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BMC Cancer. 2015 Oct 24;15:789. doi: 10.1186/s12885-015-1744-5.

Demethylation of HIN-1 reverses paclitaxel-resistance of ovarian clear cell carcinoma through the AKT-mTOR signaling pathway.

Ho CM1,2,3, Huang CJ4,5, Huang SH6, Chang SF7, Cheng WF8,9,10.

Author information

1
Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan. cmho@cgh.org.tw.
2
School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan. cmho@cgh.org.tw.
3
School of Medicine, Taipei Medical University, Taipei, Taiwan. cmho@cgh.org.tw.
4
Department of Medical Research, Cathay General Hospital, Sijhih, New Taipei, Taiwan. aaronhuang@cgh.org.tw.
5
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan. aaronhuang@cgh.org.tw.
6
Department of Pathology, Cathay General Hospital, Taipei, Taiwan. drshhuang@gmail.com.
7
Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, Taipei, Taiwan. cmbsfc21@tmu.edu.tw.
8
Department of Obstetrics and Gynecology, National Taiwan, University Hospital, Taipei, Taiwan. wenfangcheng@yahoo.com.
9
Graduate Institute of Oncology, National Taiwan, University Hospital, Taipei, Taiwan. wenfangcheng@yahoo.com.
10
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan, University, Taipei, Taiwan. wenfangcheng@yahoo.com.

Abstract

BACKGROUND:

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. 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.

METHODS:

In 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.

RESULTS:

G2-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.

CONCLUSIONS:

Demethylating agents can restore the HIN-1 expression in paclitaxel-resistant OCCC cells through the HIN-1-AKT-mTOR signaling pathway to inhibit tumor growth.

PMID:
26497956
PMCID:
PMC4619992
DOI:
10.1186/s12885-015-1744-5
[Indexed for MEDLINE]
Free PMC Article

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