title: microRNA-210 overexpression inhibits tumor growth and potentially reverses gemcitabine resistance in pancreatic cancer.
abstract: Resistance to first-line chemotherapies like gemcitabine contributes to high disease lethality in pancreatic cancer. By microarray and qRT-PCR, we observed significant downregulation of microRNA-210 in gemcitabine-resistant cells. The overexpression of microRNA-210 was toxic to gemcitabine-resistant cells and enhanced gemcitabine sensitivity. MicroRNA-210 overexpression induced caspase-3-mediated apoptosis, and inhibited colony formation. Computationally, ABCC5, a highly expressed gene in our array data, was identified as a potential target of microRNA-210 and the overexpression of ABCC5 in gemcitabine-resistant cells was confirmed by qRT-PCR. MicroRNA-210 overexpression reduced ABCC5 mRNA levels and inhibited a luciferase reporter expressing the ABCC5 3' UTR. The expression pattern of microRNA-210 and ABCC5 was mirrored in all of 5 pancreatic cancer cell lines used. Likewise, microRNA-210 transfection nearly totally inhibited tumor xenograft growth, proliferation and metastasis without obvious side effects in vivo. Also, an absence or low expression of microRNA-210 correlated to high ABCC5 expression in the majority of malignant patient tissues from a total of 101 patient tissues examined. Our observations provide at first glance, an important function for microRNA-210 in regulation of gemcitabine responsiveness by it's target gene ABCC5.
authors.affiliation: General-, Visceral- & Transplantation Surgery, Section Surgical Research, University of Heidelberg, Germany. Electronic address: amponsah@rhrk.uni-kl.de.
authors.forename: Prince Saforo
authors.initials: PS
authors.lastname: Amponsah
authors.affiliation: General-, Visceral- & Transplantation Surgery, Section Surgical Research, University of Heidelberg, Germany. Electronic address: doc.fanpei@gmail.com.
authors.forename: Pei
authors.initials: P
authors.lastname: Fan
authors.affiliation: General-, Visceral- & Transplantation Surgery, Section Surgical Research, University of Heidelberg, Germany. Electronic address: nathalie.Bauer@uni-heidelberg.de.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bauer
authors.affiliation: General-, Visceral- & Transplantation Surgery, Section Surgical Research, University of Heidelberg, Germany. Electronic address: zhefu.zhao@uni-hd.de.
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: General-, Visceral- & Transplantation Surgery, Section Surgical Research, University of Heidelberg, Germany. Electronic address: gladkich@uni-heidelberg.de.
authors.forename: Jury
authors.initials: J
authors.lastname: Gladkich
authors.affiliation: Orthopedics and Trauma Surgery, Experimental Orthopedics, University of Heidelberg, Heidelberg, Germany. Electronic address: joerg.fellenberg@med.uni-heidelberg.de.
authors.forename: Joerg
authors.initials: J
authors.lastname: Fellenberg
authors.affiliation: General-, Visceral- & Transplantation Surgery, Section Surgical Research, University of Heidelberg, Germany. Electronic address: i.herr@uni-heidelberg.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D014162:Transfection; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D035683:MicroRNAs; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Multi drug resistance; Novel therapeutics; Pancreatic cancer; microRNA