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 (Po0.05) and was significantly higher in grade IV than in grades I, II, and III adenomas (Po0.05). High levels of high-mobility group A2 expression were more frequently observed in macroadenomas than in microadenomas (Po0.05). High levels of high-mobility group A2 expression also significantly correlated with the proliferation marker Ki-67 (Po0.0001). 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 (Po0.05). An inverse correlation between let-7 and highmobility group A2 expression was evident (R ¼ À0.33, Po0.05). 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.

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

“…The let-7/miR-98 targets that have been identified include RAS, MYC, HMGA2, IMP-1, CDC25A and CDK6. [27][28][29][30][31][32][33][34][35][36] Our solid results support that Fas is a new target of let-7/miR-98, which suggests let-7/ miR-98 is involved in Fas-mediated function.…”

Treatment of Cushing's disease: a mechanistic update

“…Interestingly, miR-15a and miR-16 genes are colocalized with the Rb tumor suppressor on chromosome 13q14, which is commonly deleted in corticotropinomas. Let-7 miRNA negatively regulates high-mobility group A2 protein, which is highly expressed in pituitary adenomas, increasing aggressiveness of corticotrope adenomas and, therefore, contributing to pituitary tumorigenesis and progression (Qian et al 2009). Genetic manipulation of miRNAs may induce tumor regression and decrease the activity of corticotrope adenomas.…”

A mikro-RNS-ek szerepe az agyalapimirigy-daganatok tumorbiológiájában

“…Egy miRNS-nek a bá-zispárosodás szabályai szerint több célgénje is van, és egy célmolekula kifejeződését számos miRNS is szabályoz-hatja. A biológiai funkciók hátterében álló mechanizmusokat a sejten belüli jelátviteli útvonalakkal lehet a leginkább jellemezni, így a miRNS-ek szabályozó szerepét nemcsak egy-egy génhez (1. táblázat) [34,42,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59], hanem egy-egy jelátviteli útvonalhoz is lehet rendelni.…”

“…Több munkacsoport is leírta a HMGA-fehérjék emelkedett expresszióját humán agyalapimirigy-adenomákban [39,40]. Qian és mtsai összefüggést találtak a HMGA2 expressziója és a tumor típusa, mérete, invazivitása, stádiuma és agresszivitása (a Ki-67-index alapján) között [56]. Egyedül prolactinomákban igazolható a HMGA fokozott kifejeződéséért felelős kromoszómael-térés (12-es triszómia).…”

“…Igazolták a let-7 miRNS és a HMGA2 expressziója közötti negatív korrelációt. Azóta számos miRNS-ről igazolták, hogy célozza a HMGA1-vagy HMGA2-3'UTR-eket (1. táblázat) [47,53,54,56]. A szabályozás komplexitását jól mutatja, hogy a HMGA-fehérjék kapcsolatban vannak a JUN/Fos és a p53 indukálta apoptózis-útvonallal, ezáltal a DNS-hibajavítással, gyulladásos folyamatokkal, az epithelialis-mesenchymalis átmenettel (EMT) és a sejtciklusfehérjékkel is.…”