LRRC4 Suppresses E-Cadherin-Dependent Collective Cell Invasion and Metastasis in Epithelial Ovarian Cancer
LRRC4 Suppresses E-Cadherin-Dependent Collective Cell Invasion and Metastasis in Epithelial Ovarian Cancer
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LRRC4 抑制上皮性卵巢癌中 E-钙粘蛋白依赖性集体细胞侵袭和转移
DOI：
10.3389/fonc.2020.00144
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发表时间：
2020-02-14
影响因子：
4.7
通讯作者：
Wu, Minghua
中科院分区：
文献类型：
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作者：
Zhao, Chunhua;She, Xiaoling;Wu, Minghua
上皮性卵巢癌（EOC）是最恶性的妇科癌症，由于在已经发生转移的晚期才发现，死亡率很高。然而，EOC转移的机制尚不清楚。开放数据库分析和免疫化学实验表明，LRRC4在高级别浆液性卵巢癌（HGSC）细胞和EOC转移过程中低表达。采用三维细胞培养系统和原位卵巢异种移植模型感染含有9型腺相关病毒（AAV9）的lrrc4，在体外和体内验证细胞的集体侵袭和转移。使用Phos-tag SDS-PAGE检测LRRC4和PIK3R1的磷酸化。通过免疫共沉淀法、免疫印迹法等多项实验，探讨LRRC4和PIK3R1在EOC转移中的作用机制。在原发性EOC组织和转移性腹水的侵袭区，LRRC4和E-cadherin表达呈负相关。LRRC4结合PIK3R1的cSH2结构域并抑制PIK3R1的活性，而不破坏PIK3R1和PIK3CA之间的物理相互作用。LRRC4通过抑制pik3r1介导的AKT/GSK3β/β-catenin信号通路，通过靶向e -cadherin依赖的集体细胞侵袭来抑制EOC转移。LRRC4作为肿瘤抑制基因，通过直接结合PIK3R1的cSH2结构域，在体外和体内抑制EOC的集体侵袭转移，发挥其调控功能。我们的研究结果为肿瘤转移预后提供了一种潜在的新方法，并为肿瘤的治疗提供了新的策略。
Epithelial ovarian cancer (EOC) is the most malignant gynecological carcinoma and is of a high incidence of death due to detection at late stages when metastasis already occurs. However, the mechanism underlying metastasis of EOC remains unclear. Analysis of the open database and experiments with immunochemistry showed that LRRC4 is lowly expressed in high-grade serous ovarian cancer (HGSC) cells and during EOC metastasis. The 3D cell culture system and the orthotopic ovarian xenograft model infected with LRRC4-containing adeno-associated virus serotype 9 (AAV9) were used to confirm collective invasion and metastasis of cells in vitro and in vivo. Phos-tag SDS-PAGE was used to detect the phosphorylation of LRRC4 and PIK3R1. A number of experiments with methods such as co-immunoprecipitation and immunoblotting were performed to explore the mechanism for the actions of LRRC4 and PIK3R1 in EOC metastasis. An inverse correlation between LRRC4 and E-cadherin expression was detected in the regions of invasion in primary EOC tissues and metastatic ascites. LRRC4 binds to the cSH2 domain of PIK3R1 and inhibits the activity of PIK3R1, without disrupting the physical interactions between PIK3R1 and PIK3CA. LRRC4 inhibits EOC metastasis by targeting E-cadherin-dependent collective cell invasion and does so by inhibiting the PIK3R1-mediated AKT/GSK3β/β-catenin signaling pathway. LRRC4 functions as a tumor suppressor gene to inhibit EOC collective invasion and metastasis in vitro and in vivo and does so by directly binding to the cSH2 domain of PIK3R1 to exert its regulatory function. Our findings provide a potential novel approach for metastasis prognosis and a new strategy for the treatment of EOC.