Histopathology 2010, 56, 501–509. DOI: 10.1111/j.1365-2559.2010.03495.x
Increased expression of HMGA1 correlates with tumour invasiveness and proliferation in human pituitary adenomas Elaine Lu Wang, Zhi Rong Qian, Md Mustafizur Rahman, Katsuhiko Yoshimoto,1 Shozo Yamada,2 Eiji Kudo & Toshiaki Sano Department of Human Pathology and 1Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, and 2Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo, Japan Date of submission 11 January 2009 Accepted for publication 17 August 2009
Wang E L, Qian Z R, Rahman M M, Yoshimoto K, Yamada S, Kudo E & Sano T (2010) Histopathology 56, 501–509
Increased expression of HMGA1 correlates with tumour invasiveness and proliferation in human pituitary adenomas Aims: High-mobility group A1 (HMGA1) is highly expressed in various benign and malignant tumours. The development of pituitary adenoma in Hmga1 transgenic mice has been reported. However, no studies have investigated HMGA1 expression and its clinical significance in human pituitary adenomas. Methods and results: Immunohistochemical expression of HMGA1 was analysed with respect to various clinicopathological factors in 95 pituitary adenomas. Nuclear expression of HMGA1 was observed in 62% of pituitary adenomas, whereas normal adenohypophysial tissues were negative. Although HMGA1 expression was frequently detected in clinically non-functioning adenomas – 90% of silent adrenocorticotropic hormone (ACTH), 76.2% of follicle-stimulating hormone ⁄ luteinizing hormone and 100% of null cell adenomas – it was also detected in 48.1% of growth hormone (GH), 60%
of mixed GH ⁄ prolactin (PRL), 62.5% of PRL, 66.6% of thyroid-stimulating hormone and 37.5% of ACTH adenomas. HMGA1 expression was significantly higher in invasive adenomas or macroadenomas than in noninvasive adenomas or microadenomas (invasive versus non-invasive, P < 0.05; macroadenoma versus microadenoma, P < 0.05). In addition, HMGA1 showed the highest level in grade IV, more aggressive pituitary adenomas, than in grades I, II and III (IV versus I, P = 0.01; IV versus II, P = 0.01; IV versus III, P = 0.07). Furthermore, a significant correlation between HMGA1 expression and MIB-1 labelling index was observed (R = 0.368, P < 0.0002). Conclusions: These findings suggest that HMGA1 upregulation has an important oncogenic role in pituitary tumorigenesis, as well as being a novel molecular marker of tumour proliferation and invasiveness.
Keywords: HMGA1, pituitary adenoma, tumorigenesis Abbreviations: ACTH, adrenocorticotropic hormone; AT, adenine-thymine; FSH, follicle-stimulating hormone; GH, growth hormone; HMGA, high mobility group A; HPF, high-power field; LH, luteinizing hormone; MMP-9, matrix metalloproteinase 9; PRL, prolactin; TSH, thyroid-stimulating hormone
Introduction Pituitary adenomas are common benign, monoclonal neoplasms comprising approximately 15% of intra-
cranial tumours.1 They can cause mood disorders, sexual dysfunction, infertility, obesity, visual disturbances, hypertension, diabetes mellitus and accelerated heart disease.1 The tumours can also cause morbidity
Address for correspondence: Dr Z R Qian or Dr T Sano, Department of Human Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. e-mail:
[email protected],
[email protected] 2010 The Authors. Journal compilation 2010 Blackwell Publishing Limited.
502
E L Wang et al.
through invasive growth into surrounding brain and bony structures. The pathogenesis of tumour formation remains enigmatic. Furthermore, novel molecular determinants of tumour proliferation and aggressive behaviour are still poorly understood.2 The high mobility group A (HMGA) proteins are non-histone chromosomal proteins that bind through their adenine-thymine (AT) binding motifs to the minor groove of AT-rich DNA strands.3 The HMGA1 gene encodes the HMGA1a and HMGA1b protein isoforms,4 which function as architectural chromatinbinding proteins involved in regulating gene expression.5–8 There are no known differences in the biological activities among these isoforms.4 HMGA1 expression is very high during embryogenesis and negligible in normal adult tissues,9,10 which suggests that HMGA1 plays an important role in cell proliferation and ⁄ or differentiation. On the other hand, HMGA1 overexpression is a feature of tumorigenesis and has been documented in a wide range of human cancers such as thyroid, prostatic, colorectal, pancreatic, uterine, ovarian, breast and gastric cancer.11 A significant correlation between HMGA1 expression and poor prognosis has been found in patients with prostatic, colorectal or breast cancer.11 It has been reported that transgenic mice overexpressing Hmga1 develop mixed growth hormone (GH) ⁄ prolactin (PRL) cell pituitary adenomas and Hmga1 may play a crucial role in pituitary tumorigenesis.12 However, HMGA1 expression has not been studied in sporadic human pituitary adenomas and the clinical relevance of HMGA1 expression in pituitary adenomas remains unknown. To evaluate the potential roles of HMGA1 in tumorigenesis and progressing of pituitary adenomas, we investigated the expression of HMGA1 in a large series of 95 human pituitary adenomas of various types and in 10 normal pituitary glands. Furthermore, we compared HMGA1 expression status with tumour type, size, invasiveness, grade and proliferation marker MIB-1 labelling index.
Materials and methods h u m a n n o rm a l pi t u i t a r y g l a n d a n d p i t ui t a r y adenoma s amples Normal human adenohypophyses were obtained at autopsy in a 2–6 h post-mortem period from 10 patients without endocrine dysfunction at Tokushima University Hospital (Tokushima, Japan). These tissues were examined using haematoxylin and eosin and immunocytochemistry to exclude the possibility of
incidental tumours. Ninety-five postsurgical pituitary adenoma tissue samples were obtained from Tokushima University Hospital and Toranomon Hospital (Tokyo, Japan). These included 27 GH-producing adenomas, five mixed GH-PRL adenomas, 16 PRLproducing adenomas, 18 adrenocorticotropic hormone (ACTH)-producing adenomas (eight associated with Cushing’s disease and 10 silent), three thyroidstimulating hormone (TSH)-producing adenomas, 21 gonadotropin [follicle-stimulating hormone (FSH) ⁄ luteinizing hormone (LH)]-producing adenomas, three null cell, and two silent subtype 3 adenomas (Table 1). Tumour size and invasiveness were defined on the basis of preoperative radiological investigations and operative findings, with a modified Hardy’s classification.13 Grade I (microadenomas,
