Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma

// Haoran Peng 1,3 , Masaharu Ishida 1 , Ling Li 1 , Atsushi Saito 2 , Atsushi Kamiya 2 , James P. Hamilton 1 , Rongdang Fu 3 , Alexandru V. Olaru 1 , Fangmei An 4 , Irinel Popescu 5 , Razvan Iacob 5 , Simona Dima 5 , Sorin T. Alexandrescu 5 , Razvan Grigorie 5 , Anca Nastase 5 , Ioana Berindan-Neagoe 6,7,8 , Ciprian Tomuleasa 8,9 , Florin Graur 10,11 , Florin Zaharia 10,11 , Michael S. Torbenson 12 , Esteban Mezey 1 , Minqiang Lu 3 and Florin M. Selaru 1,13 1 Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland, USA 2 Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Hospital, Baltimore, Maryland, USA 3 Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China 4 Department of Gastroenterology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, P.R. China 5 Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania 6 Department of Immunology, The Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 7 Department of Functional Genomics, The Oncology Institute Ion Chiricuta, Cluj Napoca, Romania 8 The Research Center for Functional Genomics, Biomedicine and Translational Medicine, The Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 9 Department of Hematology, The Oncology Institute Ion Chiricuta, Cluj Napoca, Romania 10 Department of Surgery, The Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania 11 Department of Surgery, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj Napoca, Romania 12 Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA 13 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland, USA Correspondence: Florin M. Selaru, email: // Minqiang Lu, email: // Keywords : hepatocellular carcinoma, pseudogene, tumor suppressor, competitive endogenous RNA, INTS6 Received : October 15, 2014 Accepted : January 02, 2015 Published : January 21, 2015 Abstract The complex regulation of tumor suppressive gene and its pseudogenes play key roles in the pathogenesis of hepatocellular cancer (HCC). However, the roles played by pseudogenes in the pathogenesis of HCC are still incompletely elucidated. This study identifies the putative tumor suppressor INTS6 and its pseudogene INTS6P1 in HCC through the whole genome microarray expression. Furthermore, the functional studies – include growth curves, cell death, migration assays and in vivo studies – verify the tumor suppressive roles of INTS6 and INTS6P1 in HCC. Finally, the mechanistic experiments indicate that INTS6 and INTS6P1 are reciprocally regulated through competition for oncomiR-17-5p. Taken together, these findings demonstrate INTS6P1 and INTS6 exert the tumor suppressive roles through competing for oncomiR-17-5p. Our investigation of this regulatory circuit reveals novel insights into the underlying mechanisms of hepatocarcinogenesis.