<正>转录因子FoxM1(Forkhead box M1)对肿瘤细胞的生长和存活有重要的调节作用,从而在肝细胞癌的发生发展中扮演着重要的角色。然而,上调FoxM1表达的确切分子机制仍然不甚明了。本研究中我们发现,肿瘤坏死因子α(tumor necrosis factorα,TNF-α)可以转录激活FoxM1,上调其表达。我们通过5’端序列截断以及位点突

Background RhoE, an atypical Rho protein, is differently deregulated in some solid tumors, and there are conflicting data describing the role of RhoE in tumor cell migration and invasion. This study aimed to investigate RhoE expression in human colorectal cancer and its relationship with clinicopathological features and prognosis. Methods Colorectal cancer and adjacent normal tissues from 202 patients were examined by immunohistochemistry. Staining evaluation results were analyzed statistically in relation to various clinicopathological parameters, disease-free survival, and overall survival. RhoE expression was also investigated by immunohistochemistry in 80 node metastases and the corresponding primary lesions, and by Western blot test in six cancer and adjacent normal tissues. The relationship between RhoE and invasion was examined by transwell assay and Western blot test. Results The positive rate for RhoE in colorectal cancer was significantly higher than that of normal colorectal tissues. In colorectal cancer, RhoE expression was significantly correlated with depth of invasion, lymph node metastasis, and distant metastasis. Consistently, overexpression of RhoE in SW620 cells up-regulated vimentin, down-regulated E-cadherin, increased the expression of matrix metalloproteinase (MMP) 9, and enhanced cell invasion in vitro; in contrast, silencing of RhoE by a specific siRNA caused opposite effects. Most importantly, disease-free and overall survivals were significantly poorer for patients with RhoE-positive tumors than for those with RhoE-negative tumors. Conclusions These findings emphasize the positive role of RhoE in invasion and metastasis in human colorectal cancer. It could also serve as an independent prognostic marker in addition to the tumor, node, metastasis staging system.

Objectives: To develop a noninvasive and accessible diagnostic method for pancreatic cancer (PC).Design and methods: We presented a metabolomic method, pattern recognition techniques applied to H-1 nuclear magnetic resonance (H-1 NMR) spectra, to investigate the plasma metabolites obtained from 19 patients with PC, 20 patients with chronic pancreatitis (CP) and 20 healthy individuals.Results: Metabolic changes associated with PC included abnormal amino acid and lipid metabolism, and possible multiple metabolic syndrome. PC elevated plasma levels of N-acetyl glycoprotein (NAG), dimethylamine (DMA), very low density lipoprotein (VLDL), and acetone, and reduced levels of 3-hydroxybutyrate, lactate, high density lipoprotein (HDL), low density lipoprotein (LDL), citrate, alanine, glutamate, glutamine, histidine, isoleucine, lysine, and valine. These metabolites could be a biomarker group for PC that distinguishes between PC and CP patients and healthy individuals.Conclusions: NMR-based metabonomic strategy appears as a promising approach for distinguishing pancreatic cancer and identifying new strategies for prevention or therapy in the clinical practice. (C) 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

The proliferation-specific transcription factor Forkhead box M1 (FoxM1) acts as a master regulator of cancer cell growth and survival and plays an important role in the development of hepatocellular carcinoma. However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that tumor necrosis factor (TNF)-αα induced FoxM1 expression and transactivated its promoter activity in hepatoma cells. Serial 5" deletion and site-directed mutagenesis revealed that the induction of FoxM1 expression by TNF-α was dependent upon the hypoxia-inducible factor 1 (HIF1)-1 and HIF1-3/4 binding sites within the FoxM1 promoter. Furthermore, at the transcriptional level, the stabilization of HIF-1α via reactive oxygen species generation led to the binding of HIF-1α to the FoxM1 promoter and resulted in increased FoxM1 expression. The inhibition of both HIF-1α expression and reactive oxygen species generation significantly decreased TNF-α-induced FoxM1 overexpression. Consequently, the upregulation of FoxM1 promoted the proliferation of hepatoma cells and enhanced their resistance to TNF-α-induced apoptosis. Consistently, there was a positive correlation between HIF-1α and FoxM1 expression in 406 human hepatocellular carcinoma tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in hepatocellular carcinoma patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-α/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis.

Calcyclin‐binding protein or Siah‐1‐interacting protein (CacyBP/SIP), a component of the ubiquitin‐mediated proteolysis, could participate in beta‐catenin degradation, which was found to be related to the malignant phenotypes of pancreatic cancer previously. However, the role of CacyBP/SIP itself in pancreatic cancer has not been investigated. In the present study, CacyBP/SIP expression was assayed and manipulated to reveal the potential mechanism in pancreatic cancer carcinogenesis. Here, we show that CacyBP/SIP is over‐expressed in pancreatic cancer cells. Down‐regulation of CacyBP/SIP by small interference RNA (siRNA) severely suppresses the proliferation and tumorigenesis in pancreatic cancer. G1/S transition arrest induced by inhibition of CacyBP/SIP is at least partly mediated by down‐regulation of Cyclin E and CDK2 as well as up‐regulation of p27 and Rb. Collectively, CacyBP/SIP as an enhancer of pancreatic cancer malignance might develop into another possible therapeutic target. Mol. Carcinog. © 2011 Wiley‐Liss, Inc.

Hepatocellular carcinoma (HCC) is the second most common malignancy in Asia, with a 5-year survival rate of less than 5% due to high recurrence after surgery and resistance to chemotherapy. A variety of therapeutic interventions to treat HCC, particularly gene therapy, have recently been investigated in tumor model systems to provide a more complete understanding of hepatocarcinogenesis and effectively design therapeutic strategies to treat this disease. In our study, we constructed an adenoviral vector expressing small interfering RNA (siRNA) targeting a newly discovered gene named upregulated gene 11 (URG11). We introduced this vector into HCC cells to investigate the role of URG11 in HCC carcinogenesis. We observed that upon URG11 knockdown, HCC cell proliferation was inhibited through downregulation of several G1-S phase related molecules including cyclin D1 and apoptosis was induced as a result of Bcl-2 downregulation. Besides decreased expression of cyclin D1, CDK4, pRb and Bcl-2, URG11 also suppressed several other proteins including CAPN9, which was identified by cDNA microarray and 2D gel electrophoresis. Moreover, Ad-URG11-siRNA significantly suppressed HCC tumor growth in nude mice. In conclusion, Ad-URG11-siRNA can significantly suppress HCC tumor growth in vitro and in vivo by silencing the URG11 gene, and the use of this vector for gene therapy may represent a novel strategy to treat human HCC.