IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma cells

Abstract

IQ motif-containing GTPase-activating proteins (IQGAPs) belong to a conserved family, and they are involved in various intracellular processes. IQGAP1 is expressed in all cells, while IQGAP2 and IQGAP3 are mainly expressed in hepatic cells. IQGAP1 has been suggested to be an oncogene, while IQGAP2 is considered a tumor-suppressor gene. However, the relationship between RAS family genes and IQGAP genes remains unclear. We recently demonstrated this interaction in a chemically induced mouse liver cancer. In this study, IQGAP1 expression was partially silenced in human hepatocellular carcinoma (HepG2) cells. We investigated the impact of IQGAP1 silencing on the interactions of IQGAP and RAS with several apoptotic proteins, including caspase-3 (CASP3), BCL2-associated X protein (BAX), and B-cell leukemia/lymphoma 2 (BCL2). Additionally, we investigated the effects of the interactions of these genes on cell viability, proliferation, apoptosis, and invasive capacity. IQGAP1 siRNA-treated HepG2 cells showed lower invasive capacity than the control cells, and this reduction was time- and vector concentration-dependent. In addition, IQGAP1 silencing resulted in significantly lower IQGAP1 level and subsequently higher IQGAP2 and IQGAP3 expression in HepG2 cells than in the control. Flow cytometry analyses indicated that the silencing of IQGAP1 can induce early and late apoptosis in HepG2 cells. Additionally, IQGAP2, IQGAP3, CASP3, and BAX were upregulated whereas IQGAP1 and BCL2 were downregulated in the siRNA-treated cells. Furthermore, we observed that the mRNA levels of HRAS, KRAS, NRAS, and MRAS decreased upon IQGAP1 silencing. These findings indicate that IQGAP1 potentially regulates the expression of IQGAP and RAS gene families and demonstrate its regulatory role in the apoptotic network. Taken together, our findings suggest that IQGAP1 silencing plays crucial roles in the apoptosis of HepG2 cells and lowers their proliferative and invasive capacities.

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Clinical significance of β2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma

Abstract

The β2-adrenergic receptor (β2-AR) is highly expressed in various human neoplasms and has been considered a novel therapeutic target of cancer treatment. However, the clinicopathological significance of β2-AR expression in patients with gastric cancer (GC) remains unclear. The aim of this study was to explore β2-AR expression and its prognostic significance. A total of 331 patients with surgically resected GC were evaluated. Tumor sections were stained immunohistochemically for β2-AR. And, we confirmed β2-AR expression in the GC cell lines by Western blot. β2-AR was highly expressed in 30.5 % of GC patients. Expression was significantly associated with age, T factor, tumor differentiation, histology of non-signet cells, lymphatic permeation, and vascular invasion. And, all the GC cell lines expressed β2-AR. On univariate analysis, age, disease stage, T factor, N factor, lymphatic permeation, vascular invasion, and β2-AR expression were significantly associated with overall survival. Although the multivariate analysis did not indicate that β2-AR expression was independently prognostic of survival, high-level β2-AR expression was associated with significantly poorer survival of GC patients with well or moderately differentiated tumors. β2-AR expression was a significant predictor of tumor aggressiveness in, and poorer survival of, patients with GC.

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DNA damage after chronic oxytocin administration in rats: a safety yellow light?

Abstract

Adjuvant therapy is a common therapeutic strategy used for schizophrenia management. Oxytocin has shown promising results as antipsychotic adjuvant in patients with schizophrenia. Although short-term clinical studies have indicated tolerability and no major side-effect manifestation, long-term studies remain needed. In this study, we investigated whether oxytocin chronic administration in rats may lead to brain DNA damage by comet assay. Our results suggest that 21 and 56-day treatment with once daily intraperitoneal oxytocin (0.1, 1.0 and 10.0 mg/kg) may cause substantial DNA damage in hippocampus. We have not found differences on body weight gain. Our findings also point that further clinical and preclinical studies evaluating oxytocin safety after chronic exposure are necessary.

