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

PURPOSE: Carbonyl reductase 1 (CBR1) is involved in cancer progression. Recently, the authors reported that the loss of CBR1 expression is associated with a poor prognosis in uterine cervical cancer. Here, we investigated whether the decreased CBR1 expression promotes cancer progression by inducing the epithelial mesenchymal transition (EMT). METHODS: Antisense constructs of CBR1 complementary DNA (antisense clones) and the empty vectors (control clones) were transfected into human uterine cervical squamous cell carcinoma cell lines (SKG II and SiHa) and the proliferation and EMT marker expression of these clones were analyzed in vitro. In an in vivo study, 107 cells of the antisense and control clones were subcutaneously injected into nude mice and the tumorigenesis was observed for 8 weeks. RESULTS: With the decreased CBR1 expression, the proliferation of the antisense clones increased, accompanied by a decrease in epithelial markers (E-cadherin and cytokeratin) and an increase in mesenchymal markers (fibronectin, alpha-smooth muscle actin, and N-cadherin), which suggests EMT induction. In the in vivo study, the tumor volume in the antisense group was significantly larger than that in the control group. CONCLUSION: Decreased CBR1 expression promotes tumor growth by inducing EMT in uterine cervical squamous cell carcinomas.

Functional significance of transgelin-2 in uterine cervical squamous cell carcinoma.

AIM: Transgelin-2 (TAGLN2) has previously been found to be highly expressed in uterine cervical squamous cell carcinoma (SCC) tissues by proteomic analyses. The present study investigated the role of TAGLN2 in the malignant behaviors of cervical SCC cells in vitro and in vivo, and the clinical significance of TAGLN2 using immunohistochemistry for human cervical SCC tissues. METHODS: Antisense (AS) constructs of TAGLN2 cDNA (AS clones) and the empty vector (control clone) were transfected into a human uterine SCC cell line (SKG IIIa), and malignant behaviors were analyzed in vitro. In an in vivo experiment, 10(7) cells of the AS and control clones were subcutaneously inoculated into female BALB/c nude mice. In immunohistochemistry with anti-TAGLN2 antibodies for human cervical SCC, FIGO stage IA and IB (n = 75), the expression patterns of TAGLN2 were divided into two groups: weak and strong. The relation between expression pattern and prognosis was analyzed. RESULTS: Suppression of TAGLN2 inhibited cancer cell migration and secretion of matrix metalloproteinases. Tumors in the control clone group continued to grow, whereas those in the AS clone group clearly stopped growing. Six weeks after injection, the tumor size was significantly smaller in the AS clone group than in the control clone group. Immunohistochemistry revealed that the strong pattern was associated with poor overall survival compared with the weak pattern by the Kaplan-Meier method. CONCLUSION: TAGLN2 plays functional roles in the progression of cervical SCC. Suppression of TAGLN2 may be a new strategy for the treatment of cervical SCC.

Clinical implications of human leukocyte antigen class I expression in endometrial cancer.

Decreased expression of human leukocyte antigen (HLA) class I molecules, which is found in several types of cancer, is associated with worse clinical prognosis in cancer patients. The present study was undertaken to investigate the association of immunohistochemical HLA class I expression patterns with clinicopathological factors and prognosis in 96 endometrial cancer patients. HLA class I is composed of a heavy chain (HC-10) and a ß2-microglobulin (ß2-m) light chain. The HLA class I expression patterns were classified as positive when both HC-10 and ß2-m were strongly stained and negative in all other cases. The negative staining pattern was associated with advanced International Federation of Gynecology and Obstetrics stage (P<0.001), lymphovascular space involvement (LVSI) (P=0.003) and lymph node metastasis (P=0.005). Moreover, these cases exhibited worse progression-free survival (PFS) and overall survival (OS) rates compared with positive cases (P=0.005 and P=0.014, respectively). However, the multivariate analysis did not identify HLA class I expression as an independent predictive factor for PFS and OS. In conclusion, HLA class I expression may be useful for predicting postoperative outcome in endometrial cancer, as well as well-known predictive prognostic factors, such as lymph node metastasis and LVSI.

Heat shock protein 70 is involved in malignant behaviors and chemosensitivities to cisplatin in cervical squamous cell carcinoma cells.

AIM: Heat shock protein 70 (HSP70) was previously found to be highly expressed in cervical squamous cell carcinoma (SCC) tissues compared with normal tissues by proteomic analyses. The present study investigated the roles of HSP70 in malignant behaviors and chemosensitivity to cisplatin in cervical SCC cells in vitro. METHODS: Effects of HSP70 knockdown on activities of cell migration, cell invasion and cell proliferation, cell cycle status, and apoptosis were examined using siRNA in two human cervical cancer cells (SiHa and SKG II). Furthermore, the effect of HSP70 knockdown on the apoptotic effect by cisplatin was examined. RESULTS: HSP70 knockdown significantly suppressed activities of cell migration, cell invasion and cell proliferation. The cell cycle was arrested at the S- and G2/M-phases with the increase in apoptosis by HSP70 knockdown. Although cisplatin had no apoptotic effect in the control cell, it showed a dose-dependent apoptotic effect in the HSP70 knockdown cells in SiHa. In SKG II, 5 µg/mL of cisplatin induced apoptosis, and the apoptotic effect by cisplatin was enhanced by HSP70 knockdown. CONCLUSION: It was suggested that HSP70 played functional roles in the progression of uterine cervical SCC, and HSP70 knockdown enhanced chemosensitivities to cisplatin in cervical SCC cells.

Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance.

Human carbonyl reductase 1 (CBR1) is an enzyme that catalyse the reduction of many compounds by using NADPH-dependent oxydoreductase activity. Although CBR1 is known to regulate the tumour progression, the molecular mechanisms of CBR1 in cancer progression and the clinical significance of CBR1 status remain unclear. Here, we investigated the molecular mechanisms by which CBR1 affects cancer cell behaviour in vitro and the clinical significance of CBR1 using immunohistochemical analyses in endometrial cancer. Here, the role of CBR1 in cancer cell invasion and metastasis, and its molecular mechanisms were investigated by transfection of sense and antisense CBR1 cDNAs into a human endometrial adenocarcinoma cell line. The relationship between CBR1 expression analysed by immunohistochemistry and prognosis such as progression free survival (PFS) and overall survival (OS) was examined in endometrial cancer tissues from FIGO stage I-IV (n=109). Suppression of CBR1 by antisense CBR1 cDNA increased cancer cell invasion, and suppressed E-cadherin expression and capacity for cellular aggregation. In contrast, over-expression of CBR1 by sense CBR1 cDNA increased E-cadherin expression and capacity for cellular aggregation, and suppressed cancer cell invasion. The expression of transcriptional suppressors of E-cadherin, Snail and ZEB1, were increased by CBR1 suppression, but suppressed by CBR1 over-expression. Immunohistochemical analyses showed that decreased CBR1 expression is significantly related with poor PFS and OS compared with strong CBR1 expression. In multivariate analyses, decreased CBR1 expression was an independent prognostic factor for PFS and OS. CBR1 regulates cancer cell invasion in endometrial adenocarcinomas by regulating the epithelial mesenchymal transition. A decreased CBR1 expression can be a useful marker of an unfavourable clinical outcome in patients with endometrial cancer.