Anti-Cancer Agents in Medicinal Chemistry - Volume 16, Issue 4, 2016

B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) was identified as a biomarker of cancer stem cells, and over-expression of Bmi1 might enhance tumor aggressive clinical behavior in gastric cancer (GC). Our aim of this meta-analysis is to investigate the prognostic role and clinicopathological differences of Bmi1 in GC patients. A total of 6 studies up to September 2014 were included in our study. Our results showed that there were no relationships between Bmi1 expression and the gender (pooled OR=0.87, 95%CI=0.66-1.14, P=0.319, fixed effect), age (pooled OR=1.22, 95%CI=0.95-1.59, P=0.126, fixed effect) and differentiation (pooled OR=1.15, 95%CI=0.71-1.86, P=0.582, random effect) in GC patients. But high Bmi1 expression was significantly correlated with the clinical stage (pooled OR=3.04, 95%CI=1.31-7.07, P=0.010, random effect), tumor size (pooled OR=2.01, 95%CI=1.14-3.55, P=0.016, random effect), T classification (pooled OR=2.79, 95%CI=1.94-4.03, P<0.001, fixed effect), lymph node metastasis (pooled OR=2.24, 95%CI=1.47-3.39, P<0.001, random effect) and distant metastasis (pooled OR=5.05, 95%CI=1.29-19.70, P=0.020, random effect), and led to a poor overall survival (OS) in GC patients (RR=3.38, 95%CI=2.43-4.69, P<0.001, fixed effect). These findings suggested that Bmi1 might serve as a novel and effective prognostic biomarker in GC, and could be a promising emerging molecular target in GC therapy.

MicroRNAs (miRNAs) have been integrated into tumorigenic programs by regulating genes at post-transcriptional level. Long non-coding RNAs (lncRNAs) are novel targets for miRNAs. Here, we reported that miR-203 down-regulation was closely linked to advanced clinical features and poor overall survival (OS) of patients with hepatocellular carcinoma. We also confirmed that miR-203 and oncogene ADAM9 (a disintegrin and metalloproteinase 9)/oncogenic long non-coding RNA HULC (highly up-regulated in liver cancer) were inversely expressed in hepatocellular carcinoma (HCC) tissues or cell lines. More intriguingly, up-regulation of miR-203 diminished the expression of ADAM9 and HULC in HCC cancer cells. Over-expression of miR-203 could markedly inhibit cell proliferation, invasion and induce cell apoptosis. Furthermore, we identified that miR-203 modulated ADAM9 and HULC in a novel post-transcriptional regulatory mechanism. Over-expression of HULC partly rescued the miR-203-mediated antitumor effects. These results suggested that miR-203 played tumor suppressive roles by downregulating ADAM9 and HULC and indicated its potential application in cancer treatment.

Circulating microRNAs are novel and non-invasive tumor biomarkers for colorectal cancer (CRC) detection. In this study, we investigated miR-372 expression in serum and tissues in CRC and colorectal precancerous lesions (CPL) patients by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Our data demonstrated that serum or tissue miR-372 levels were significantly up-regulated in patients with CRC or CPL, compared to healthy control (HC) subjects or normal tissues (P<0.05). High miR-372 expression in early colorectal cancer (ECRC) tissues were statistically significantly associated with tumor size (P<0.05), Tumor-Nodes-Metastasis (TNM) stage (P<0.05), and led to a worse overall survival (P=0.012). Postoperative serum miR-372 levels in ECRC patients significantly dropped, compared to the corresponding preoperative levels (P<0.05). The AUC of serum miR-372 expression for ECRC diagnosis was 0.854, which was significantly higher than that of combined tumor markers (CEA, CA19-9 and CA12-5) (0.613) (P<0.05). The sensitivity and specificity of serum miR-372 expression for ECRC diagnosis were 81.9 % and 73.3 %. All these findings provided an evidence that serum miR-372 could be a noninvasive biomarker for the early detection and prognosis of CRC.

