Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas

Zhi Rong Qian, Sylvia L. Asa, Haruhiko Siomi, Mikiko C. Siomi, Katsuhiko Yoshimoto, Shozo Yamada, Elaine Lu Wang, Md Mustafizur Rahman, Hiroshi Inoue, Mitsuo Itakura, Eiji Kudo, Toshiaki Sano

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102 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)431-441
Number of pages11
JournalModern Pathology
Volume22
Issue number3
DOIs
Publication statusPublished - 2009 Jan 12
Externally publishedYes

Keywords

  • HMGA2
  • Pituitary adenoma
  • Tumorigenesis
  • let-7

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    Qian, Z. R., Asa, S. L., Siomi, H., Siomi, M. C., Yoshimoto, K., Yamada, S., Wang, E. L., Rahman, M. M., Inoue, H., Itakura, M., Kudo, E., & Sano, T. (2009). Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas. Modern Pathology, 22(3), 431-441. https://doi.org/10.1038/modpathol.2008.202