title: Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas.
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.
authors.affiliation: Department of Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School of Medicine, Tokushima, Japan. zrqian@basic.med.tokushima-u.ac.jp
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Siomi
authors.forename: Mikiko C
authors.initials: MC
authors.lastname: Siomi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Shozo
authors.initials: S
authors.lastname: Yamada
authors.forename: Elaine Lu
authors.initials: EL
authors.lastname: Wang
authors.forename: Md Mustafizur
authors.initials: MM
authors.lastname: Rahman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
authors.forename: Eiji
authors.initials: E
authors.lastname: Kudo
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sano
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D025743:HMGA2 Protein / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human