BackgroundCryptopleurine, a phenanthroquinolizidine alkaloid, was known to exhibit anticancer activity; however, the underlying mechanism is poorly understood. Because the nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, and development and progression of cancer, we investigated the effects of cryptopleurine on tumor necrosis factor alpha (TNF-α)-induced NF-κB activation pathway and on the expression of NF-κB-regulated gene products associated with many pathophysiological processes.Methodology and Principal FindingMDA-MB231, MDA-MB435, MCF-7, HEK293, RAW264.7 and Hep3B cells were used to examine cryptopleurine's effect on the NF-κB activation pathway. Major assays were promoter-reporter gene assay, electrophoretic mobility shift assay (EMSA), in vitro immune complex kinase assay, real-time PCR, Western blot analysis, and Matrigel invasion assay. Experiments documenting cell proliferation and apoptosis were analyzed by MTT method and flow cytometry, respectively. The results indicated that cryptopleurine suppressed the NF-κB activation through the inhibition of IκB kinase (IKK) activation, thereby blocking the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα) and the nuclear translocation and DNA-binding activity of p65. The suppression of NF-κB by cryptopleurine led to the down-regulation of gene products involved in inflammation, cell survival, proliferation, invasion, and angiogenesis.Conclusions and SignificanceOur results show that cryptopleurine inhibited NF-κB activation pathway, which leads to inhibition of inflammation, proliferation, and invasion, as well as potentiation of apoptosis. Our findings provide a new insight into the molecular mechanisms and a potential application of cryptopleurine for inflammatory diseases as well as certain cancers associated with abnormal NF-κB activation.

As an important transcription factor that is widely expressed in most tissues of the human body, Myc-associated zinc finger protein (MAZ) has been reported highly expressed in many malignant tumors and thought to be a promising therapeutic target for cancer treatment. In this review, we aim to offer a comprehensive understanding of MAZ regulation in malignant tumors. The carboxy terminal of MAZ protein contains six C2H2 zinc fingers, and its regulation of transcription is based on the interaction between the GC-rich DNA binding sites of target genes and its carboxy-terminal zinc finger motifs. MAZ protein has been found to activate or inhibit the transcriptional initiation process of many target genes, as well as play an important role in the transcriptional termination process of some target genes, so MAZ poses dual regulatory functions in the initiation and termination process of gene transcription. Through the transcriptional regulation of c-myc and Ras gene family, MAZ poses an important role in the occurrence and development of breast cancer, pancreatic cancer, prostate cancer, glioblastoma, neuroblastoma, and other malignant tumors. Our review shows a vital role of MAZ in many malignant tumors and provides novel insight for cancer diagnosis and treatment.

#2125 Despite significant advances in diagnosis and treatment, breast cancer remains the world's leading cause of cancer mortality in women. In this study we employed differential expression analysis tools to mine the BioExpress®(1) database of transcriptional profiles and found that Angiogtensin II receptor 1 (AT1-R) mRNA expression was highly correlated with expression of estrogen receptor alpha (ERα) in biopsies from patients with infiltrating ductal carcinoma (IDC). Specifically, AT1-R transcript was up-regulated 12.5 fold in ER+ primary IDC relative to ER- primary IDC (P = 0.0001).
 Experiments using ER+ (T47D) and ER– (HCC1143) breast cancer cell lines derived from human mammary gland ductal carcinoma demonstrated that only the ER+ line responded to angiotensin II-mediated growth stimulation, and this effect was dramatically suppressed in a concentration dependent manner by AT1-R blockers (ARBs). Additional cell culture experiments evaluating eight cell lines derived from IDC further validated the concept that co-expression of both ERα and AT1-R was required for responsiveness to angiotensin II-induced cell proliferation. We have also found that ARBs significantly enhanced the anti-proliferative activity of both tamoxifen, an ER modulator, and formestane, an aromatase inhibitor. Most importantly, we have shown in a T47D tumor xenograft model that ARBs, candesartan and irbesartan, dose-dependently inhibited tumor progression in NODScid mice. Currently, we are evaluating the synergistic/additive effects of ARBs with tamoxifen in additional T47D xenograft models.
 In conclusion, our data provides evidence that ARBs may have utility in the prevention and treatment of ER+ IDC. These observations further validate reports that ARBs may suppress tumor cell proliferation, angiogenesis, and cancer progression. To our knowledge our findings represent the first example of a potential means to stratify a patient population for ARB-based tumor therapy using a clinically accepted biomarker, findings which may have significant clinical implications for the treatment of IDC.
 1) BioExpress® is a knowledgebase of human disease biology comprising over 20,000 individual patient samples profiled over the entire human transcriptome representing > 400 disease states including approximately 200 human breast cancer samples (169 diagnosed as IDC) and 68 normal breast tissue controls. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2125.

Objective: The study aims to explore the prognostic significance of zona pellucida glycoprotein 3 (ZP3) in hepatocellular carcinoma (HCC) tissues. Methods: The expression of ZP3 protein in HCC tissues was detected by immunohistochemistry (IHC) to study its effects on the clinicopathological characteristics and prognosis of HCC patients. The Cancer Genome Atlas (TCGA) database was used to confirm the expression of ZP3 in HCC tissues and Gene set enrichment analysis (GSEA) was performed to obtain potential ZP3-related pathways in HCC. Results: IHC detection found that ZP3 had a high expression in HCC tissues and was associated with cirrhosis, and hepatitis B virus infection of HCC patients (P<0.05). TCGA database also showed that ZP3 was up-regulated in HCC tissues. Further survival evaluation confirmed that ZP3 expression caused an impact on the overall survival time and disease-free survival time of HCC patients (P<0.05), implying a potential role in HCC prognosis. GSEA analysis indicated that the 187 differential gene sets were mainly involved in 10 signaling pathways, including 5 up-regulated and 5 down-regulated pathways. Conclusion: High expression of ZP3 in HCC tissues shows an important role in HCC development and prognosis.

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