3p的海绵。
Background and Aims 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.Approach and Results 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.Conclusions 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.