A functional microRNA library screen reveals miR-410 as a novel anti-apoptotic regulator of cholangiocarcinoma.
Cholangiocarcinoma is characterized by late diagnosis and a poor survival rate. MicroRNAs have been involved in the pathogenesis of different cancer types, including cholangiocarcinoma. Our aim was to identify novel microRNAs regulating cholangiocarcinoma cell growth in vitro and in vivo.



A functional microRNA library screen was performed in human cholangiocarcinoma cells to identify microRNAs that regulate cholangiocarcinoma cell growth. Real-time PCR analysis evaluated miR-9 and XIAP mRNA levels in cholangiocarcinoma cells and tumors.



The screen identified 21 microRNAs that regulated >50 % cholangiocarcinoma cell growth. MiR-410 was identified as the top suppressor of growth, while its overexpression significantly inhibited the invasion and colony formation ability of cholangiocarcinoma cells. Bioinformatics analysis revealed that microRNA-410 exerts its effects through the direct regulation of the X-linked inhibitor of apoptosis protein (XIAP). Furthermore, overexpression of miR-410 significantly reduced cholangiocarcinoma tumor growth in a xenograft mouse model through induction of apoptosis. In addition, we identified an inverse relationship between miR-410 and XIAP mRNA levels in human cholangiocarcinomas.



Taken together, our study revealed a novel microRNA signaling pathway involved in cholangiocarcinoma and suggests that manipulation of the miR-410/XIAP pathway could have a therapeutic potential for cholangiocarcinoma.
Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, 650 Charles E. Young Dr., CHS 44-133, Los Angeles, CA, 90095-7278, USA.
Tiziana
T
Palumbo
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
George A
GA
Poultsides
2nd Department of Propedeutic Surgery, University of Athens School of Medicine, Athens, Greece.
Grigorios
G
Kouraklis
3rd Department of Surgery, University of Athens School of Medicine, Attikon University Hospital, Athens, Greece.
Theodore
T
Liakakos
Division of Hematology/Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Alexandra
A
Drakaki
4th Department of Surgery, University of Athens School of Medicine, Attikon University Hospital, Athens, Greece.
George
G
Peros
Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, 650 Charles E. Young Dr., CHS 44-133, Los Angeles, CA, 90095-7278, USA. M.Hatziapostolou@soton.ac.uk.|Centre for Biological Sciences, University of Southampton, Southampton, UK. M.Hatziapostolou@soton.ac.uk.
Maria
M
Hatziapostolou
Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, 650 Charles E. Young Dr., CHS 44-133, Los Angeles, CA, 90095-7278, USA. diliopoulos@mednet.ucla.edu.
Dimitrios
D
Iliopoulos
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D015153:Blotting, Western; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000235:genetics
C568527:MIRN410 microRNA, human; D035683:MicroRNAs; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human
Cholangiocarcinoma; XIAP; apoptosis; miR-410; microRNA screen; microRNA therapy