Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer and their associations with disease outcomes and expression of let-7a and IGF-II Lingeng Lu a , Dionyssios Katsaros b , Khvaramze Shaverdashvili a , Biyun Qian a,c , Yixing Wu a , Irene A. Rigault de la Longrais b , Mario Preti b , Guido Menato b , Herbert Yu a, * a Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034, United States b Department of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin, Turin, Italy c Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China ARTICLE INFO Article history: Received 4 March 2009 Received in revised form 28 April 2009 Accepted 1 May 2009 Available online 26 May 2009 Keywords: Epithelial ovarian cancer Lin-28 Let-7 IGF-II Prognosis ABSTRACT Lin-28 and lin-28B are RNA-binding proteins which can block microRNA let-7 maturation and affect the differentiation and proliferation of embryonic stem cells. Lin-28 may also regulate the expression of insulin-like growth factor II (IGF-II). As one of the pluripotent fac- tors involved in making induced pluripotent stem cells (iPS), lin-28 is considered a potential therapeutic target for cancer treatment. To further understand the role of lin-28 in cancer, we analysed the expression of lin-28 and its homologue lin-28B in tumour samples, and eval- uated their associations with let-7a maturation, IGF-II expression, disease features and out- comes in 211 patients with primary epithelial ovarian cancer. The analysis showed that both lin-28 and lin-28B were positively correlated with primary and pre-let-7a-3; lin-28B, not lin-28, was inversely correlated with mature let-7a. A positive correlation was also observed between lin-28B and IGF-II expression, while no association was found between lin-28B and IGF-I or IGFBP-3. The study further demonstrated that lin-28B expression was associated with the risk of disease progression and death; patients with high lin-28B had shorter progression-free and overall survival than those with low lin-28B. These results seem to support the findings of recent in vitro experiments, showing that lin-28 blocks the process of let-7a maturation. Our study also suggests that lin-28B may promote ovarian cancer progression and serve as an unfavourable prognostic marker for the disease. The cor- relation between lin-28B and IGF-II indicates that the growth factor may mediate the effect of lin-28B on tumour growth. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Let-7 has been identified as a critical microRNA (miRNA) in the regulation of essential cellular activities. 1,2 This small non-coding RNA can directly and indirectly regulate hundreds of genes, many of which are involved in cell proliferation, dif- ferentiation and apoptosis. 2,3 High mobility group A2 (Hmga2) and RAS are two of the let-7 targets. Let-7 represses their expression through complementarily pairing to the 3 0 -UTR of their transcripts. Studies have shown that loss of let-7-di- rected repression of Hmga2 and RAS promotes malignant transformation, whereas inhibition of Hmga2 and RAS through increasing let-7 expression prevents tumour progres- sion. 4–6 Reduced let-7 expression has been observed in many 0959-8049/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2009.05.003 * Corresponding author: Tel.: +1 203 785 5688; fax: +1 203 785 2850. E-mail address: herbert.yu@yale.edu (H. Yu). EUROPEAN JOURNAL OF CANCER 45 (2009) 2212 – 2218 available at www.sciencedirect.com journal homepage: www.ejconline.com