Chien-Feng Li

CEBPD Reverses RB/E2F1-Mediated Gene Repression and Participates in HMDB-Induced Apoptosis of Cancer Cells

Purpose: Recent evidence indicates that a tumor suppressor gene CEBPD (CCAAT/enhancer-binding protein delta) is downregulated in many cancers including cervical cancer, which provides a therapeutic potential associated with its reactivation. However, little is known for CEBPD activators and the effect of reactivation of CEBPD transcription upon anticancer drug treatment. In this study, we identified a novel CEBPD activator, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB). The purpose of this study is to characterize the mechanism of HMDB-induced CEBPD activation and its potential effect in cancer therapy. Experimental Design: Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced CEBPD transcription. Furthermore, a consequence of HMDB-induced CEBPD expression was linked with E2F1 and retinoblastoma (RB), which discloses the scenario of CEBPD, E2F1, and RB bindings and transcriptional regulation on the promoters of proapoptotic genes, PPARG2 and GADD153. Finally, the anticancer effect of HMDB was examined in xenograft mice. Results: We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates CEBPD transcription through the p38/CREB pathway, thus leading to transcriptional activation of PPARG2 and GADD153. Furthermore, increased level of CEBPD attenuates E2F1-induced cancer cell proliferation and partially rescues RB/E2F1-mediated repression of PPARG2 and GADD153 transcription. Moreover, HMDB treatment attenuates the growth of A431 xenografts in severe combined immunodeficient mice mice. Conclusions: These results clearly demonstrate that HMDB kills cancer cells through activation of CEBPD pathways and suggest that HMDB can serve as a superior chemotherapeutic agent with limited potential for adverse side effects. Clin Cancer Res; 16(23); 5770–80. ©2010 AACR.

CCAAT/Enhancer-binding Protein δ Mediates Tumor Necrosis Factor α-induced Aurora Kinase C Transcription and Promotes Genomic Instability

Epidemiologic and clinical research indicates that chronic inflammation increases the risk of certain cancers, possibly through chromosomal instability. However, the mechanism of inflammation-dependent chromosomal instability associated with tumorigenesis is not well characterized. The transcription factor CCAAT/enhancer-binding protein δ (C/EBPδ, CEBPD) is induced by tumor necrosis factor α (TNFα) and expressed in chronically inflamed tissue. In this study, we show that TNFα promotes aneuploidy. Loss of CEBPD attenuated TNFα-induced aneuploidy, and CEBPD caused centromere abnormality. Additionally, TNFα-induced CEBPD expression augmented anchorage-independent growth. We found that TNFα induced expression of aurora kinase C (AURKC) through CEBPD, and that AURKC also causes aneuploidy. Furthermore, high CEBPD expression correlated with AURKC expression in inflamed cervical tissue specimens. These data provide insight into a novel function for CEBPD in inducing genomic instability through the activation of AURKC expression in response to inflammatory signals.

Is preoperative anemia a risk factor for upper tract urothelial carcinoma following radical nephroureterectomy

PURPOSE We aimed to identify the effect of preoperative anemia on oncologic outcomes in patients with upper tract urothelial carcinoma (UTUC) who had different levels of renal function. METHODS Between 2000 and 2013, we enrolled 370 patients who underwent radical nephroureterectomy for nonmetastatic UTUC. Preoperative anemia was defined as hemoglobin <130g/l in men and <120g/l in women based on the World Health Organization classification. Kaplan-Meier method was applied to estimate the effect anemia on survival, and hazard ratios (HR) of anemia and other clinicopathological parameters were evaluated by Cox regression model. The analyses were also performed in patients with different chronic kidney disease (CKD) stages. RESULTS In all, 242 (65.4%) patients were anemic before surgery. Those with preoperative anemia had worse CKD stage (P<0.001) and higher pathological tumor stage (P = 0.023). In univariate analysis, metastasis-free and cancer-specific survival rates were not significantly associated with preoperative anemia (HR = 1.51, 95% CI: 0.93-2.44, P = 0.093 and HR = 1.59, 95% CI: 0.93-2.72, PP = 0.094, respectively). However, in patients without stage 5 CKD, those with preoperative anemia had apparently inferior metastasis-free and cancer-specific survival than those without (HR = 1.88, 95% CI: 1.14-3.01, P = 0.014 and HR = 2.03, 95% CI: 1.16-3.56, P = 0.010, respectively). A multivariate Cox proportional hazards model indicated that preoperative anemia was an independent predictor for both metastasis-free (HR = 2.17, 95% CI: 1.21-3.90, P = 0.010) and cancer-specific survival (HR = 2.21, 95% CI: 1.15-4.21, P = 0.017). CONCLUSIONS Among patients without stage 5 CKD, preoperative anemia was a significant prognostic factor to predict metastatic progression and cancer-specific death in UTUC following radical nephroureterectomy. It was important to be aware of patients׳ renal function while evaluating the effect of anemia on outcome of UTUC.

