Abstract
Overwhelming evidence has demonstrated that the aberrant expression of the human trophoblast cell-surface antigen (TROP2) was associated with tumor aggressiveness and poor prognosis in a variety of human cancers, however the roles of TROP2 in cervical cancer have not been investigated. The purpose of our study was to elucidate the prognostic significance of TROP2 expression in patients with cervical cancer and determine its effect on tumor progression. Immunohistochemistry assay showed that 88.7% (94/106 cases) of cervical cancer specimens were positively stained with TROP2, and the overexpression of TROP2 was closely related with FIGO stage, histological grades, lymphatic metastasis, invasive interstitial depth and high expression of Ki-67. Patients with TROP2-positive staining exhibited a significantly decreased overall survival and progression free survival; it was also an independent predictor for prognosis according to multivariate analysis. Moreover, down-regulation of TROP2 mediated by siRNA in Siha and CaSki cells resulted in a strong inhibition of proliferation and invasion, TROP2 abrogation also elevated the apoptotic ratio and caused G1 arrest. Conversely, enforced expression of TROP2 in HeLa and C33A cells remarkably promoted cell growth, migration and invasion. In addition, the tumorigenic function of TROP2 was associated with the increased expressions of cyclin D1, cyclin E, CDK2 and CDK4 but reduced expression of p27 and E-cadherin via the activation of Erk1/2 signaling pathway. Furthermore, the inhibition of TROP2 expression in cervical cancer cell lines enhances sensitivity to cisplatin. The present study suggest that overexpression of TROP2 may play crucial roles in the development and pathogenesis of human cervical cancer, therefore, TROP2 may represent a prospective prognostic indicator and a potential therapeutic target of cervical cancer.
Highlights
IntroductionEarly-stage patients (I–IIA) can get a satisfying outcome through radical surgery or radiotherapy, with an overall 5-year survival of .65%
Cervical cancer is the third most prevalent malignancy among women worldwide [1], with an estimated approximately 530000 new cases and 275,000 women death each year.Early-stage patients (I–IIA) can get a satisfying outcome through radical surgery or radiotherapy, with an overall 5-year survival of .65%
The expression of Trophoblast cell surface antigen 2 (TROP2) was gradually increased from CINI (50%) to CINII (66.7%) and CINIII (76.9%; Figure 1C) (p = 0.037), indicating TROP2 expression was significantly correlated with the development and progression of cervical cancer
Summary
Early-stage patients (I–IIA) can get a satisfying outcome through radical surgery or radiotherapy, with an overall 5-year survival of .65%. Patients with advanced stage (IIB–IV) can only be treated with radiotherapy or plus chemotherapy, the 5year survival rate for patients with stage III is 25 to 35%, but for stage IV is 15% or fewer [2,3]. There are several high risk factors are thought to be closely associated with unfavorable clinical outcome, including advanced International Federation of Obstetrics and Gynecology (FIGO) stage, large tumor size, lymph node metastasis, deep cervical stromal invasion and lymphovascular space invasion. Patients with the high risk factors always develop resistance to chemotherapy and radiotherapy, died of local recurrence or distant metastasis. There is an urgent need to look for novel biomarkers as a complementary predictive indicator for early diagnosis and accurate prognosis assessment, which would be helpful in targeting therapies of cervical cancer
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