Abstract
BackgroundThe mitochondrial fission protein, Dynamin related protein 1 (Drp1), and its upstream protein calcium/calmodulin–dependent protein kinase I (CaMKI) play a critical role in chemoresistance in ovarian cancer (OVCA). Thus, we examined the expression of Drp1, CaMKI and their phosphorylated forms and their prognostic impact in epithelial OVCA patients.MethodsExpression analysis was performed by immunohistochemistry (IHC) of paraffin-embedded tumor samples from 49 patients with epithelial OVCA. Staining intensity and the percentage of positively stained tumor cells were used to calculate an immunoreactive score (IRS) of 0–12. The expression scores calculated were correlated with clinicopathological parameters and patient survival.ResultsHigh immunoreactivity of phospho-Drp1Ser637 was significantly correlated with high-grade serous carcinoma (HGSC) (p = 0.034), residual postoperative tumor of > 1 cm (p = 0.006), and non-responders to adjuvant chemotherapy (p = 0.007), whereas high expression of CaMKI was significantly correlated with stage III/IV [International Federation of Gynecologists and Obstetricians (FIGO)] (p = 0.011) and platinum-resistant recurrence (p = 0.030). ROC curve analysis showed that Drp1, phospho-Drp1Ser637 and CaMKI could significantly detect tumor progression with 0.710, 0.779, and 0.686 of area under the curve (AUC), respectively. The Kaplan-Meier survival curve showed that patients with high Drp1, phospho-Drp1Ser637 and CaMKI levels had significantly poorer progression free survival (PFS) (p = 0.003, p < 0.001 and p = 0.017, respectively). Using multivariate analyses, phospho-Drp1Ser637 was significantly associated with PFS [p = 0.043, hazard ratio (HR) 3.151, 95% confidence interval (CI) 1.039–9.561].ConclusionsDrp1 and CaMKI are novel potential candidates for the detection and prognosis of epithelial OVCA and as such further studies should be performed to exploit their therapeutic significance.
Highlights
The mitochondrial fission protein, Dynamin related protein 1 (Drp1), and its upstream protein calcium/calmodulin–dependent protein kinase I (CaMKI) play a critical role in chemoresistance in ovarian cancer (OVCA)
A calcium mobilizing agent, Saikosaponin-d, suppresses phosphoDrp1Ser637 content and calcium/calmodulin–dependent protein kinase I (CaMKI) phosphorylation - which has been reported to up-regulate Drp1 - leading to mitochondrial fission and subsequently apoptosis [17]. Extending from these in vitro findings, we have examined in this current study the clinical relevance and prognostic impact of Drp1, CaMKI and their phosphorylated forms in epithelial OVCA
Based on the findings of computed tomography after last cycle of adjuvant chemotherapy, patients were evaluated for treatment response, which was classified into four categories: complete response when there was resolution of all evidence of disease for at least 1 month; partial response when there was a decrease of ≥50% in the product of the diameters of all measurable lesions without the development of new lesions for at least 1 month; stable disease if there was a decrease of < 50% or an increase of < 25% in the product of the diameters of all measurable lesion; and progressive disease if there was an increase of ≥25% in the product of the diameters of all measurable
Summary
The mitochondrial fission protein, Dynamin related protein 1 (Drp1), and its upstream protein calcium/calmodulin–dependent protein kinase I (CaMKI) play a critical role in chemoresistance in ovarian cancer (OVCA). Regardless, Plasma tumor markers such as carbohydrate antigen 125 (CA125) is widely used for differential diagnosis of ovarian tumor and prognosis, tumor recurrence and the Tsuyoshi et al BMC Cancer (2020) 20:467 prediction of treatment response [2, 3]. Circulating plasma gelsolin (pGSN) has recently been shown to be effective in detecting early stage OVCA and predicting residual disease compared with CA125; a large patient cohort is needed to substantiate these findings [5]. The combination of pGSN and CA125 provided a 100% sensitivity in detecting early stage OVCA [5] providing an evidence that combining multiple tumor markers on a panel could increase OVCA diagnosis and revolutionize treatment. In terms of the prediction of treatment response or prognosis, various genomic, transcriptomic and proteomic biomarkers have been reported [6]. The identification of reliable biomarkers applied for all patient is urgently needed
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