title: May Sonic Hedgehog proteins be markers for malignancy in uterine smooth muscle tumors?
abstract: Several studies have demonstrated that the Sonic Hedgehog signaling pathway (SHH) plays an important role in tumorigenesis and cellular differentiation. We analyzed the protein expression of SHH pathway components and evaluated whether their profile could be useful for the diagnosis, prognosis, or prediction of the risk of malignancy for uterine smooth muscle tumors (USMTs). A total of 176 samples (20 myometrium, 119 variants of leiomyoma, and 37 leiomyosarcoma) were evaluated for the protein expression of the SHH signaling components, HHIP1 (SHH inhibitor), and BMP4 (SHH target) by immunohistochemistry. Western blot analysis was performed to verify the specificity of the antibodies. We grouped leiomyoma samples into conventional leiomyomas and unusual leiomyomas that comprise atypical, cellular, mitotically active leiomyomas and uterine smooth muscle tumors of uncertain malignant potential. Immunohistochemical analysis showed that SMO, SUFU, GLI1, GLI3, and BMP4 expression gradually increased depending on to the histologic tissue type. The protein expression of SMO, SUFU, and GLI1 was increased in unusual leiomyoma and leiomyosarcoma samples compared to normal myometrium. The inhibitor HHIP1 showed higher expression in myometrium, whereas only negative or basal expression of SMO, SUFU, GLI1, and GLI3 was detected in these samples. Strong expression of SHH was associated with poorer overall survival. Our data suggest that the expression of SHH proteins can be useful for evaluating the potential risk of malignancy for USMTs. Moreover, GLI1 and SMO may serve as future therapeutic targets for women with USMTs.
authors.affiliation: Laboratory of Molecular and Structural Gynecology, Disciplina de Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil 01245-903.
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia
authors.affiliation: Laboratory of Molecular and Structural Gynecology, Disciplina de Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil 01245-903.
authors.forename: Nilo
authors.initials: N
authors.lastname: Bozzini
authors.affiliation: CIPE, International Research Center, Hospital A C Camargo Cancer Center, Sao Paulo, Brazil 01509-010.
authors.forename: Glauco
authors.initials: G
authors.lastname: Baiocchi
authors.affiliation: CIPE, International Research Center, Hospital A C Camargo Cancer Center, Sao Paulo, Brazil 01509-010.
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: da Cunha
authors.affiliation: Laboratory of Molecular and Structural Gynecology, Disciplina de Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil 01245-903.
authors.forename: Gustavo Arantes
authors.initials: GA
authors.lastname: Maciel
authors.affiliation: Laboratory of Molecular and Structural Gynecology, Disciplina de Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil 01245-903.
authors.forename: José Maria
authors.initials: JM
authors.lastname: Soares Junior
authors.affiliation: CIPE, International Research Center, Hospital A C Camargo Cancer Center, Sao Paulo, Brazil 01509-010.
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.affiliation: Laboratory of Molecular and Structural Gynecology, Disciplina de Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil 01245-903.
authors.forename: Edmund Chada
authors.initials: EC
authors.lastname: Baracat
authors.affiliation: Laboratory of Molecular and Structural Gynecology, Disciplina de Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil 01245-903. Electronic address: carvalhokc@gmail.com.
authors.forename: Katia Candido
authors.initials: KC
authors.lastname: Carvalho
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D055415:Bone Morphogenetic Protein 4 / Q000032:analysis; D002352:Carrier Proteins / Q000032:analysis; D005260:Female; D053823:Hedgehog Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007889:Leiomyoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D007890:Leiomyosarcoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009215:Myometrium / Q000737:chemistry* / Q000473:pathology; D011379:Prognosis; D043562:Receptors, G-Protein-Coupled / Q000032:analysis; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013997:Time Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis; D014594:Uterine Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000071676:Zinc Finger Protein GLI1
chemical_list: C525809:BMP4 protein, human; D014408:Biomarkers, Tumor; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; C400551:GLI1 protein, human; C117596:HHIP protein, human; D053823:Hedgehog Proteins; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: Immunohistochemistry; Prognosis; Sonic Hedgehog; Tissue microarray; USMTs