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SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Aβ 1–42 into hippocampus of mice

Abstract

A high co-morbidity between Alzheimer's disease (AD) and depression suggests there might be similar mechanisms underlying the course of these diseases. Previous studies have shown that p38MAPK plays a critical role in the pathophysiology of AD and depression. However, little is known about whether SB203580, a selective inhibitor of p38MAPK, may protect against AD-associated cognitive impairments and depression-like behavior, simultaneously. Herein, we have shown, for the first time, that SB203580 may reverse memory impairments and depression-like behavior induced by hippocampal infusion of β-amyloid 1–42 (Aβ_1–42), as measured by novel object recognition, Morris water maze, tail-suspension and forced-swimming tests. In addition, phorbol 12-myristate 13-acetate (PMA), a PKC activator which also activates p38MAPK, significantly abolished the effects of SB203580. Moreover, Aβ_1–42 causes increased phosphorylation of p38MAPK and decreased phosphorylation of Ser9-glycogen synthase kinase 3β (GSK3β) and cAMP-response element binding protein (CREB) in the hippocampus of mice, which could be significantly reversed by SB203580. Our results suggest that SB203580 reversed Aβ_1–42-induced cognitive impairments and depression-like behavior via inhibiting p38MAPK signaling pathway, which not only supports p38MAPK as a therapeutic target for AD-associated cognitive dysfunction and depression-like behavior, but also provides experimental basis for the use of SB203580 in co-morbidity of AD and depression.

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Neuroprotective effect of Cucumis melo Var. flexuosus leaf extract on the brains of rats with streptozotocin-induced diabetes

Abstract

The central nervous system is one of the most vulnerable organs affected by the oxidative stress associated with diabetes mellitus. Healthy food provides an important source for antioxidants. Therefore, the protective effect of Cucumis melo var. flexuosus (C. melo var. flexuosus) leaf extract on the brains of diabetic rats was investigated. Adult male albino rats divided into 5 groups of 6 rats each were assigned into a normal control group and four diabetic groups. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg bw). One of the four diabetic groups was left untreated and was considered as a diabetic control group while the three other groups were treated with C. melo var. flexuosus leaf extract at the doses of 30, 60 and 120 mg/kg bw for a period of 30 days. After completion of experimental duration plasma and brains were used for evaluating biochemical changes. The obtained data showed that C. melo var. flexuosus leaf extract treatment lowered blood glucose, glycated hemoglobin, brain tumor necrosis factor-alpha, interleukin levels, brain malondialdehyde content and caspase-3 activity. Furthermore, the treatment resulted in a marked increase in plasma dopamine, melatonin, brain vascular endothelial growth factor-A levels, brain catalase and superoxide dismutase activities. From the present study, it can be concluded that the C. melo var. flexuosus leaf extract exerts a neuroprotective effect against oxidative damage associated with diabetes.

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Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient

Abstract

Background

Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells.

Methods

T cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy.

Results

We evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti-tumor therapy. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vβ04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy.

Conclusions

Our results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in two ways, by restoring the responsiveness of T cells by increasing the frequency and activation in peripheral blood of tumor specific T cells present in the tumor before therapy.

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Long-Term Outcomes and Prognostic Factors in Periampullary Carcinoma

Abstract

Purpose

The aim of the study was to analyze the long-term survival and the various prognostic factors that influence overall survival in patients undergoing pancreaticoduodenectomy (PD) with non-pancreatic periampullary carcinomas.

Methods

A retrospective analysis of consecutive patients diagnosed with non-pancreatic periampullary carcinomas who underwent PD at a tertiary cancer center was performed. Univariate analysis of various prognostic factors influencing the disease-free survival (DFS) was performed using log-rank test. Factors identified to be significant in univariate analysis were included in the multivariate analysis, which was performed using the Cox proportional hazard model. The survival estimates were calculated by life-table method. Statistical significance was considered when p value was <0.05. The SPSS v16.0.1 software was used for statistical analysis.

Results

Between 1995 and 2010, 78 patients underwent PD with or without (Whipple's operation) pylorus preservation for non-pancreatic periampullary adenocarcinomas. Of these, eight patients received adjuvant chemotherapy. The most common subsite was ampulla (60 patients), followed by the second part duodenum (11 patients), and distal common bile duct (7 patients). The median duration of follow-up of all patients in this study was 50 months. The recurrence rate was 39.7 %. The 5-year disease-free survival and overall survival was 57 %. Patients without nodal metastasis had a non-significant trend towards better 5-year disease-free survival when compared to those with nodal metastasis (64 vs 45 %, p = 0.11). On multivariate analysis, it was found that male gender (p = 0.05) and presence of lymphovascular invasion (p = 0.04) predicted a significantly poor 5-year disease-free survival.

Conclusion

Periampullary carcinomas have a favorable prognosis after surgery. Male gender and presence of lymphovascular invasion are independent prognostic factors in patients diagnosed with non-pancreatic periampullary carcinomas who underwent PD in this study.

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