Decreased carbonyl reductase 1 expression promotes tumor growth via epithelial mesenchymal transition in uterine cervical squamous cell carcinomas

Nishimoto, Yuki; Murakami, Akihiro; Sato, Shun; Kajimura, Takuya; Nakashima, Kengo; Yakabe, Kazuyuki; Sueoka, Kotaro; Sugino, Norihiro

doi:10.1002/rmb2.12086

Cited by 10 publications

(8 citation statements)

References 41 publications

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“…Total protein were extracted and subjected to SDS-PAGE and then transferred to membrane as described previously 18,44 . The membranes were incubated for overnight with the following antibodies: C/EBPβ (Santa Cruz Biotechnology), HIF1α (Novus Biologicals, USA) and Histone H3 (Cell Signaling Technology, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

C/EBPβ regulates Vegf gene expression in granulosa cells undergoing luteinization during ovulation in female rats

Shinoda

Tamura

Maekawa

et al. 2019

Sci Rep

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The ovulatory LH-surge increases Vegf gene expression in granulosa cells (GCs) undergoing luteinization during ovulation. To understand the factors involved in this increase, we examined the roles of two transcription factors and epigenetic mechanisms in rat GCs. GCs were obtained from rats treated with eCG before, 4 h, 8 h, 12 h and 24 h after hCG injection. Vegf mRNA levels gradually increased after hCG injection and reached a peak at 12 h. To investigate the mechanism by which Vegf is up-regulated after hCG injection, we focused on C/EBPβ and HIF1α. Their protein expression levels were increased at 12 h. The binding activity of C/EBPβ to the Vegf promoter region increased after hCG injection whereas that of HIF1α did not at this time point. The C/EBPβ binding site had transcriptional activities whereas the HIF1α binding sites did not have transcriptional activities under cAMP stimulation. The levels of H3K9me3 and H3K27me3, which are transcriptional repression markers, decreased in the C/EBPβ binding region after hCG injection. The chromatin structure of this region becomes looser after hCG injection. These results show that C/EBPβ regulates Vegf gene expression with changes in histone modifications and chromatin structure of the promoter region in GCs undergoing luteinization during ovulation.

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Section: Methodsmentioning

confidence: 99%

C/EBPβ regulates Vegf gene expression in granulosa cells undergoing luteinization during ovulation in female rats

Shinoda

Tamura

Maekawa

et al. 2019

Sci Rep

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“…Cervical cancer is the second most common malignant tumor in women worldwide, and the second most common cause of cancer-related death in women. [1,2] The International Federation of Obstetrics and Gynecology (FIGO) reported that although surgical techniques, radiotherapy equipment, and techniques have been greatly improved and developed, the survival rate of cervical cancer has not improved since 1950, and the overall 5-year survival rate keeps around 40%. [3] There are 2 clinical variants including cervical squamous cell carcinomas (CSCC) occupying 85% to 90% and adenocarcinoma carcinomas comprising 10% to 15% of cases.…”

Section: Introductionmentioning

confidence: 99%

High expression of survivin predicts poor prognosis in cervical squamous cell carcinoma treated with paclitaxel and carboplatin

Zhang¹,

Yan

Li³

et al. 2019

Medicine

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Lack of effective biomarkers is one of the challenges in current neoadjuvant chemotherapy to predict drug response and sensitivity of cervical squamous cell carcinoma (CSCC). The present study was designed to investigate the correlation of the expression of survivin, an inhibitor of apoptosis with the prognosis of CSCC patients undergoing neoadjuvant chemotherapy. A total of 117 CSCC patients treated with paclitaxel and carboplatin between May 2015 and April 2017 in the Second Hospital of Lanzhou University were retrospectively analyzed. The pathologic diagnosis and classification of CSCC were based on the Guidelines of the International Federation of Gynaecology and Obstetrics (FIGO). The efficacy was defined as complete remission (CR), partial remission (PR), and stability disease (SD). The expressions of survivin, vascular endothelial growth factor (VEGF), and Ki67 were determined with immunohistochemistry. Data were analyzed with SPSS software. Univariate analysis showed that survivin expression had no correlation with ages, FIGO stage, macroscopic type, lymphovascular invasion, depth of lymphovascular invasion, lymph node metastasis, and tumor size among 117 CSCC patients. However, survivin expression was positively correlated with pathological grade ( R = 0.691, P < .001). Multivariate analysis revealed that survivin expression was independently correlated with grades ( P < .001). In addition, the analysis of correlation indicated that survivin expression is positively correlated with VEGF expression ( R = 0.820, P < .001) and Ki67 expression ( R = 0.673, P < .001). The numbers (percentages) of complete remission (CR), partial remission (PR), and stability disease (SD) were 11 (9.4%), 91 (77.8%), and 15 (12.8%) respectively after the treatment of paclitaxel and carboplatin. Univariate analysis showed that efficacy of treatment was negatively correlated with pathological grade ( R = 0.513, P < .001), Ki67 expression ( R = 0.586, P < .001), VEGF expression ( R = 0.476, P < .001) and survivin expression ( R = 0.519, P < .001). Multivariate analysis revealed that efficacy of treatment was independently correlated with grades ( P = .028), Ki67 ( P < .001), and survivin expression ( P = .015). The results suggested that survivin expression is negatively correlated with the prognosis of CSCC patients treated with paclitaxel and carboplatin. Therefore, survivin expression might be a marker for prognosis in CSCC following neoadjuvant chemotherapy.

