[1027] Overexpression of the Hedgehog Pathway Component Gli2 in Uterine Leiomyosarcoma (LMS) and STUMP: A Morphoproteomic Approach.

Sadhna Dhingra, Xuizhen Duan, Robert E Brown. University of Texas- Medical School, Houston

Background: Glioma-associated oncogene 2 (Gli2) is a zinc finger transcription factor whose nuclear expression has been associated with aggressive behavior and invasiveness in melanomas and urothelial carcinomas. Downregulation of Gli2 is associated with the inhibition of proliferation. Gli2 is generally regarded as an effector of the hedgehog signaling pathway but can also be induced by the transforming growth factor-beta/Smad3 signal transduction. Its role in myometrial tumors has not been previously studied.
Design: We examined the expression of Gli2 in a spectrum of uterine smooth muscle tumors. A tissue microarray block was assembled from 11 uterine LMS, 16 smooth muscle tumor of uncertain malignant potential (STUMPs), 14 leiomyomas (LM) and 11 normal myometria. Morphoproteomics uses bright-field microscopy and immunohistochemistry to study the signal intensity, subcellular compartmentalization and extent of distribution in a tumor of protein analytes in signal transduction pathways. Immunohistochemical stains were performed using antibody against Gli2. The intensity (1-3+) and percentage of chromogenic signal was determined, and a composite score (CS), the product of the intensity and percentage was calculated. The significance of difference in means was determined by one way ANOVA.
Results: Gli 2 expression was localized to the nucleus. Gli 2 was positive in 81% (9/11) uterine leiomyosarcomas and majority of Gli2 positive LMS {8/9 (89%)} show moderate to strong (2-3+) signal intensity. The average CS of LMS is 140 (range 0-300). In contrast, 71% (10/14) leiomyomas show mild (1+) positivity with an average CS of 71 (range 0 -100). Three of eleven (27%) of normal myometria showed mild (1+) positivity with an average CS of 21 (range 0 -100). Fifteen of sixteen (93%) STUMPs showed Gli2 positivity with 33% (5/16) showing moderate to strong (2-3+) positivity and an average CS of 115 (range 0-200). Statistical analysis demonstrated significant difference in Gli 2 expression in LMS versus leiomyoma and normal myometria and in STUMP versus normal myometria.
Conclusions: Gli2 expression with nuclear translocation shows a progressive increase from normal myometria to leiomyoma to STUMP to leiomyosarcoma supporting its role in tumorigenesis and malignant transformation. In this context, targeting Gli2 pathways represents a therapeutic option and should forestall the process.
Category: Gynecologic & Obstetrics

Monday, February 28, 2011 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 137, Monday Morning

 

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