MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets

    1. Stan B Sidhu1,2,5,
    1. 1Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Departments of
      2Endocrine and Oncology Surgery
      4Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia
      5Faculty of Medicine, The University of Sydney, Sydney, New South Wales 2006, Australia Departments of
      7Endocrinology, Faculty of Medical and Health Sciences, Waikato Clinical School, University of Auckland, Auckland 1142, New Zealand
      8Endocrine Surgery Research Laboratories, Department of Surgery, The University of Wisconsin (UW), and UW Carbone Cancer Centre, Madison, Wisconsin 1142, USA
      9Department of Surgical Sciences, University Hospital, Uppsala SE-751 85, Sweden
      10Departments of Surgery and Pathology, University of California at San Francisco, San Francisco, California 93143, USA
      11Endocrine Oncology Section, Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892-1201, USA
    1. (Correspondence should be addressed to S B Sidhu who is now at AMA House, 202/69 Christie Street, St Leonards, New South Wales 2065, Australia; Email: stansidhu{at}nebsc.com.au)


    MicroRNAs (miRNAs) are small RNAs (∼22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs. These results were validated in a separate cohort of ten benign and ten malignant samples using real-time quantitative RT-PCR; benign samples had a minimum follow-up of at least 2 years. It was found that IGF2 as well as its intronic miR-483-5p was over-expressed, while miR-15a and miR-16 were under-expressed in malignant tumours compared with benign tumours. These miRNAs were found to be diagnostic and prognostic markers for malignant pheochromocytoma. The functional role of miR-15a and miR-16 was investigated in vitro in the rat PC12 pheochromocytoma cell line, and these miRNAs were found to regulate cell proliferation via their effect on cyclin D1 and apoptosis. These data indicate that miRNAs play a pivotal role in the biology of malignant pheochromocytoma, and represent an important class of diagnostic and prognostic biomarkers and therapeutic targets warranting further investigation.

    | Table of Contents