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“…CBR1 is present in a variety of organs including liver, kidney, breast, ovary, and vascular endothelial cells, and its primary function is considered to control fatty acid metabolism (15). Interestingly, CBR1 has been reported to regulate malignant behaviors of cancer cells: Decreasing the expression of CBR1 induced cell proliferation and tumorigenesis in vitro and in vivo experiments accompanied by a decreased expression of E-cadherin, and activated matrix metalloproteinases (MMPs) in ovarian, uterine cervical, or uterine endometrial cancers (16–21). This suggests that the decreased expression of CBR1 promotes tumor growth and invasion activities.…”

Section: Introductionmentioning

confidence: 99%

“…Regarding the mechanism of EMT, transforming growth factor (TGF)-β, which has roles in cell proliferation, differentiation, and tumorigenesis, has been reported to be closely associated with EMT in many epithelial and mesenchymal tumors (34,35). We previously analyzed pathways that are regulated by CBR1 in a uterine cervical cancer cell line overexpressing CBR1 (21). Of 15 pathways that were analyzed, the TGF-β signaling pathway was found to be the most important.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of carbonyl reductase 1 inhibits malignant behaviors and epithelial mesenchymal transition by suppressing TGF‑β signaling in uterine leiomyosarcoma cells

et al. 2019

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Carbonyl reductase 1 (CBR1) has been reported to be involved in cancer progression. Recently, we found that CBR1 overexpression inhibited malignant behaviors and the epithelial mesenchymal transition (EMT) in uterine cervical cancer. It remained unclear whether this was also the case in uterine leiomyosarcoma (uLMS), which is derived from mesenchymal cells and is a much more malignant gynecological tumor. A number of previous studies suggested that malignant behaviors are associated with EMT, even in mesenchymal malignant tumors. In the present study, we investigated whether CBR1 inhibits malignant behaviors and EMT in uLMS. We established clones of uLMS cells (SKN cells) and uterine sarcoma cells (MES-SA cells) that overexpressed CBR1. Cell proliferative, migratory and invasive activities were suppressed by CBR1 overexpression, accompanied by increases in the expressions of epithelial markers (E-cadherin and cytokeratin) and decreases in the expressions of mesenchymal markers (N-cadherin and fibronectin), suggesting that CBR1 overexpression inhibits malignant behaviors and EMT in uLMS cells. In addition, transforming growth factor-β (TGF-β) production and the subsequent signaling and phosphorylation of Smad were suppressed in the clones. To investigate the association between TGF-β and EMT, SKN cells were treated with TGF-β or a TGF-β receptor blocker (SB431542). EMT was promoted by TGF-β and inhibited by SB431542. In conclusion, this is the first study, to the best of the authors' knowledge, showing that CBR1 overexpression inhibits malignant behaviors and EMT in uLMS cells. The present study provided novel insight demonstrating that the suppressive effect of CBR1 is mediated through TGF-β signaling.

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Decreased carbonyl reductase 1 expression promotes tumor growth via epithelial mesenchymal transition in uterine cervical squamous cell carcinomas

Cited by 10 publications

References 41 publications

C/EBPβ regulates Vegf gene expression in granulosa cells undergoing luteinization during ovulation in female rats

C/EBPβ regulates Vegf gene expression in granulosa cells undergoing luteinization during ovulation in female rats

High expression of survivin predicts poor prognosis in cervical squamous cell carcinoma treated with paclitaxel and carboplatin

Overexpression of carbonyl reductase 1 inhibits malignant behaviors and epithelial mesenchymal transition by suppressing TGF‑β signaling in uterine leiomyosarcoma cells

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