Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death in men throughout the world. is fact results from the limited knowledgebased treatment strategies [1]
We analyzed the mRNA and protein levels of citron Rhointeracting serine/threonine kinase (CIT) in five PDAC cell lines (Capan-1, BxPC-3, AsPC-1, MiaPaCa II, and PANC-1) and one normal control cell line, the human pancreatic duct epithelial cell line (H6C7). e Quantitative Real-Time PCR (qPCR) and western blot results showed that the expression of CIT in PDAC cell lines was much higher than that in the H6C7 cells
We selected Capan-1 and BxPC-3 cells with stable CIT knockdown or overexpression (Figure 2(a)), and the cells were subjected to cellular proliferation and colony formation experiments. e results showed that CIT knockdown significantly decreased the rate of proliferation of Capan-1 and BxPC-3 cells (Figure 2(b))
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death in men throughout the world. is fact results from the limited knowledgebased treatment strategies [1]. Recent immune landscape analysis has identified some rate-limiting immune checkpoints for the development and therapeutic resistance for PDAC [6,7,8,9]. The current therapeutic choice for PDAC is still limited, and the information for individual risk gene or protein is far from clear, which requires us to have a better understanding of the mechanism underlying this malignancy. CypA is secreted by cells in response to inflammatory stimuli. Via its receptor CD147, the secreted CypA binds to the cell surface and induces the production and secretion of inflammatory cytokines [10]. CypA has various functions in inflammatory conditions and diseases, including viral infections, cardiovascular diseases, neurodegeneration, aging, rheumatoid arthritis, periodontitis, sepsis, and asthma [11]. CypA has various functions in inflammatory conditions and diseases, including viral infections, cardiovascular diseases, neurodegeneration, aging, rheumatoid arthritis, periodontitis, sepsis, and asthma [11]. e roles of CypA in the development of human cancer have been widely
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