title: ADAM17 is associated with EMMPRIN and predicts poor prognosis in patients with uterine cervical carcinoma.
abstract: Metalloproteinase activities of a disintegrin and metalloproteinase 17 (ADAM17), amphiregulin (AREG), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMPs) are involved in tumor biology. In patients with uterine cervical carcinoma, the expression and prognostic significance of ADAM17 remain to be fully elucidated. The expression of ADAM17, AREG, EMMPRIN, phospho-epidermal growth factor receptor (p-EGFR), phospho-extracellular signal-regulated kinase (p-ERK), MMP-2, and MMP-9 was assessed by immunohistochemistry and/or Western blotting from cervical carcinoma cell lines, SiHa and HeLa cells, and cervical carcinoma tissues. AREG activity was measured by ELISA assay. The correlation of ADAM17, AREG, EMMPRIN, and MMP-9 expression with patients' survival rates was assessed by Kaplan-Meier and Cox regression analyses. RNA interference (RNAi) experiment was performed using small interfering mRNA to ADAM17 and EMMPRIN. ADAM17, EMMPRIN, and MMP-9 protein content was overexpressed in cervical carcinoma tissues compared with normal cervical tissues (P < 0.05). Strong expression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly associated with stages, lymph node metastasis, differentiation, and parametrium invasion (P < 0.05). Overexpression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly correlated with short progression-free survival and overall survival (P < 0.05). Multivariate analysis suggested that lymph node metastasis, parametrium invasion, and ADAM17 expression were independent prognostic indicators for cervical cancer. ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP-2, and MMP-9 proteins in SiHa and HeLa cells. ELISA assay revealed that AREG activity was stimulated by ADAM17 and was reversed by ADAM17 RNAi in SiHa and HeLa cells. Our data suggest that the increased expression of ADAM17 in cervical cancer is significantly associated with aggressive progression and poor prognosis. ADAM17 may be a molecular marker for predicting the progression and prognosis in cervical cancer.
authors.affiliation: Department of Gynecology, Fujian Provincial Cancer Hospital, Fuzhou, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.forename: Mingang
authors.initials: M
authors.lastname: Ying
authors.forename: Guilin
authors.initials: G
authors.lastname: Chen
authors.forename: Ang
authors.initials: A
authors.lastname: Lin
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Xie
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ohara
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhou
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D066258:Amphiregulin; D051926:Basigin / Q000502:physiology*; D066255:EGF Family of Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C497886:BSG protein, human; D066255:EGF Family of Proteins; D051926:Basigin; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human