Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Osawa,Yuki; Yokoyama,Yoshihito; Shigeto,Tatsuhiko; Futagami,Masayuki; Mizunuma,Hideki

doi:10.3892/ijo.2014.2810

Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Authors:
- Yuki Osawa
- Yoshihito Yokoyama
- Tatsuhiko Shigeto
- Masayuki Futagami
- Hideki Mizunuma
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
Published online on: December 30, 2014 https://doi.org/10.3892/ijo.2014.2810
Pages: 1252-1258

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Carbonyl reductase 1 (CBR1) expression level is related to tumor progression. Decreased CBR1 expression is associated with poor prognosis in ovarian cancer. We investigated the relationship between CBR1 expression level and malignant potential of ovarian cancer. OVCAR‑3 cells overexpressing CBR1 or knocked down for CBR1 were obtained by transfecting CBR1 plasmid DNA (pDNA) or small interfering RNA (siRNA) by electroporation. In vitro cell proliferation and invasion were compared between the two cell types. Subcutaneous CBR1‑overexpressed OVCAR‑3 cells (n=10) and wild‑type ones (n=5) were injected into nude mice. The CBR1 siRNA was then injected twice a week into five of the 10 CBR1‑overexpressed OVCAR‑3 tumors. Tumor growth and metastatic behavior were observed 3 weeks after cell transplantation. Cell proliferation significantly decreased in CBR1‑overexpressed cells as compared to the control, whereas cell proliferation and invasion significantly increased in CBR1‑suppressed cells as compared to the control. The size of the CBR1 siRNA‑injected tumors (n=5) increased significantly as compared to the other two groups (n=5 for each group). The number of metastatic foci in the lungs was significantly higher in mice injected with CBR1 siRNA (7.0±2.0) compared to CBR1‑overexpressed and wild‑type tumors (0 and 2.0±2.0, respectively). Western blot analysis showed that, while vascular endothelial growth factor (VEGF)‑C expression was stable in the CBR1‑siRNA‑injected tumors, E‑cadherin expression was decreased, whereas matrix metalloproteinase (MMP)‑9 was increased in CBR1‑siRNA‑injected tumors compared to the other two groups. These results showed that CBR1 decreases promoted tumor proliferation and growth as well as invasion and metastasis, suggesting that CBR1 has potential to become a new candidate for molecular targeting therapy.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Heintz AP, Odicino F, Maisonneuve P, et al: Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 95(Suppl 1): S161–S192. 2006. View Article : Google Scholar : PubMed/NCBI
3	Yokoyama Y, Futagami M, Watanabe J, et al: Redistribution of resistance and sensitivity to platinum during the observation period following treatment of epithelial ovarian cancer. Mol Clin Oncol. 2:212–218. 2014.PubMed/NCBI
4	Gonzalez-Covarrubias V, Ghosh D, Lakhman SS, Pendyala L and Blanco JG: A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity. Drug Metab Dispos. 35:973–980. 2007. View Article : Google Scholar : PubMed/NCBI
5	Wermuth B, Bohren KM, Heinemann G, von Warthburg JP and Gabbay KH: Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein. J Biol Chem. 263:16185–16188. 1988.PubMed/NCBI
6	Plebuch M, Soldan M, Hungerer C, Koch L and Maser E: Increased resistance of tumor cells to daunorubicin after transfection of cDNAs coding for anthracycline inactivating enzymes. Cancer Lett. 255:49–56. 2007. View Article : Google Scholar : PubMed/NCBI
7	Olson LE, Bedja D, Alvey SJ, Cardounel AJ, Gabrielson KL and Reeves RH: Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1. Cancer Res. 63:6602–6606. 2003.PubMed/NCBI
8	Schieber A, Frank RW and Ghisla S: Purification and properties of prostaglandin 9-ketoreductase from pig and human kidney. Identity with human carbonyl reductase. Eur J Biochem. 206:491–502. 1992. View Article : Google Scholar : PubMed/NCBI
9	Waclawik A and Ziecik AJ: Differential expression of prostaglandin (PG) synthesis enzymes in conceptus during peri-implantation period and endometrial expression of carbonyl reductase/PG 9-ketoreductase in the pig. J Endocrinol. 194:499–510. 2007. View Article : Google Scholar : PubMed/NCBI
10	Sheng H, Shao J, Morrow JD, Beauchamp RD and DuBois RN: Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 58:362–366. 1998.PubMed/NCBI
