TY - JOUR
T1 - Hypoxia-induced Maspin Expression Affects the Prognosis of Ovarian Clear Cell Carcinoma
AU - Lee, Eun Ji
AU - Park, Soo Jin
AU - Lee, Cheol
AU - Yim, Ga Won
AU - Kim, Jae Weon
AU - Kim, Hee Seung
N1 - Publisher Copyright:
© 2022 International Institute of Anticancer Research. All rights reserved.
PY - 2022/2
Y1 - 2022/2
N2 - Background/Aim: To investigate the role of the expression of hypoxia-related genes on the prognosis of ovarian clear cell carcinoma (OCCC). Materials and Methods: Basal mRNA levels of eight hypoxia-related genes were compared. Cell viability was assayed after treating ES-2 cells under hypoxic conditions. The mRNA and protein levels were evaluated after the induction of hypoxia and administration of increased doses of N-acetylcysteine (NAC). Finally, the prognostic role of their expression levels was evaluated in 61 patients with OCCC. Results: The mRNA and protein levels of maspin increased gradually with the induction of hypoxia. Maspin protein expression decreased after treatment with paclitaxel and NAC. High expression of maspin was related to poor progression-free and overall survival in patients with OCCC (adjusted hazard ratios, 3.97 and 7.47; 95% confidence intervals=1.34-11.81, and 1.98-28.13). Conclusion: High expression of maspin induced by hypoxia might be associated with poor prognosis of OCCC. Ovarian cancer is a heterogeneous group of diseases and consists of different histologic types, demonstrating distinct biological properties (1). Even though type II ovarian cancers, including high grade serous carcinoma, have valuable biomarkers such as CA-125 and human epididymis protein 4, there are few diagnostic or prognostic biomarkers for type I ovarian cancers representing low-grade serous, mucinous, endometrioid, and clear cell carcinoma (2). Thus, it is difficult to predict the clinical prognosis of type I ovarian cancers due to the lack of biomarkers (3). Since previous studies demonstrated the correlation between hypoxia and ovarian cancer progression (4, 5), further investigations for identifying new biomarkers related to hypoxia are still meaningful. Among them, ovarian clear cell carcinoma (OCCC) shows rather unique entity in terms of clinical, genetic, and histological features (6). Notably, chronic inflammation and oxidative stress in precancerous lesions such as endometriosis have been suggested to trigger its malignant transformation to OCCC (7, 8). Although hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are related to carcinogenesis and progression of ovarian cancer by inducing chemo-resistance (9-11), other hypoxia-related genes such as HIF-1β, cAMP-response element-binding protein-binding protein (CBP), adenovirus early region 1A-binding protein P300 (P300), factor-inhibiting hypoxia-inducible factor (FIH), von Hippel-Lindau (VHL), and maspin have not been investigated sufficiently for their roles affecting drug resistance and prognosis. There is also a lack of relevant studies about the role of hypoxia-related genes as prognostic factors in ovarian cancer. Thus, this study aimed to investigate the role of the expression of hypoxia-related genes as potential prognostic biomarkers in type I ovarian cancer, especially OCCC.
AB - Background/Aim: To investigate the role of the expression of hypoxia-related genes on the prognosis of ovarian clear cell carcinoma (OCCC). Materials and Methods: Basal mRNA levels of eight hypoxia-related genes were compared. Cell viability was assayed after treating ES-2 cells under hypoxic conditions. The mRNA and protein levels were evaluated after the induction of hypoxia and administration of increased doses of N-acetylcysteine (NAC). Finally, the prognostic role of their expression levels was evaluated in 61 patients with OCCC. Results: The mRNA and protein levels of maspin increased gradually with the induction of hypoxia. Maspin protein expression decreased after treatment with paclitaxel and NAC. High expression of maspin was related to poor progression-free and overall survival in patients with OCCC (adjusted hazard ratios, 3.97 and 7.47; 95% confidence intervals=1.34-11.81, and 1.98-28.13). Conclusion: High expression of maspin induced by hypoxia might be associated with poor prognosis of OCCC. Ovarian cancer is a heterogeneous group of diseases and consists of different histologic types, demonstrating distinct biological properties (1). Even though type II ovarian cancers, including high grade serous carcinoma, have valuable biomarkers such as CA-125 and human epididymis protein 4, there are few diagnostic or prognostic biomarkers for type I ovarian cancers representing low-grade serous, mucinous, endometrioid, and clear cell carcinoma (2). Thus, it is difficult to predict the clinical prognosis of type I ovarian cancers due to the lack of biomarkers (3). Since previous studies demonstrated the correlation between hypoxia and ovarian cancer progression (4, 5), further investigations for identifying new biomarkers related to hypoxia are still meaningful. Among them, ovarian clear cell carcinoma (OCCC) shows rather unique entity in terms of clinical, genetic, and histological features (6). Notably, chronic inflammation and oxidative stress in precancerous lesions such as endometriosis have been suggested to trigger its malignant transformation to OCCC (7, 8). Although hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are related to carcinogenesis and progression of ovarian cancer by inducing chemo-resistance (9-11), other hypoxia-related genes such as HIF-1β, cAMP-response element-binding protein-binding protein (CBP), adenovirus early region 1A-binding protein P300 (P300), factor-inhibiting hypoxia-inducible factor (FIH), von Hippel-Lindau (VHL), and maspin have not been investigated sufficiently for their roles affecting drug resistance and prognosis. There is also a lack of relevant studies about the role of hypoxia-related genes as prognostic factors in ovarian cancer. Thus, this study aimed to investigate the role of the expression of hypoxia-related genes as potential prognostic biomarkers in type I ovarian cancer, especially OCCC.
KW - Clear cell
KW - Hypoxia
KW - Maspin
KW - Ovarian cancer
KW - Prognosis
UR - http://www.scopus.com/inward/record.url?scp=85123036787&partnerID=8YFLogxK
U2 - 10.21873/INVIVO.12693
DO - 10.21873/INVIVO.12693
M3 - Article
C2 - 34972717
AN - SCOPUS:85123036787
SN - 0258-851X
VL - 36
SP - 212
EP - 220
JO - In Vivo
JF - In Vivo
IS - 1
ER -