Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
Biomed Res Int. 2020 Feb 22;2020:9210891. doi: 10.1155/2020/9210891. eCollection 2020.
In human pancreatic ductal adenocarcinoma (PDAC), the cyclophilin A (CypA) is overexpressed and promotes the development of PDAC. However, the mechanism underlying cyclophilin A expression remains elusive. Here, we reported that the citron Rho-interacting serine/threonine kinase (CIT) promotes the HIF1a-CypA signaling and growth of PDAC cells. CIT expression was higher in PDAC cells compared with the normal epithelial cells, and clinical data showed that CIT was overexpressed in PDAC tissues and high expression of CIT predicted poor overall and disease-free survival. In PDAC cells, knockdown of CIT expression repressed the rate of proliferation and capacity of colony formation, which were accomplished with an increased percentage of apoptotic cells and cell cycle arrest. The knockdown of CIT in PDAC cells reduced the expression of CypA while overexpression of CIT promoted the expression of CypA. We observed that the effects of CIT on the expression of CypA relied on the transcriptional factor HIF1a, which was previously reported to transcriptionally activate the expression of CypA in PDAC cells. Furthermore, the effects of CIT on apoptosis, cell cycle, proliferation, and colony formation of PDAC cells relied on its role in the regulation of CypA expression. Collectively, our data showed that CIT promoted the activation of HIF1-CypA signaling and enhanced the growth of PDAC cells.
在人类胰腺导管腺癌（PDAC）中，亲环素 A（CypA）过表达并促进 PDAC 的发展。然而，CypA 表达的机制仍不清楚。在这里，我们报道了柠檬 Rho 相互作用丝氨酸/苏氨酸激酶（CIT）促进了 HIF1a-CypA 信号和 PDAC 细胞的生长。与正常上皮细胞相比，PDAC 细胞中的 CIT 表达更高，临床数据表明 CIT 在 PDAC 组织中过表达，CIT 高表达预示着总生存率和无病生存率较差。在 PDAC 细胞中，CIT 表达的敲低抑制了增殖率和集落形成能力，这伴随着凋亡细胞比例增加和细胞周期停滞。PDAC 细胞中 CIT 的敲低降低了 CypA 的表达，而过表达 CIT 则促进了 CypA 的表达。我们观察到 CIT 对 CypA 表达的影响依赖于转录因子 HIF1a，先前的研究表明 HIF1a 在 PDAC 细胞中转录激活 CypA 的表达。此外，CIT 对 PDAC 细胞凋亡、细胞周期、增殖和集落形成的影响依赖于其对 CypA 表达的调节作用。总之，我们的数据表明 CIT 促进了 HIF1-CypA 信号的激活，并增强了 PDAC 细胞的生长。
