Abstract
Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na+/K+-ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression levels of FXYD2 were significantly higher in advanced-stage of OCCC and positively correlated with patients' prognoses. Silencing of FXYD2 expression in OCCC cells inhibited Na+/K+-ATPase enzyme activity and suppressed tumor growth via induction of autophagy-mediated cell death. We found that high FXYD2 expression in OCCC was transcriptionally regulated by the transcriptional factor HNF1B. Furthermore, upregulation of FXYD2 expression significantly increased the sensitivity of OCCC cells to cardiac glycosides, the Na+/K+-ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo. Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC.
| Original language | English |
|---|---|
| Pages (from-to) | 62925-62938 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 39 |
| DOIs | |
| Publication status | Published - 2016 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Oncology
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Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma. / Hsu, I. Ling; Chou, Cheng-Yang; Wu, Yi Ying; Wu, Jia En; Liang, Chen Hsien; Tsai, Yao Tsung; Ke, Jhen Yu; Chen, Yuh-Ling; Hsu, Keng-Fu; Hong, Tse-Ming.
In: Oncotarget, Vol. 7, No. 39, 01.01.2016, p. 62925-62938.Research output: Contribution to journal › Article
TY - JOUR
T1 - Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma
AU - Hsu, I. Ling
AU - Chou, Cheng-Yang
AU - Wu, Yi Ying
AU - Wu, Jia En
AU - Liang, Chen Hsien
AU - Tsai, Yao Tsung
AU - Ke, Jhen Yu
AU - Chen, Yuh-Ling
AU - Hsu, Keng-Fu
AU - Hong, Tse-Ming
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na+/K+-ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression levels of FXYD2 were significantly higher in advanced-stage of OCCC and positively correlated with patients' prognoses. Silencing of FXYD2 expression in OCCC cells inhibited Na+/K+-ATPase enzyme activity and suppressed tumor growth via induction of autophagy-mediated cell death. We found that high FXYD2 expression in OCCC was transcriptionally regulated by the transcriptional factor HNF1B. Furthermore, upregulation of FXYD2 expression significantly increased the sensitivity of OCCC cells to cardiac glycosides, the Na+/K+-ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo. Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC.
AB - Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na+/K+-ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression levels of FXYD2 were significantly higher in advanced-stage of OCCC and positively correlated with patients' prognoses. Silencing of FXYD2 expression in OCCC cells inhibited Na+/K+-ATPase enzyme activity and suppressed tumor growth via induction of autophagy-mediated cell death. We found that high FXYD2 expression in OCCC was transcriptionally regulated by the transcriptional factor HNF1B. Furthermore, upregulation of FXYD2 expression significantly increased the sensitivity of OCCC cells to cardiac glycosides, the Na+/K+-ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo. Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC.
UR - http://www.scopus.com/inward/record.url?scp=84993990175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84993990175&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7497
DO - 10.18632/oncotarget.7497
M3 - Article
VL - 7
SP - 62925
EP - 62938
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 39
ER -