High GD2 expression defines breast cancer cells with enhanced invasiveness.

INTRODUCTION: Breast cancer is the most frequently diagnosed cancer among women. Cancer stem cells (CSCs) are suggested to be responsible for tumor initiation, progression, metastasis, recurrence and drug resistance. This study was conducted to evaluate the clinical significance of GD2, a newly suggested CSC marker and two other traditional CSC markers, CD44 and CD24 in breast cancer patients. MATERIAL AND METHODS: A total of 168 primary breast cancer tissues were evaluated in terms of GD2, CD44 and CD24 expression using tissue microarray. Then, the correlation of expression levels of these markers with patients' clinicopathological characteristics was assessed. RESULTS: Higher GD2 expression was mainly found in patients with advanced histological grade (p = 0.02), presence of lymph node invasion (p = 0.04), larger size of tumors (p = 0.04) and older age (p = 0.04). Breast cancer samples with advanced histological grade also showed higher CD44 (p = 0.03) and CD24 expression (p = 0.05). A significant positive association was found between increased CD24 expression and lymph node involvement (p = 0.01). Furthermore, GD2-high/CD44-high/CD24-low phenotype was frequently seen in breast cancer samples with positive lymph node involvement (p = 0.05). CONCLUSION: In summary, increased expression of GD2 may define more aggressive tumor behavior in breast cancer. GD2 can well be considered as a diagnostic and prognostic marker in breast cancer.

Induction of miR-31 causes increased sensitivity to 5-FU and decreased migration and cell invasion in gastric adenocarcinoma.

Drug resistance is the main obstacle in the treatment of gastric cancer, the third most common cause of cancer-related death in the world. Due to their small size, easy entrance to cells and multiple targets, microRNAs (miRs) are considered novel and attractive targets. In the current study, parental MKN-45, MKN-45-control vector, and MKN-45-miR-31 populations were compared in terms of cell cycle transitions, migration, cell invasion, and proliferation. In addition, downstream targets of miR-31, including E2F6, and SMUG1 were examined using Real-time RT-PCR and western blotting. MKN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups (p = 0.0001, p = 0.01 and p = 0.01, respectively). There was a significant increase in the percentage of cells in G1/pre-G1 phase in MKN-45-miR-31 relative to the control groups (p = 0.001). Induction of miR-31 expression in MKN-45 caused a significant reduction of E2F6 and SMUG1 genes. Our findings indicated that induction of miR-31 expression could increase drug sensitivity, and diminish tumor cell migration and invasion of gastric cancer cells. Therefore, miR-31 can be considered as a potential target molecule in the targeted therapy of gastric cancer (Fig. 2, Ref. 43). Keywords: gastric cancer, miR-31, drug resistance, E2F6, SMUG1.

Human Adipose-Derived Mesenchymal Stem Cells Promote Liver Regeneration.

BACKGROUND AND AIMS: Liver regeneration (LR) is of crucial importance to patients with acute liver failure, those undergoing live donor liver transplantations or extended liver resections. Effective treatment strategies aimed at accelerating liver regeneration could offer major benefits in these patients. Due to easy accessibility, human adipose-derived mesenchymal stem cells (HADMSC) are an attractive source for regenerative medicine. Herein, we investigated the effect of HADMSC on LR in a murine model. We hypothesized that HADMSC will promote LR. METHODS: Mice were subjected to CCl4-induced acute liver failure (ALF). Animals in the experimental arm were treated with HADMSC prior to CCl4-induced ALF. Liver injury was evaluated using serum levels of alanine aminotransferase (ALT), serum interleukin-6 (IL-6), and histopathology. Liver samples were stained for a specific marker of regeneration, proliferating cell nuclear antigen (PCNA). RESULTS: Histology, serum IL-6, and ALT release revealed that HADMSC treatment attenuated liver injury compared with control animals. In addition, animals treated with HADMSC were observed to have improved survival and increased number of PCNA positive cells on histology when compared with controls. CONCLUSION: HADMSCs represent a potential therapeutic strategy to promote liver regeneration.

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats.

AIM: The aim of this study was to investigate the hypothesis that the opioid system is involved in the development of hepatic fibrosis. METHODS: The effect of naltrexone (an opioid receptor antagonist) on hepatic fibrosis in bile duct ligated (BDL) or sham rats was assessed by histology and hepatic hydroxyproline levels. Liver matrix metalloproteinase 2 (MMP-2) was measured by zymography, and alpha smooth muscle actin (alpha-SMA) and CD45 (leucocyte common antigen) by immunohistochemistry. The redox state of the liver was assessed by hepatic glutathione (GSH)/oxidised glutathione (GSSG) and S-nitrosothiol levels. Subtypes of opioid receptors in cultured hepatic stellate cells (HSCs) were characterised by reverse transcriptase-polymerase chain reaction, and the effects of selective delta opioid receptor agonists on cellular proliferation, tissue inhibitor of metalloproteinase 1 (TIMP-1), and procollagen I expression in HSCs determined. RESULTS: Naltrexone markedly attenuated the development of hepatic fibrosis as well as MMP-2 activity (p<0.01), and decreased the number of activated HSCs in BDL rats (p<0.05). The development of biliary cirrhosis altered the redox state with a decreased hepatic GSH/GSSG ratio and increased concentrations of hepatic S-nitrosothiols, which were partially or completely normalised by treatment with naltrexone, respectively. Activated rat HSCs exhibited expression of delta1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to delta(1) and delta(2) agonists, respectively. CONCLUSIONS: This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.