11	Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M and DuBois RN: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 93:705–716. 1998. View Article : Google Scholar : PubMed/NCBI
12	Murakami A, Fukushima C, Yoshidomi K, et al: Suppression of carbonyl reductase expression enhances malignant behaviour in uterine cervical squamous cell carcinoma: carbonyl reductase predicts prognosis and lymph node metastasis. Cancer Lett. 311:77–84. 2011. View Article : Google Scholar : PubMed/NCBI
13	Murakami A, Yakabe K, Yoshidomi K, et al: Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance. Cancer Lett. 323:69–76. 2012. View Article : Google Scholar : PubMed/NCBI
14	Umemoto M, Yokoyama Y, Sato S, Tsuchida S, Al-Mulla F and Saito Y: Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer. Br J Cancer. 85:1032–1036. 2001. View Article : Google Scholar : PubMed/NCBI
15	Wang H, Yokoyama Y, Tsuchida S and Mizunuma H: Malignant ovarian tumors with induced expression of carbonyl reductase show spontaneous regression. Clin Med Insights Oncol. 6:107–115. 2012.PubMed/NCBI
16	Yokoyama Y, Xin B, Shigeto T, et al: Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer. Mol Cancer Ther. 6:1379–1386. 2007. View Article : Google Scholar : PubMed/NCBI
17	Yang J and Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
18	Alshenawy HA: Immunohistochemical expression of epidermal growth factor receptor, E-cadherin, and matrix metalloproteinase-9 in ovarian epithelial cancer and relation to patient deaths. Ann Diagn Pathol. 14:387–395. 2010. View Article : Google Scholar : PubMed/NCBI
19	Wakui M, Yokoyama Y, Wang H, Shigeto T, Futagami M and Mizunuma H: Efficacy of a methyl ester of 5-aminolevulinic acid in photodynamic therapy for ovarian cancers. J Cancer Res Clin Oncol. 136:1143–1150. 2010. View Article : Google Scholar : PubMed/NCBI
20	Ismail E, Al-Mulla F, Tsuchida S, et al: Carbonyl reductase: a novel metastasis-modulating function. Cancer Res. 60:1173–1176. 2000.PubMed/NCBI
21	Cano A, Pérez-Moreno MA, Rodrigo I, et al: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI
22	Li LN, Zhou X, Gu Y and Yan J: Prognostic value of MMP-9 in ovarian cancer: a meta-analysis. Asian Pac J Cancer Prev. 14:4107–4113. 2013. View Article : Google Scholar : PubMed/NCBI
23	Ozalp S, Tanir HM, Yalcin OT, Kabukcuoglu S, Oner U and Uray M: Prognostic value of matrix metalloproteinase-9 (gelatinase-B) expression in epithelial ovarian tumors. Eur J Gynaecol Oncol. 24:417–420. 2003.PubMed/NCBI
24	Sillanpää S, Anttila M, Voutilainen K, et al: Prognostic significance of matrix metalloproteinase-9 (MMP-9) in epithelial ovarian cancer. Gynecol Oncol. 104:296–303. 2007. View Article : Google Scholar
25	Cowden Dahl KD, Symowicz J, Ning Y, et al: Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res. 68:4606–4613. 2008. View Article : Google Scholar : PubMed/NCBI
26	Yokoyama Y, Charnock-Jones DS, Licence D, et al: Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer. 88:237–244. 2003. View Article : Google Scholar : PubMed/NCBI
27	Tammela T and Alitalo K: Lymphangiogenesis: molecular mechanisms and future promise. Cell. 140:460–476. 2010. View Article : Google Scholar : PubMed/NCBI
28	Abbasi MM, Monfaredan A, Hamishehkar H, Seidi K and Jahanban-Esfahlan R: Novel DOX-MTX nanoparticles improve oral SCC clinical outcome by down regulation of lymph dissemination factor VEGF-C expression in vivo: oral and IV modalities. Asian Pac J Cancer Prev. 15:6227–6232. 2014. View Article : Google Scholar : PubMed/NCBI
29	Ikeda K, Oki E, Saeki H, et al: Intratumoral lymphangiogenesis and prognostic significance of VEGFC expression in gastric cancer. Anticancer Res. 34:3911–3915. 2014.PubMed/NCBI
30	Gyftopoulos K, Lilis I, Kourea H and Papadaki H: The expression of vascular endothelial growth factor-C correlates with lymphatic microvessel density and lymph node metastasis in prostate carcinoma: an immunohistochemical study. Urol Ann. 6:224–230. 2014. View Article : Google Scholar
31	Peppicelli S, Bianchini F and Calorini L: Inflammatory cytokines induce vascular endothelial growth factor-C expression in melanoma-associated macrophages and stimulate melanoma lymph node metastasis. Oncol Lett. 8:1133–1138. 2014.PubMed/NCBI