2nd International Cancer Study & Therapy Conference
Feb 20-22, 2017, Baltimore, USA
FOXO3a-driven epigenetic alternation of metabolism dictates the gemcitabine sensitivity of pancreatic cancer
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Gemcitabine has been a first-line therapeutic agent for pancreatic ductal adenocarcinoma (PDAC); however, the acquisition of resistance to gemcitabine remains a major challenge.Here, we investigated the metabolite profiles by liquid chromatographymass spectrometry between gemcitabine–resistant PDAC and parental PDAC cells, and found that lactic acid amount and lactate dehydrogenase activity were increased in gemcitabine–resistant PDAC cells. We observed the elevated lactate dehydrogenase A (LDHA) expression significantly correlated with recurrent pancreatic cancer patients following gemcitabine treatment and with cancer stem cell (CSC) properties. By approachingthe comparative array-based microRNA (miRNA)expression and miRNA transcription analysis, we further identified that FOXO3a-induced miR-4259 directly targeted the 3ʼuntranslated region ofLDHAand reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer in vitro and in vivo. Our findings suggest that LDHA might serve as a potential prognostic markerand therapeutic target for pancreatic cancer, particularly gemcitabine-resistant pancreatic cancer, and may provide evidence of an underlying epigenetic regulation of LDHA by FOXO3a/miR-4259, which appears to be involved in cancer stemness and the chemoresistance of pancreatic cancer.
Ching-Feng Chiu has completed his Ph.D from National Cheng Kung University of Taiwan and postdoctoral studies from Taipei Medical University and National Health Research Institutes. Now he serves as an Independent-Postdoctoral Fellowship of National Institute of Cancer Research in National Health Research Institutes, and hisstudies focus onthe roles of microRNAs and metabolism in tumor metastasisand drug resistance from basic research to clinical application. Over the past 5 years, he has published more than 12 original research papers, and he was awarded the9th National Innovation Award in 2012 and obtainedthe three-year research grant of Ministry of Science & Technologyof Taiwan in 2015.