Abstract
BackgroundMethylation of HIN-1 is associated with poor outcomes in patients with ovarian clear cell carcinoma (OCCC), which is regarded to be an aggressive, chemo-resistant histological subtype. This study aimed to evaluate whether 5-aza-2-deoxycytidine (5-aza-2-dC) can reverse methylation of the HIN-1 gene to restore chemo-sensitivity of OCCC and the possible mechanism.MethodsIn vitro flow cytometric analysis and evaluation of caspase-3/7 activity of paclitaxel-sensitive and resistant OCCC cell lines were performed. Methylation status and expression changes of HIN-1 in the OCCC cell lines treated with 5-aza-2-dC were evaluated, and immunohistochemical staining of HIN-1 in OCCC tissues was performed. In vivo tumor growth with or without 5-aza-2-dC treatment was analyzed, and Western blotting of AKT-mTOR signaling-related molecules was performed.ResultsG2-M phase arrest was absent in paclitaxel-resistant OCCC cells after treatment with the cytotoxic drug. The caspase activities of the chemo-resistant OCCC cells were lower than those of the chemo-sensitive OCCC cells when treated with paclitaxel. Methylation of HIN-1 was noted in paclitaxel-resistant OCCC cell lines and cancerous tissues. 5-aza-2-dC reversed the methylation of HIN-1, re-activated the expression of HIN-1, and then suppressed the in vivo tumor growth of paclitaxel-resistant OCCC cells. Immunoblotting revealed that phospho-AKT473 and phospho-mTOR were significantly increased in HIN-1-methylated paclitaxel-resistant OCCC cell lines. However, the expressions of phospho-AKT at Ser473 and Thr308 and phospho-mTOR decreased in the OCCC cells with a high expression of HIN-1.ConclusionsDemethylating agents can restore the HIN-1 expression in paclitaxel-resistant OCCC cells through the HIN-1-AKT-mTOR signaling pathway to inhibit tumor growth.
Highlights
Methylation of HIN-1 is associated with poor outcomes in patients with ovarian clear cell carcinoma (OCCC), which is regarded to be an aggressive, chemo-resistant histological subtype
Compared to ovarian serous carcinoma, OCCC is relatively resistant to platinum or taxane-based chemotherapy, and this chemo-resistance is associated with a lower response rate to chemotherapy and a poor prognosis [5, 6, 8, 9]
We recently reported that methylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in patients with OCCC, and that the ectopic expression of the HIN-1 gene increases paclitaxel sensitivity partly through the Akt pathway [16]
Summary
Methylation of HIN-1 is associated with poor outcomes in patients with ovarian clear cell carcinoma (OCCC), which is regarded to be an aggressive, chemo-resistant histological subtype. For second-line or salvage treatment, the response rate for recurrent or refractory OCCC is far lower than that for other histological tumors, Ho et al BMC Cancer (2015) 15:789 and even in patients with platinum-sensitive OCCC the response rate is lower than 10 % [10]. In order to improve the survival of patients with OCCC, the development of novel treatment strategies for both first-line and salvage treatment for recurrent disease is urgently needed. To achieve this goal, the identification of targets associated with chemo-resistance and elucidation of the molecular mechanisms of this process are urgently required
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