miR-101 is an outstanding tumor suppressor in various cancers, while its role in pancreatic cancer (PC) is still unknown. The aim of this study was to investigate the role of miR-101 in epithelial-to-mesenchymal transition (EMT) and its clinical relevance in PC. Our data showed that the miR-101 expression was significantly decreased in human PC tissues, compared to non-tumor counterparts (p<0.05), which was reversely correlated to clinical characteristics, including lymph node metastasis, more venous infiltration, higher expression of CA19-9 and TNM stage (p<0.05). Low miR-101 expression was also confirmed to be associated with a poorer overall survival rate in PC patients (p<0.05). We identified high-mobility group AT-hook 2 (HMGA2) gene as a putative target of miR-101 in PC by bioinformatics analysis, dual luciferase activity and western blot assay, and found that miR-101 could specifically target the HMGA2 3’-untranslated region (3’-UTR) (p<0.05). Knockdown of HMGA2 reversed EMT resembling that of miR-101 over-expression. An inverse correlation between miR-101 and HMGA2 was observed in patients with PC (p<0.05). Taken together, our findings speculated that miR-101 might act as an inhibiting factor in EMT process in PC and up-regulation of miR-101 might be considered as a potentially key molecular treatment strategy for PC patients.

The cell cycle is regulated via important biological mechanisms. Controlled expression of cell cycle regulatory proteins is crucial to maintain cell cycle progression. However, unbalanced protein expression leads to many diseases, such as cancer. Previous research suggests that SCYL1-BP1 function might be related to cell cycle progression and SCYL1-BP1 dysfunction to diseases through undefined mechanisms. In this research, an unbiased yeast two-hybrid screen was used to find protein(s) with potential biological relevance to SCYL1-BP1 function, and a novel interaction was recognized between SCYL1-BP1 and Cyclin F. This interaction was chosen as a paradigm to study SCYL1-BP1 function in cell cycle progression and its possible role in tumorigenesis. We found that SCYL1-BP1 binds to Cyclin F both in vivo and in vitro. SCYL1-BP1 overexpression promoted expression of the CCNF gene and simultaneously delayed Cyclin F protein degradation. SCYL1-BP1 knockdown reduced the expression of endogenous Cyclin F. It was also demonstrated in functional assays that SCYL1-BP1 overexpression induces G2/M arrest in cultured liver cells. Furthermore, SCYL1-BP1 sustained RRM2 protein expression by reducing its ubiquitination. Thus, we propose that SCYL1- BP1 affects the cell cycle through increasing steady state levels of Cyclin F and RRM2 proteins, thus constituting a dual regulatory circuit. This study provides a possible mechanism for SCYL1-BP1-mediated cell cycle regulation and related diseases.

MicroRNA-183 (miR-183) has recently been identified to be implicated in a variety of critical processes in multiple human malignancies, and its fuction has been poorly characterized in gastric cancer (GC). Here we reported that miR-183 was markedly over-expressed in GC and its up-regulation was markedly associated with GC clinicopathologicalcharacters. Endogenous miR-183 was inhibited in GC cells, which dramatically attenuated cell proliferation, colony formation, migration, invasion and adhesion and enhancedGC cells apoptosis in vitro. Furthermore, in this study we demonstrated that the tumor suppressor gene PDCD4 was a target of miR-183 in GC. Collectively, these observations showed that miR-183 maybe function as an oncogene by regulating GC cell proliferation, apoptosis and metastasis and the oncogenic effect of miR-183 may relate the direct targeting PDCD4.

PTENP1 has been demonstrated to function as a tumor suppressor in several cancer cells. However, its expression and biological roles in gastric cancer (GC) have not yet been investigated. In this study, we demonstrated that PTENP1 was frequently decreased in GC tissues and cell lines, which might be partly associated with DNA hypermethylation, and lower PTENP1 expression was associated with larger tumor size, more advanced stage, deeper invasion depth and lymphatic metastasis. In addition, our data suggested that PTENP1 could regulate GC cell proliferation, apoptosis, migration and invasion in vitro. Furthermore, we demonstrated that PTENP1 could modulate the PTEN protein expression. Taken together, these results suggest that PTENP1 functions as a novel tumor suppressor in GC and its suppressive ability may be involved in the modulation of PTEN.

1,2,4-triazole is an important nucleus present in a large number of compounds. More than thirty-five compounds containing this nucleus are introduced into the market. 1,2,4-triazole nucleus is stable to metabolism and acts as an important pharmacophore by interacting at the active site of a receptor as hydrogen bond acceptor and as a donor. Due to its polar nature, the triazole nucleus can increase the solubility of the ligand and it can significantly improve the pharmacological profile of the drug. A large number of 1,2,4-triazole derivatives are reported to possess a wide range of bioactivities including anti-cancer activity. This review article describes the role of 1,2,4-triazole nucleus in different types of anti-cancer agents such as nucleoside based anti-cancer agents, kinase inhibitors, tubulin modulators, aromatase and steroid sulfatase inhibitors, methionine aminopeptidase inhibitors, tankyrase inhibitors and metal complex based anti-cancer agents. It is expected that the current review article will provide insight into various ligand-receptor interactions and help in the rational design and development of novel 1,2,4-triazole based anti-cancer drugs with improved selectivity for cancer cells.

