Ligustrazine, a bioactive component contained in Chuanxiong (Ligusticum chuanxiong Hort), is widely applied in the treatment of vascular diseases in China, e.g. myocardial and cerebral infarction. The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the clinical effect of Ligustrazine on diabetic nephropathy (DN). PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI) Database, etc. were searched by computer and manual methods to identify RCTs that were used to evaluate the clinical effect of Ligustrazine on DN patients. Twenty five studies comprising 25 RCTs were involved including 1645 patients (858 in the treatment group and 787 in the control group). The meta-analysis suggests that compared with the control group, Ligustrazine injection has a significant therapeutic effect on improving renal function (blood urea nitrogen [BUN] and serum creatinine [SCr]) and reducing in urine protein (24 h urine protein, urine micro albumin and urinary albumin excretion rate [UAER]) in DN patients.

RAB27A is a member of Rab family GTPases involved in cellular vesicle trafficking, and TP53 has recently been implicated in regulating the exosome secretion pathway. Because exosome secretion plays an important role in modulating tumor microenvironment and invasive growth, we hypothesized that RAB27A and TP53 expression might be associated with aggressive behavior in pancreatic ductal adenocarcinoma (PDAC), one of the most deadly human malignancies. We determined protein expression of RAB27A and TP53 in 265 pancreatic tissues (186 carcinomas and 79 normal or benign tissues) by immunohistochemistry analysis on tissue microarray and found their expression was correlated with patients' clinical parameters and overall survival. We found that RAB27A and TP53 protein expression was significantly higher in cancerous tissues compared to normal and benign tissues. High RAB27A protein expression (RAB27A+) was significantly associated with tumor stage and vascular invasion. No correlation between RAB27A and TP53 expression was observed. Patients with high RAB27A expression and high TP53 expression had a poor overall survival. Our data indicate that RAB27A expression is an independent prognostic marker for PDAC, and RAB27A-regulated exosome secretion pathway may represent a novel therapeutic target in pancreatic cancer .

Growing evidence has demonstrated that human epidermal growth factor receptor 2 (HER2) is involved in the radiation response to breast cancer. However, the underlying mechanism remains elusive. Therefore, we investigated if HER2 overexpression is associated with radiosensitivity of breast cancer. We constructed breast cancer cell lines differing in HER2 expression by transducing HER2 cDNA or short hairpin RNA against HER2. We then assessed the radiosensitivity and investigated the potential mechanism by using cell proliferation assay, cell adhesion assays, anoikis assays, colony formation assays, and western blotting analyses. We found that HER2 introduction in breast cancer cell lines MCF-7 (low HER2 expression) and MDA-MB-231 (HER2 is not expressed) promoted cell proliferation and invasion and enhanced cell adhesion and resistance to anoikis. Moreover, HER2 reduced radiosensitivity in these two cells compared with the corresponding control. The opposite results were observed when HER2 was silenced in breast cancer cell lines ZR-7530 and SK-BR-3 (both cells with high expression of HER2) using HER2 shRNA. In addition, animal experiment results showed HER2 could enhance the radioresistance of xenograft tumors. Further studies showed HER2 promoted the phosphorylation of focal adhesion kinase (Fak) and thereby up-regulated the expression of proteins associated with the epithelial-to-mesenchymal transition such as Claudin-1, ZO-1, and ZEB-1. The inhibition of Fak activity using the Fak inhibitor (PF-562281) restored the radiosensitivity in HER2-overexpressing cells. In conclusion, HER2 reduces the radiosensitivity of breast cancer by activating Fak in vitro and in vivo. Fak might be a potential target for the radiosensitization of HER2-overexpressed breast cancer.

The prognosis of breast cancer patients with metastases is generally poor, so it is essential to elucidate related molecules mechanisms. Forkhead Box J2 (FOXJ2) is a member of Forkhead Box transcription factors, many of which have been reported to participate in tumor migration and invasion. In this study, we showed the expression of FOXJ2 was higher in primary breast cancer tissues without lymph nodes metastases than those with, and there was statistical significance between the expression of FXOJ2 and the clinical factors. Hence, we identified a novel function of metastasis, which was not previously known for FOXJ2. Overexpression of FOXJ2 decreased the motility property of highly migrative MDA‐MB‐231 cells in vitro by wound healing assays and trans‐well migration assays, and it was concurrent with the increased expression of epithelial marker E‐cadherin and the decreased expression of mesenchymal marker vimentin by Western blot analysis, reverse transcription PCR analysis, and immunofluorescence analysis. Consistent with these observations, the repression of FOXJ2 in weakly metastatic MCF‐7 cells remarkably promoted cellular motility. Our study demonstrates that FOXJ2 can inhibit the metastasis of human breast cancer by regulating the EMT key markers E‐cadherin and vimentin. J. Cell. Biochem. 113: 2729–2737, 2012. © 2012 Wiley Periodicals, Inc.