Hypoxia-regulated MicroRNA-210 Overexpression is Associated with Tumor Development and Progression in Upper Tract Urothelial Carcinoma

Background: Hypoxia has been shown to facilitate tumor progression. Hypoxia-regulated microRNA-210 (miR-210) may play an important role in carcinogenesis and tumor progression. In this study, we evaluated the clinical significance of miR-210 expression in upper tract urothelial carcinoma (UTUC). Methods: Eighty-three UTUC patients participated in this study. All of them provided cancer tissue samples and 50 of them provided non-cancerous urothelium samples. Clinicopathologic data were collected by reviewing medical records. The expression of miR-210 and hypoxia-inducible factor-1α (HIF-1α) was determined by quantitative real-time polymerase chain reaction. The relationship between clinicopathologic variables and the expression of miR-210 and HIF-1α was analyzed statistically. Results: MiR-210 is overexpressed in UTUC compared to non-cancerous urothelium (p < 0.001); it is also upregulated in high-stage and high-grade tumors (p = 0.020 and 0.049, respectively). HIF-1α is overexpressed in UTUC and correlates positively with miR-210 expression (r = 0.442, p = 0.001). Conclusion: Both miR-210 and HIF-1α are involved in promoting UTUC carcinogenesis. MiR-210 is also correlated with tumor progression. Further studies are needed to clarify the underlying mechanism.

Prognostic value of leptin receptor overexpression in upper tract urothelial carcinomas in Taiwan

Objectives Leptin and its receptor (LEPR) are key players in the regulation of energy balance and body weight control and act as a growth factor for specific organs in both normal and disease states. However, LEPR accumulation may be involved in carcinogenesis, progression, and metastasis in many cancers. This study evaluated the clinical significance of LEPR expression in upper tract urothelial carcinoma (UTUC). Materials and Methods LEPR expression was examined in 110 tissue samples from patients with UTUC, using immunohistochemistry, and an analysis was performed to identify evidence of association between LEPR expression and different clinicopathologic variables. Results LEPR expression was significantly correlated with patients with increased body mass index (P < .001) and high serum creatinine levels (P = .005). We found, using the log‐rank test, that high LEPR expression was associated with poor recurrence‐free (P = .009) and cancer‐specific survival (P = .001). This finding was supported by our results using Cox regression analysis, which showed that LEPR expression was an independent predictor of poor recurrence‐free survival (hazard ratio = 2.55; P = .011) and cancer‐specific survival (hazard ratio = 2.26; P = .006). Conclusions Our findings indicate that LEPR expression is a potential biomarker for predicting patient survival in UTUC. Further study is necessary to investigate the role of LEPR in carcinogenesis of UTUC. Micro‐Abstract Leptin receptor is involved in cancer development and progression. We examined leptin receptor expression in upper tract urothelial carcinoma by immunohistochemistry. Leptin receptor expression could predict patient survival.

Abstract 4926: Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC ZBRK1, a zinc finger protein that interacts with breast cancer 1 (BRCA1) and KRAB-ZFP-associated protein 1 (KAP1), has been suggested to serve as a tumor suppressor via repression of tumor metastasis/invasion. To date, the detailed molecular mechanisms for how BRCA1 and KAP1 participate in ZBRK1-mediated transcriptional repression, metastasis and invasion as well as the associated clinical relevance remain unclear. In this study, we demonstrated that both the N- and C-terminal domains of ZBRK1 are important for inhibiting cell proliferation and anchorage-independent growth in cervical cancer. Specifically, the N-terminal KRAB domain of ZBRK1 displayed a more crucial role in inhibiting metastasis and invasion through modulation of KAP1 function in a transcriptionally dependent manner. The loss of ZBRK1 results in an increase of KAP1 expression, which enhanced migration and invasion of cervical cancer cells both the in vitro and in vivo. Moreover, an inverse correlation of expression levels was observed between ZBRK1 and KAP1 following tumor progression from in situ carcinoma to invasive/metastatic cervical cancer specimens. Taken together, the current results indicate that a loss of ZBRK1 contributes to the increased expression of KAP1, potentiating its role to enhance metastasis and invasion. Citation Format: Wei-Jan Wang, Li-Fang Lin, Chien-Feng Li, Wen-Ming Yang, Dennis Ding-Hwa Wang, Wen-Chang Chang, Wen-Hwa Lee, Ju-Ming Wang, Ju-Ming Wang. Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4926. doi:10.1158/1538-7445.AM2013-4926