Abstract
Recent studies have shown that the non-enzymatic function of CD73 plays a key role in tumor progression, but this function of CD73 in pancreatic cancer cells has not been studied. Furthermore, little is known about the mechanism involved in CD73 regulation in tumors. Here, we found that CD73 expression was upregulated in pancreatic ductal adenocarcinoma (PDAC) and that its expression correlated with poor prognosis. CD73 knockdown inhibited cell growth and induced G1 phase arrest via the AKT/ERK/cyclin D signaling pathway. We also found that tumor necrosis factor receptor (TNFR) 2 was involved in CD73-induced AKT and ERK signaling pathway activation in PDAC. Further, miR-30a-5p overexpression significantly increased the cytotoxic effect of gemcitabine in pancreatic cancer by directly targeting CD73 messenger RNA (mRNA), suggesting that regulation of the miR-30a-5p/CD73 axis may play an important role in the development of gemcitabine resistance in pancreatic cancer. In summary, this regulatory network of CD73 appears to represent a new molecular mechanism underlying PDAC progression, and the mechanistic interaction between miR-30a-5p, CD73, and TNFR2 may provide new insights into therapeutic strategies for pancreatic cancer.Key messagesCD73 was upregulated in PDAC and correlated with poor prognosis.CD73 knockdown inhibited cell growth and induced G1 phase arrest.TNFR2 was involved in CD73-induced AKT and ERK signaling pathway.miR-30a-5p targeted CD73 and increased the sensitivity to gemcitabine.
Highlights
Pancreatic cancer is the fourth leading cause of cancer-related death in the USA, with a 5-year survival rate of only 3% to 6%
We first analyzed gene expression data from the GSE15471 database and found that the messenger RNA expression of CD73 was significantly higher in pancreatic cancer compared with normal tissues (p < 0.01) (Fig. 1a). qRT-polymerase chain reaction (PCR) and western blot analysis confirmed high expression of CD73 in six pancreatic cancer cell lines compared with pancreatic ductal epithelial cells (HPDE6-C7) as controls (Fig. 1b, c)
Previous studies have demonstrated that CD73 promotes the growth of cancer cells depending on its enzymatic activity, that is, the production of adenosine [28]
Summary
Pancreatic cancer is the fourth leading cause of cancer-related death in the USA, with a 5-year survival rate of only 3% to 6%. CD73 has both enzymatic and non-enzymatic functions in cells [4, 5]. Gao et al [8] found that CD73 promotes the proliferation and migration of human cervical cancer cells independent of its enzymatic activity. The non-enzymatic function of CD73 has not been well studied. Previous studies demonstrated that CD73 is overexpressed in many types of cancer cell lines and promotes tumor progression [9,10,11,12,13,14,15,16,17,18]. The precise role of CD73 in pancreatic cancer remains unclear and. We examined the expression of CD73 in pancreatic cancer and its underlying mechanisms. Our findings may provide new insights into developing novel therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC)
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