PFTK1 was a cell division cycle 2-related serine/threonine protein kinase, which was up-regulated in breast cancer tissues and breast cancer lines. And up-regulated PFTK1 was highly associated with grade, axillary lymph node status, and Ki-67. Moreover, Kaplan-Meier curve showed that up-regulated PFTK1 was related to the poor breast carcinoma patients' overall survival. Here, we first discovered and confirmed that cyclin B was a new interacting protein of PFTK1, and the complex might increase the amount of DVL2, which triggers Wnt/β-catenin signaling pathway. Furthermore, knockdown of PFTK1 attenuated cell proliferation, anchorage-independent cell growth, and cell migration and invasion by inhibiting the transcriptional activation of β-catenin for cyclin D1, MMP9, and HEF1, whereas exogenous expression of PFTK1 might promote MDA-MB-231 cells proliferation, migration, and invasion via promoting PFTK1-DVL2-β-catenin axis. Our findings supported the notion that up-regulated PFTK1 might promote breast cancer progression and metastasis by activating Wnt signaling pathway through the PFTK1-DVL2-β-catenin axis.

S-phase kinase protein 2 (Skp2) is oncogenic and overexpressed in human breast cancer. The objective of this study was to examine the effect of early mitotic inhibitor-1 (Emi1) over-expression on Skp2 expression and related signaling pathway in breast cancer. Immunohistochemical analysis was performed in 98 human breast carcinoma samples and the data were correlated with clinicopathologic features. Furthermore, Western blot analysis was performed for Emi1 and Skp2 in breast carcinoma samples and cell lines to evaluate their protein levels and molecular interaction. We found that the expression of Emi1 was positively related with Skp2 expression (P < 0.01) and Emi1 expression correlated significantly with histologic grade (P = 0.005), meanwhile Skp2 expression obtained similar results. Kaplan-Meier analysis revealed that survival curves of low versus high expressers of Emi1 and Skp2 showed a highly significant separation in human breast cancer (P < 0.01). While in vitro, following release of breast cancer cell lines from serum starvation, the expression of Emi1, Skp2, phosphor-Akt (p-Akt) was up-regulated, whereas p27(Kip1) was down-regulated. Treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 could arrest cells growth and diminish Emi1 expression. These results suggested that Emi1's anti-apoptotic and proliferative abilities appear to be triggered at least in part by the modulation of Skp2, combined Emi1 and Skp2 expressions, may be prognostic for patients with invasive breast carcinomas, which also associated with p-Akt and enabled p27(kip1) degradation. Emi1 may serve as a potential therapeutic strategy aimed at PI3K for the management of breast cancer.

Eg5 is a motor protein belonging to the kinesin-5 family and has been suggested to exert important function in tumors. In this study, we determined the mRNA and protein expression levels of Eg5 in cancerous and non-cancerous breast tissue by quantitative real-time polymerase chain reaction (qRT-PCR) and tissue microarray immunohistochemistry analysis (TMA-IHC) respectively. The results of 20 fresh-frozen BC samples demonstrated that Eg5 mRNA levels were significantly higher in BC tissues compared with corresponding non-cancerous tissue (p = 0.0009). TMA-IHC analysis in 127 BC tissues revealed that Eg5 expression obviously correlated with clinicopathologial parameters, including tumor grade (p = 0.004), ER status (p = 0.030), Ki67 status (p = 0.005), molecular classification (p = 0.026), N stage (p = 0.015), and TNM stage (p = 0.001). Kaplan-Meier survival curve indicated that high Eg5 expression (p = 0.012), Ki67 status (p = 0.014) and TNM stage (p = 0.026) were independent factors to predict poor prognosis for patients with breast cancer. Our data suggest that Eg5 is not only overexpressed in BC, it may be also served as a potential prognostic marker.

BackgroundHypoxia-inducible factor-1 (HIF-1) is a ubiquitously expressed oxygen-regulated transcription factor composed of α and β subunits. HIF-1 activates the transcription of various genes including those involved in the formation and metastatic growth of hepatocellular carcinoma (HCC).ObjectivesTo investigate the levels of hepatic and circulating HIF-1α expression in a range of patients with liver disease in order to determine how it can be used in the diagnosis of HCC and in establishing prognosis.Patients and MethodsTotal RNA was extracted from a self-controlled HCC and paracancerous specimen. HIF-1α mRNA was amplified by nested RT-PCR and confirmed by sequencing. Tissue HIF-1α was analyzed by immunohistochemistry. The levels of HIF-1α, vascular endothelial growth factor (VEGF), and angiopoietin-2 (Ang-2) expression in the sera of 220 patients with liver disease were quantitatively detected by ELISA.ResultsThe positive staining of liver HIF-1α was brown and granule-like and was mainly present in the cytoplasm, with lower levels in the nucleus of hepatocytes. Its incidence was 80% in HCC cells and 100% in paracancerous tissues, with no significant difference in HIF-1α expression in relation to tumor number, degree of differentiation, or hepatitis B surface antigen (HBsAg) positivity, but with some correlation between HIF-1α and tumor size. HIF-1α expression was detected in the sera of HCC patients at a significantly higher level than in cases of benign liver disease, with pathological characteristics associated with the levels of circulating VEGF and Ang-2 expression, the size of the tumor, and the level of extrahepatic metastasis, but not with patients’ gender, age, or alpha-fetoprotein (AFP) levels.ConclusionsHepatic HIF-1α expression is associated with the development and prognosis of HCC, and circulating HIF-1α level is a useful marker for HCC diagnosis and prognosis.