Original Article Expression of Sonic hedgehog signaling molecules in normal, hyperplastic and carcinomatous endometrium Kyung Hee Kim, 1 Jin Man Kim, 2 Yoon-La Choi, 3 Young Kee Shin, 4 Ho-chang Lee, 5 In Ock Seong, 1 Bum Kyung Kim, 6 Seoung Wan Chae, 7 Yun-Shin Chung 8 and Seok-Hyung Kim 3 1 Department of Pathology, Eulji University College of Medicine, 2 Cancer Research Institute and Infection Signaling Network Research Center, Chungnam National University, School of Medicine, 6 Department of Pathology, Konyang University College of Medicine, Daejeon, 3 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 4 Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University College of Pharmacy, 7 Department of Pathology, Kangbuk Samsung Hospital Sungkyunkwan University College of Medicine, 8 Transplantation Research Center, Clinical Research Institute, Samsung Medical Center, Seoul and 5 Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Korea The aim of the present study was to determine the expres- sion profile of the hedgehog (Hh) signaling molecules in normal, hyperplastic, and carcinomatous uterine endometrium. For this purpose, 271 endometrial tissue samples, (62 of normal endometrium, 127 of endometrial hyperplasias, and 82 endometrial adenocarcinomas) were studied using antibodies recognizing Hh-related signaling proteins, such as, sonic hedgehog (Shh), Patched (PTCH), Smoothened (Smo), Suppressor of fused [Su(Fu)], Gli-1, Gli-2, and Gli-3 by immunohistochemistry. The mRNA expression of these molecules was also assessed on reverse transcription–polymerase chain reaction. In the normal endometrium, the expression of Hh signaling mol- ecules was generally downregulated except for Su(Fu), Gli-2, and Shh. In particular, the expression of both PTCH and Smo was very low or almost absent. Overall expression of Hh signaling molecules increased in hyperplastic endometrium; in particular, PTCH and Smo were signifi- cantly highly expressed in complex and atypical hyper- plasia. In carcinoma samples extensive alterations were observed in the expression pattern of the signaling mol- ecules. Nuclear Gli-2, cytoplasmic Gli-3, and Su(Fu) were overexpressed, whereas Shh, PTCH, and Smo expression were significantly reduced compared with the hyperplastic endometrium. The results suggest that the alteration of Hh signaling may be implicated in tumorigenesis of the endometrium. Key words: adenocarcinoma, endometrium, Gli protein, hedge- hog proteins, hyperplasia, patched receptors, sonic hedgehog protein, Smoothened protein The hedgehog (Hh) signaling pathway is central to embryonic pattern formation during development and regulates stem cell renewal in adult tissues. 1 In mammals, three Hh homo- logues have been identified: Sonic (Shh), Indian, and Desert. The Hh proteins activate a membrane-receptor complex formed by Patched (PTCH) and Smoothened (Smo), where PTCH normally inhibits Smo. When Hh binds to PTCH, the repression of Smo by PTCH is released, allowing Smo to activate the Gli proteins, 2 which are large, multifunctional transcription factors. There are three Gli proteins that behave differently, with partially redundant functions: Gli-1 and Gli-2 can mediate Hh signals and have been implicated in tumori- genesis. Gli-1 functions primarily as an oncogene; in con- trast, Gli-2 and Gli-3 either function as an oncogene or a tumor suppressor, depending on the type of mutation and cellular context. 3 Suppressor of fused [Su(Fu)] negatively regulates the Hh-signaling network by repressing Gli- mediated transcription. 4,5 The deregulation of the Hh signaling pathway has been implicated in several types of cancer. 6–8 The mutational activation of the Hh signaling pathway is associated with tumorigenesis in a small subset of tissues, predominantly skin, the cerebellum, and skeletal muscle. 9,10 Extensive acti- vation of the Shh signaling pathway has been reported in Correspondence: Seok-Hyung Kim, MD, PhD, Department of Path- ology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, 50 Ilwon-dong, Gangnam-Gu, Seoul 135-710, South Korea. Email: platoshkim@daum.net Received 8 September 2008. Accepted for publication 5 January 2009. © 2009 The Authors Journal compilation © 2009 Japanese Society of Pathology Pathology International 2009; 59: 279–287 doi:10.1111/j.1440-1827.2009.02366.x