Abstract
Ovarian Clear Cell Carcinoma (OCCC) displays distinctive clinical and molecular characteristics and confers the worst prognosis among all ovarian carcinoma histotypes when diagnosed at advanced stage, because of the lack of effective therapy. IGF2BP3 is an RNA binding protein that modulates gene expression by post-transcriptional action. In this study, we investigated the roles of IGF2BP3 in the progression of OCCC. We used 328 OCCCs from the AOVT (the Alberta Ovarian Tumor Type study) and the COEUR (the Canadian Ovarian Experimental Unified Resource) cohorts to elucidate the associations between IGF2BP3 expression and clinicopathological parameters, with positive IGF2BP3 expression defined as diffuse block staining, being more frequently observed at stage III (P = 0.0056) and significantly associated with unfavorable overall survival (HR = 1.59, 95% CI 1.09–2.33) in multivariate analysis. IGF2BP3 mRNA gene expression was markedly increased in OCCC cell lines compared to normal tissues such as ovarian surface epithelium. We chose two IGF2BP3-overexpressing cell lines ES2 and OVMANA for in vitro and in vivo knockdown experiments. The proliferation and viability of both cell lines were significantly inhibited by two IGF2BP3 siRNAs and similar suppression was observed in cell migration and invasion by Wound Healing and Transwell assays. The percentage of apoptotic cancer cells was enhanced by both IGF2BP3 siRNAs. In vivo experiments showed significantly reduced sizes of tumors when treated with IGF2BP3 siRNA compared to controls. Furthermore, cancer metastasis-indicators MMP2 and MMP9 proteins were down-regulated. In conclusion, our study shows that IGF2BP3 expression is a promising biomarker for prognostication of women diagnosed with OCCC with multiple effects on key cell functions, supporting its role as an important cellular regulator with potential oncogenic activity, and as a potential target for future intervention strategies.
Highlights
Ovarian clear cell carcinoma (OCCC) accounts for a higher proportion of ovarian carcinomas among Asian than Caucasian (∼10%) ethnic groups [1, 2]
IGF2BP3 expression was significantly associated with overall survival in patients diagnosed at stage I (5-year survival rate 89.3%, SE = 3.4% for non-block vs. 76.5%, SE = 2.8% for block staining, log rank p = 0.029; hazard ratios (HR) = 2.70, 95% confidence intervals (CI) 1.03–6.85)
IGF2BP3 expression was closely associated with clinicopathological parameters, with positive IGF2BP3 expression being frequently present at stage III (P = 0.0056) but no associations with age or treatment (Table 1)
Summary
Ovarian clear cell carcinoma (OCCC) accounts for a higher proportion (up to 25%) of ovarian carcinomas among Asian than Caucasian (∼10%) ethnic groups [1, 2]. Recurrence is not infrequent after surgery and platinum-based treatment and occurs in ∼30% of OCCC patients diagnosed at stage I or II [2, 4]. When OCCC develops to stage III or IV, the outcome is worse than highgrade serous carcinomas, because response rates to secondline chemotherapies for platinum-resistant ovarian CCCs are dismal [5]. Genetic alterations driving OCCC pathogenesis, such as mutations in ARID1A, PI3CA, KRAS, and TERT promoters, have been identified [6]. These genetic traits may become useful markers for clinical applications, such as in early diagnosis and targeted therapy
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