Eukaryotic initiation factor 3b regulates the development and progression of breast cancer.

The tumorigenesis of breast cancer is a complex process involving multiple factors, among which abnormal gene expression is a key event. Nevertheless, studies on the regulation of gene expression have focused primarily on the transcriptional level, although the abnormal translation regulation is also closely related to tumorigenesis. Accumulating evidence has indicated the dysregulation of eukaryotic initiation factor (eIF) subunits in a variety of tumors, which contributes to the malignant transformation, tumor growth, metastasis, and the prognosis of patients. In this study, we examined the expression of eIF3b and found an upregulation of eIF3b in breast cancer cell lines as well as tumor tissues. In addition, the expression of eIF3b was related to the tumor stage with highest eIF3b expression in TNM stage III-IV and/or lymph node metastatic breast cancer. Furthermore, in vitro experiments demonstrated that eIF3b knockdown markedly inhibited tumor hyperplasia as well as the migration and invasion of breast cancer cells, while eIF3b overexpression showed the opposite effects. Importantly, eIF3b silencing inhibited the growth and pulmonary metastasis of xenograft tumor in breast cancer mouse model. Mechanistically, we found that eIF3b downregulation suppressed the malignant development of breast cancer by modulating Wnt/ß-catenin pathway. Collectively, our data suggested that eIF3b might not only participate in the tumorigenesis of breast cancer, but also promote the proliferation, invasion, and metastasis of tumor cells. Thus, eIF3b may service as a potential therapeutic target for the treatment of patients with breast cancer.

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents.

Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer.

BACKGROUND: Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs. RESULTS: In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis. CONCLUSIONS: Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.

Neurotoxicity of low bisphenol A (BPA) exposure for young male mice: Implications for children exposed to environmental levels of BPA.

To investigate the neuron toxicities of low-dose exposure to bisphenol A (BPA) in children, mice were used as an animal model. We examined brain cell damage and the effects of learning and memory ability after BPA exposure in male mice (4 weeks of age) that were divided into four groups and chronically received different BPA treatments for 8 weeks. The comet assay and hippocampal neuron counting were used to detect the brain cell damage. The Y-maze test was applied to test alterations in learning and memory ability. Long term potentiation induction by BPA exposure was performed to study the potential mechanism of performance. The percentages of tail DNA, tail length and tail moment in brain cells increased with increasing BPA exposure concentrations. Significant differences in DNA damage were observed among the groups, including between the low-dose and control groups. In the Y-maze test, the other three groups qualified for the learned standard one day earlier than the high-exposed group. Furthermore, the ratio of qualified mice in the high-exposed group was always the lowest among the groups, indicating that high BPA treatment significantly altered the spatial memory performance of mice. Different BPA treatments exerted different effects on the neuron numbers of different regions in the hippocampus. In the CA1 region, the high-exposed group had a significant decrease in neuron numbers. A non-monotonic relationship was observed between the exposure concentrations and neuron quantity in the CA3 region. The hippocampal slices in the control and medium-exposed groups generated long-term potentiation after induction by theta burst stimulation, but the low-exposed group did not. A significant difference was observed between the control and low-exposed groups. In conclusion, chronic exposure to a low level of BPA had adverse effects on brain cells and altered the learning and memory ability of adolescent mice.

[The expression of E-cadherin, vimentin, ß-catenin, transforming growth factor-ß1 in oral squamous cell carcinomas].

OBJECTIVE: To investigate the expression of E-cadherin, vimentin, ß-catenin and transforming growth factor-ß1 (TGF-ß1) in oral squamous cell carcinomas (OSCC). METHODS: Eighty-nine cases of OSCC and 20 cases of normal oral mucosa were collected. Then the 89 cases of OSCC were classified as grade I, II, III. The semiquantitative method was used to calculated the positive intensity and positive rate. The relationship between the OSCC differentiation and the four biomarkers was analyzed. RESULTS: The median of E-cadherin was 9.00 in the normal tissue, 9.00, 6.00 and 6.00 in OSCC I, II and III, respectively. There was significant difference between the normal group and OSCC group (Z=-4.211, P=0.000). The median of vimentin was 0.00 in the normal tissue, 0.00, 0.00 and 4.00 in OSCC I, II and III, respectively. There was significant difference between the normal group and OSCC group (Z=-3.675, P=0.000). The median of ß-catenin was 9.00 in the normal tissue, 3.00, 4.00 and 3.00 in OSCC I, II and III, respectively. There was significant difference between the normal group and OSCC group (Z=-6.300, respectively. There was significant difference between the normal group and OSCC group (Z=-3.329, P=0.000). E-cadherin expression was positively correlated to ß-catenin expression (r=0.327, P=0.002), negtively correlated to vimentin expression (r=-0.386, P=0.001) and positively correlated to TGF-ß1 expression (r=-0.304, P=0.004). Vimentin expression was positively correlated to TGF-ß1 expression (r=0.401, P=0.000). CONCLUSIONS: E-cadherin and ß-catenin in OSCC had a down-regulated expression, while the vimentin has an up-regulated expression.

[Expression and action of vascular endothelial growth factor and its receptor in a rat model of retinopathy of prematurity].

OBJECTIVE: To explore the expression of vascular endothelial growth factor (VEGF) and its receptors (flt-1 and flk-1) in the retina of retinopathy of prematurity (ROP), and its relation to the alteration of retinal blood vessels. METHODS: Eighty-six newborn Sprague-Dawley rats were randomly divided into hyperoxia and air groups, then each group was further divided into 1, 3, 7 and 14 days subgroups. The rats in hyperoxia group inhaled 75% oxygen and ROP model was thus set up. These animals were sacrificed respectively after 1, 3, 7 and 14 days, then the retinal endothelial cells were marked by CD34 to observe the change of retinal blood vessels. The expression of VEGF, flt-1 and flk-1 in the retina was measured by immunohistochemistry. RESULTS: The retinal capillary density index (RCDI) in control group increased as days went on (F = 21.589, P < 0.01, but it was the least on the 7th day in hyperoxia group, after the rats had been returned to air for 7 days, RCDI increased significantly (F = 67.885, P < 0.01); In the control group, the expression of VEGF and flk-1 was the strongest in the retina on the 7th day, the result had significant difference as compared with the 1st and 14th day (P < 0.05). The expression of VEGF and flk-1 on the 7th day in hyperoxia group was weaker than that of control group (P < 0.05). But on the 14th day in hyperoxia group, they were stronger than that of control (P < 0.05). The localization of the expression of flt-1 was changed when blood vessels altered, but there was no significant difference in expression intensity as a whole (P > 0.05). CONCLUSION: When the premature retina was exposed to hyperoxia, the expression of VEGF and flk-1 was reduced, and retinal blood vessels were also decreased; but the expression of VEGF and flk-1 was stronger in retina when premature rats were exposed to relative hypoxia, and the retinal blood vessels also increased significantly. It is concluded that VEGF and flk-1 may play important roles in the development of retinal blood vessels and its change in ROP. However, flt-1 has less effect compared with flk-1.