Abstract
To explore the function of fibulin-3 in cervical carcinoma malignant cell growth and metastasis, fibulin-3 expression in normal cervical tissue, cervical intraepithelial neoplasia (CIN), and cervical carcinoma were evaluated by immunohistochemistry. Quantitative real-time-polymerase chain reaction, western blotting, and immunocytochemistry were performed to assess the expression of fibulin-3 at mRNA and protein levels in different invasive clone sublines. Fibulin-3 shRNA and fibulin-3 cDNA were used to transfect the strongly and weakly invasive clone sublines. Using in vitro and in vivo functional assays, we investigated the effects of down-regulating and up-regulating fibulin-3 expression on the proliferation and invasion of different clone sublines. Epithelial mesenchymal transition (EMT) and its signaling pathways PI3K/AKT and ERK were studied carefully in lentiviral transfection systems. Fibulin-3 was upregulated in cervical carcinoma, and its overexpression was significantly related with malignant phenotype and poor prognosis of cervical carcinoma. Fibulin-3 promoted cervical cancer cell invasive capabilities by eliciting EMT and activating the PI3K-Akt-mTOR signal transduction pathway. Fibulin-3 could facilitate the process of cervical cancer development. The results presented here will help develop novel prognostic factors and possible therapeutic options for patients with cervical cancer.
Highlights
Cervical cancer is the fourth most common malignancy in women worldwide, with an estimated global incidence of more than 500,000 new cases and approximately 233,000 deaths per year[1]
Fibulin-3 overexpression was significantly related with malignant phenotype and poor prognosis of cervical carcinoma in clinical samples, and high fibulin-3 expression was positively correlated with proliferation capacity and invasion ability of cervical cancer cells
Similar outcomes were reported by En-lin S et al.[23] that fibulin-3 up-regulation was markedly related to positive lymph node metastasis, vascular invasion, and poor prognosis in patients with cervical carcinoma
Summary
Cervical cancer is the fourth most common malignancy in women worldwide, with an estimated global incidence of more than 500,000 new cases and approximately 233,000 deaths per year[1]. The combined treatments, including surgery, radiotherapy, and chemotherapy, have been attempted to treat cervical cancer, recurrence and metastasis in patients at an advanced stage still result in 5-year survival rates lower than 50%3. Studying the underlying functional molecular and regulation mechanisms of tumor invasion and metastasis will provide further insight into the tumorigenesis and development of cervical cancer. Recent studies have yielded conflicting results about the function of fibulin-3 in tumor biology, showing that affinity or anti-tumor biological activity upon up- or downregulated expression depends on the type of cancer. In ovarian cancer[7,8], osteosarcoma[9], pancreatic cancer[10], and glioblastoma[11], fibulin-3 up-regulation was associated with poor prognosis because of malignant cell growth and invasion. Our purpose was to investigate the prognostic effect of fibulin-3 in cervical cancer, and to determine the role of fibulin-3 in cervical cancer cell proliferation and metastasis in vitro and in vivo
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