Abstract
Purpose: To determine the role of embryonal transcription factor OCT4 in cisplatin treatment of testicular embryonal carcinoma.Methods: In vitro assays were employed to assess the effect of cisplatin treatment on testicular embryonal carcinoma cell lines under OCT4 silencing. Following treatment with 500 ng/μL cisplatin, MTT assay was used to examine cell proliferation of 2012-EP and 833K-E cells with or without OCT silencing, while wound healing assay was used to examine cell migration ability. Transwell assay and crystal violet staining were employed to measure cell invasive capacity, whereas the distribution pattern of cell cycle was assessed by flow cytometry. The expression levels of several critical components in tumorigenicity related pathways with or without OCT silencing were determined by Western-blot analysis.Results: Cisplatin enhanced OCT4-silenced cell viability at all concentration (p < 0.01) when compared to control cells. Upon treatment with 500 ng/μL cisplatin, OCT4-silenced cells showed 2- to 3-fold enhancement in cell proliferation (p < 0.001), 2-fold increase in cell migration capacity (p < 0.001), and about 1.5-fold enhancement in invasive capacity (p < 0.001) when compared to control cells. In addition, OCT4 silencing upregulated the expression level of the proteins involved in cell proliferation, cell mobility, cancer metastasis and cell cycle control.Conclusion: The results suggest that OCT4 may serve as a therapeutic target for testicular embryonal carcinoma treatment in combination with cisplatin by modulating OCT4 expression level. This physiological evidence indicates that OCT4 downregulation contributes to cisplatin resistance in chemotherapy and subsequent disease relapse.Keywords: OCT4, Cisplatin resistance, Testicular embryonal carcinoma, Chemotherapy
Highlights
Testicular cancer is the foremost causal factor for cancer-related mortality in adolescents and men aged 15 to 40 years worldwide [1,2], and extensive effort has been devoted to developing the most effective therapeutics [1]
The results indicate that OCT4-silenced cells have greater viability after treatment with any of the tested concentrations of cisplatin compared to control cells (p < 0.01)
Resistance of testicular germ cell tumors to cisplatin-based chemotherapy is responsible for the poor prognosis of the subgroup of patients bearing this kind of tumor
Summary
Testicular cancer is the foremost causal factor for cancer-related mortality in adolescents and men aged 15 to 40 years worldwide [1,2], and extensive effort has been devoted to developing the most effective therapeutics [1]. It has been found that OCT4 downregulation is involved in cisplatin resistance of testicular embryonal carcinoma [4,7]. Treatment of testicular embryonal carcinoma cells with cisplatin [8] or hypoxia [9] can result in OCT4 downregulation. Downregulation of OCT4 reduces the levels of Noxa, Puma, and microRNAs (e.g., miR17/106b), and increases the level of the cyclin-dependent kinase inhibitor p21 [10] This reduces apoptosis in testicular embryonal carcinoma. The aim of this study, is to establish the relationship, if any, between OCT4 and cisplatin treatment in testicular carcinoma cell lines using in vitro assays. These combined results indicated that 2102EP and 833K-E displayed relatively high expression levels of OCT4 These cell lines were selected for further experiments.
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