Aims: Selenium (Se) is an essential trace element for human health which also has antitumor properties. Little is known about its effects on brain tumor cells (BTC). The aim of this study was to investigate the anticancer effects of sodium selenite (SS) including histone deacetylase (HDAC) activity in three human glioblastoma (GBM) cell lines (LN229, T98G and U87). Materials & Methods: LN229, T98G and U87 GBM cell lines were treated with variable doses of SS for time varying from 24 to 72h. HDAC activity, cell proliferation, toxicity, cell death process, caspase-3 and MMP2 activities and Se absorption were evaluated. Results: SS modulated all the parameters tested in a dose- and time-dependent manner. We found that SS decreased HDAC activity, blocked cell proliferation and cell cycle at the G2 phase, triggered an apoptotic cell death process caspase-3-dependent and reduced MMP2 activities. All these effects were performed whereas SS was weakly absorbed (<2%). Conclusions: SS decreasing HDAC activity exhibited interesting antitumor properties in GBM cells which may be taken into account in the novel strategies for achieving tumor growth inhibition and cytotoxicity. Epigenetic modifications induced by SS should be evaluated in further studies.

Accumulated evidences suggested that microRNAs (miRs) play an important role in non-small cell lung cancer (NSCLC). However, how miRs perform their functions in lung adenocarcinoma cancer stem cells (CSCs) remains unknown. Notably, most studies pay more attention to the effects of miRNAs on the metastasis traits whereas the growth activities of CSCs are rather undervalued. In our report, using A549CD133+cells, we examined the inhibitory effects and the underlying mechanisms of microRNA-31 (miR-31) on the growth of lung adenocarcinoma CSC-like cells. Initially, we determined the level of miR-31 in A549 and A549CD133+ cells. Over-expression of miR-31 was found in A549CD133+ cells by microarray and real-time quantitative PCR (RTqPCR) assays. Experiments in multiple NSCLC cell lines in vitro and A549CD133+ cells xenograft models in vivo confirmed that down regulation of miR-31 resulted in increase of A549CD133+ cells growth, whereas overexpression of miR-31 led to the inhibition of adenocarcinoma cell proliferation. Also, MET proto-oncogene has been determined to be a direct target of miR-31 by dual luciferase report, RT-qPCR and western blot analysis. Down regulation of MET inhibited viability of A549CD133+ cells. The levels of PI3Kinase, Akt and p-Akt as well as downstream proteins were consequently decreased. These results suggest that miR-31 might inhibit the growth of lung adenocarcinoma cancer stem-like cells via down regulation of the MET-PI3K-Akt signaling pathway.

Breast cancer is a most common malignancy especially in Iraqi women accounting for high morbidity and mortality. Mutations in BRCA1 gene is one of the important genetic predisposing factors inbreast cancer. Similarly ERBB2 and TP53 are also key prognostic markers in breast cancer treatment.We were interested to explore the gene expression profiles of BRCA1, ERBB2 and TP53 in breast cancer women patients from Iraq so as to assess the potential of such markers in breast cancer treatment. The mRNA levels were significantly over-expressed in tumor tissues in comparison to normal ones with p values (p<0.005) observed between malignant BRCA1 and control tissue samples. Similarly significant difference (p<0.001) was observed between malignant ERBB2 in comparison to control, and malignant TP53 and benign tissue samples as well. However in blood samples, no considerable expression of these markers was observed. Out of three selected genes, ERBB2 expression was significantly expressed in comparison to BRCA1 and TP53 in cancer tissue. Mutation analysis of BRCA1, ERBB2 and TP53 has been made to find out the region most susceptible to mutations in these genes The BRCA1 exon 11, ERBB2 16 and TP53 exon 5 displayed increased chances of having mutations. We can conclude from the study that differential gene expression of BRCA1, ERBB2 and TP53 at mRNA levels may act as a diagnostic marker of circulating tumor cells having important prognostic value in breast cancer patients.