Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.
Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.
a b s t r a c tBoth deregulation of tumor-suppressor genes and misexpression of microRNAs (miRNAs) have been implicated in the development of pancreatic cancer, but their relationship during this process remains less clear. Here, we report that the expression of miR-483-3p is strongly enhanced in pancreatic cancer tissues compared to side normal tissues using a miRNA-array differential analysis. Furthermore, DPC4/Smad4 is identified as a target of miR-483-3p and their expression levels are inversely correlated in human clinical specimens. Ectopic expression of miR-483-3p significantly represses DPC4/Smad4 protein levels in pancreatic cancer cell lines, and simultaneously promotes cell proliferation and colony formation in vitro. Our findings identify miR-483-3p as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for the treatment of DPC4/ Smad4-driven pancreatic cancer.
MicroRNAs (miRNAs), which regulate gene expression by partial complementarity to the 3' untranslated region of their target genes, have been implicated in cancer initiation and progression. However, the molecular mechanism underlying the regulation of miRNA expression during pancreatic tumorigenesis has not been extensively reported. In this study, we first compared the miRNA expression in human pancreatic cancers and adjacent normal tissues by miRNA array and identified 12 differentially expressed miRNAs. miR-132, which is downregulated in tumors, was further studied in greater detail. Decreased expression of miR-132 was confirmed in 16 of 20 pancreatic carcinomas (P < 0.0001), compared with their respective benign tissues by TaqMan miRNA assays. miR-132 expression was remarkably influenced by promoter methylation in PANC1 and SW1990 cells. Promoter hypermethylation was observed in tumor samples but not in the normal counterparts, and the expression of miR-132 negatively correlated with its methylation status (P = 0.013). miR-132 was transcribed by RNA polymerase II, and Sp1 played a major role in miR-132 transcription. The expression of Sp1 correlated with that of miR-132 in tissues. Moreover, cancerous tissues showed significantly lower Sp1-binding affinity to the miR-132 promoter, relative to non-tumor samples. Proliferation and colony formation of pancreatic cancer cells were suppressed in cells transfected with miR-132 mimics and enhanced in cells transfected with miR-132 inhibitor by negatively regulating the Akt-signaling pathway. Our present findings illustrate the mechanism driving miR-132 downregulation and the important role of miR-132 in pancreatic cancer development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.