1. ¹Department of Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School of Medicine, Tokushima, Japan
2. ²Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
3. ³Division of Gene Function Analysis, Institute for Genome Research, The University of Tokushima, Tokushima, Japan
4. ⁴Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
5. ⁵Department of Neurosurgery, Toranomon Hospital, Tokyo, Japan
6. ⁶Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima, Japan

Correspondence: Dr ZR Qian, MD, PhD and Dr T Sano, MD, PhD, Department of Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mails: zrqian@basic.med.tokushima-u.ac.jp and sano@basic.med.tokushima-u.ac.jp

Received 24 September 2008; Revised 13 November 2008; Accepted 19 November 2008; Published online 9 January 2009.

Abstract

High-mobility group A2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that high-mobility group A2 is negatively regulated by the let-7 microRNAs (miRNAs) family in vitro. The development of pituitary adenomas in high-mobility group A2 transgenic mice showed that high-mobility group A2 may be involved in pituitary tumorigenesis. However, no studies have investigated the clinical significance of high-mobility group A2 and its relationship to the let-7 miRNA family in human pituitary adenomas. Using immunohistochemistry, we analyzed high-mobility group A2 expression with respect to various clinicopathologic factors in 98 pituitary adenomas. Overexpression of high-mobility group A2 was observed in 39% (38/98) of pituitary adenomas compared with normal adenohypophysial tissue and was frequently found in adenomas including prolactin (PRL), adrenocorticotrophic hormone, or follicle-stimulating hormone/luteinizing hormone and in null cell adenomas, but relatively rare in growth hormone (GH) and mixed GH/PRL adenomas. High-mobility group A2 expression was significantly associated with tumor invasion (P<0.05) and was significantly higher in grade IV than in grades I, II, and III adenomas (P<0.05). High levels of high-mobility group A2 expression were more frequently observed in macroadenomas than in microadenomas (P<0.05). High levels of high-mobility group A2 expression also significantly correlated with the proliferation marker Ki-67 (P<0.0001). Real-time quantitative RT-PCR analysis was carried out to evaluate the expression of let-7 in 55 pituitary adenomas. Subsequently, decreased expression of let-7 was confirmed in 23 of 55 (42%) adenomas and was correlated with high-grade tumors (P<0.05). An inverse correlation between let-7 and high-mobility group A2 expression was evident (R=-0.33, P<0.05). These findings support a causal link between let-7 and high-mobility group A2 whereby loss of let-7 expression induces high-mobility group A2 upregulation that represents an important mechanism in pituitary tumorigenesis and progression.