Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway
Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway
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Discoidin 结构域受体 1 通过调节 SLC1A5 和 mTORC1 信号通路促进肝细胞癌进展
DOI：
10.1007/s13402-022-00659-8
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发表时间：
2022-01-28
影响因子：
6.6
通讯作者：
Zhang, Bixiang
中科院分区：
文献类型：
--
作者：
Pan, Yonglong;Han, Mengzhen;Zhang, Bixiang
目的肝细胞癌是世界上最常见的癌症之一，具有很高的死亡率。受体酪氨酸激酶在多种癌症的发生发展中起着重要作用。盘状蛋白结构域受体1(DDR1)是一种特殊类型的跨膜受体酪氨酸激酶。在这里，我们发现DDR1在肝细胞癌中的表达显著增加，并且与不良的临床预后有关。方法采用Western blotting和免疫组织化学方法检测DDR1在肝癌细胞系和原代肝细胞癌标本中的表达。我们还研究了DDR1和SLC1A5在原发性肝细胞癌标本中表达的相关性。采用体外CCK8和集落形成实验检测细胞增殖情况。采用基因敲除和过表达实验、CHX、NH4CL和MG132干扰实验和免疫沉淀实验，以及裸鼠移植瘤模型，研究了DDR1在体内外促进肿瘤发生的机制。结果发现DDR1促进肝癌细胞增殖，促进肝癌移植瘤生长，而DDR1表达下调则起相反作用。我们还发现，DDR1表达的缺失或增强影响了肝癌细胞的周期进程。从机制上，我们发现DDR1与属于溶质载体(SLC)家族的SLC1A5相互作用，并调节其稳定性，从而影响mTORC1信号通路。此外，我们还发现DDR1对SLC1A5的调节可以被溶酶体抑制剂恢复。我们还发现，DDR1在肝细胞癌组织中高度表达，并且DDR1表达增加预示着总生存期(OS)较短。我们还发现SLC1A5的表达与DDR1的表达呈正相关。综上所述，我们的数据表明，DDR1作为一种肿瘤促进因子，可以通过溶酶体依赖的方式稳定SLC1A5来控制肝癌细胞的增殖和细胞周期进展。结论本研究揭示了DDR1促肝癌作用的新机制。我们还发现，DDR1的表达可以作为一个独立的预后指标，并且在临床标本中，DDR1和SLC1A5的表达水平呈正相关。我们的发现为了解肝细胞癌的发展提供了新的视角，并为肝细胞癌的治疗和管理提供了新的靶点。
Purpose Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with a high mortality rate. Receptor tyrosine kinases play important roles in the occurrence and development of various cancers. Discoid protein domain receptor 1 (DDR1) is a special type of transmembrane receptor tyrosine kinase. Here, we show that the expression of DDR1 is significantly increased in HCC and is related to a poor clinical prognosis. Methods The expression of DDR1 in HCC cell lines and primary HCC specimens was evaluated using Western blotting and immunohistochemistry. A correlation between DDR1 and SLC1A5 expression was also investigated in primary HCC specimens. Cell proliferation was evaluated using in vitro CCK8 and colony formation assays. Gene knock-down and overexpression assays, CHX, NH4CL and Mg132 interference tests and immunoprecipitation, as well as nude mouse xenograft models were used to assess the mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo. Results We found that DDR1 promotes the proliferation of HCC cells and accelerates the growth of HCC tumor xenografts, while DDR1 downregulation had the opposite effect. We also found that loss or gain of DDR1 expression affected HCC cell cycle progression. Mechanistically, we found that DDR1 interacts with SLC1A5, which belongs to the solute carrier (SLC) family of transporters, and regulates its stability, thereby affecting the mTORC1 signaling pathway. In addition, we found that SLC1A5 regulation by DDR1 can be restored by lysosome inhibitors. We also found that DDR1 is highly expressed in HCC tissues and that increased DDR1 expression predicts a shorter overall survival (OS) time. We additionally found that the expression of SLC1A5 was positively correlated with that of DDR1. Together, our data indicate that DDR1 acts as a tumor-promoting factor that can control HCC cell proliferation and cell cycle progression by stabilizing SLC1A5 in a lysosome-dependent way. Conclusions Our study reveals a new mechanism by which DDR1 plays a liver cancer-promoting role. We also found that DDR1 expression serves as an independent prognostic marker, and that DDR1 and SLC1A5 expression levels are positively correlated in clinical samples. Our findings provide a new perspective for understanding HCC development and offers new targets for the treatment and management of HCC.