SPHK1-induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination
SPHK1-induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination
复制标题
SPHK1诱导腹膜间皮细胞自噬增强胃癌腹膜播散
DOI：
10.1002/cam4.2041
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发表时间：
2019-04-01
期刊：
影响因子：
4
通讯作者：
Xu, Huimian
中科院分区：
文献类型：
--
作者：
Yin, Songcheng;Miao, Zhifeng;Xu, Huimian
胃癌腹膜播散（GCPD）是进展期胃癌最常见的转移形式，其生存率不容乐观。间皮细胞的损伤在GCPD中起重要作用。然而，其分子机制并不完全清楚。在这里，我们专注于鞘氨醇激酶1（SPHK 1）在人腹膜间皮细胞（HPMCs），调节HPMCs自噬GCPD进展。首先，我们对120例胃癌腹膜组织中SPHK 1的表达进行了化学分析，发现SPHK 1的高表达与LC 3B表达和腹膜复发显著相关，导致预后不良。在共培养体系中，我们观察到GC细胞促进HPMCs的自噬，阻断GC细胞分泌的TGF-β 1可抑制这一过程。自噬性HPMCs可诱导胃癌细胞粘附和侵袭。我们还证实，HPMCs中SPHK 1表达的敲低抑制了TGF-β 1诱导的自噬。此外，SPHK 1驱动的HPMCs自噬在体外和体内加速GC细胞GCPD的发生。此外，我们探讨了自噬和纤维化之间的关系在HPMCs，观察SPHK 1过表达诱导HPMCs纤维化，而抑制自噬削弱HPMCs纤维化。总之，我们的研究结果为理解GCPD的机制提供了新的见解，并将SPHK 1确定为GCPD的新靶点。
Gastric cancer peritoneal dissemination (GCPD) has been recognized as the most common form of metastasis in advanced gastric cancer (GC), and the survival is pessimistic. The injury of mesothelial cells plays an important role in GCPD. However, its molecular mechanism is not entirely clear. Here, we focused on the sphingosine kinase 1 (SPHK1) in human peritoneal mesothelial cells (HPMCs) which regulates HPMCs autophagy in GCPD progression. Initially, we analyzed SPHK1 expression immunohistochemically in 120 GC peritoneal tissues, and found high SPHK1 expression to be significantly associated with LC3B expression and peritoneal recurrence, leading to poor prognosis. Using a coculture system, we observed that GC cells promoted HPMCs autophagy and this process was inhibited by blocking TGF-beta 1 secreted from GC cells. Autophagic HPMCs induced adhesion and invasion of GC cells. We also confirmed that knockdown of SPHK1 expression in HPMCs inhibited TGF-beta 1-induced autophagy. In addition, SPHK1-driven autophagy of HPMCs accelerated GC cells occurrence of GCPD in vitro and in vivo. Moreover, we explored the relationship between autophagy and fibrosis in HPMCs, observing that overexpression of SPHK1 induced HPMCs fibrosis, while the inhibition of autophagy weakened HPMCs fibrosis. Taken together, our results provided new insights for understanding the mechanisms of GCPD and established SPHK1 as a novel target for GCPD.