Current Molecular Medicine - Volume 15, Issue 5, 2015

Apoptosis is a prominent characteristic in the pathogenesis of liver disease. The molecular mechanism of hepatic apoptosis is not well understood. Liver injury induces a downregulation of hepatocyte nuclear factor 6 (HNF6) that is negatively correlated with the degree of apoptosis. However, an enhancement of HNF6 can relieve hepatic apoptosis and impede the progression of liver disease. HNF6 has distinct mechanisms to modulate hepatic apoptosis. Pathophysiological role of HNF6 may be apoptosis-resistant and liver-protective during different types of liver injury. The enhancing modality of HNF6 is a novel therapeutic intervention for liver disease.

KRAS mutations are detected in over one third of lung adenocarcinomas, most frequently in Caucasian and smoker patients. The impact of KRAS mutations on lung adenocarcinoma prognosis is currently subject to debate, as is their impact on the response to chemotherapy and EGFR tyrosine kinase inhibitors. The different methods for KRAS status assessment, based on histological and cytological samples or biological fluids, offer varying sensitivities. Since no treatments are available in clinical routine for KRAS-mutated lung cancer patients, one of the current major challenges in thoracic oncology is developing new dedicated strategic therapies. Different molecules can be developed that act on a post-transcriptional KRAS protein level, blocking its cytoplasmic membrane recruitment. The efficacy of these molecules' targeting of the different signaling pathways activated by the KRAS mutation (such as the MEK and BRAF pathways) is related to the particular KRAS mutation subtype. New therapeutic strategies are currently focused on certain genes linked with KRAS inducing a synthetic lethal interaction. The purpose of this work is to provide an overview of i) the recent epidemiological and molecular findings concerning KRASmutated lung adenocarcinoma, ii) the prognostic impact of KRAS mutations, in particular during response to treatment, iii) the available methods for detecting this mutation, and iv) the current molecules under development for new therapeutic strategies and the clinical trials targeting this genomic alteration.

Human Influenza A virus (IAV), a relatively newer threat to mankind, is becoming invincible due to non availability of proper antiviral drug or effective long lasting vaccine against it. All existing measures to control this virus are overpowered by the phenomena of genetic shift and drift shown by Influenza A virus (IAV). Throughout the world, researchers are exploring the therapeutic potential of antisense technology (AST) to fight against this genetically variable virus. Antisense technology refers to the laboratory manipulation and/or modification of DNA or RNA so that its components (nucleotides) hybridize with target nucleic acid or mRNA or protein itself to inhibit the protein finally encoded. RNA inhibitory (RNAi) mechanism (particularly siRNA) seems to be the most promising among the different agents of AST. However, other agents like oligonucleotides, ribozymes and DNAzymes also show great potential. Decoys and aptamers, alone or in conjunction with other agents, are also being explored to inhibit the replication of virus. Presently, most of these agents have passed initial level of in vitro and in vivo experiments, passing through various levels of clinical trials but none of them has been approved for human purpose till date. Present review consolidates the efforts of researchers worldwide in this particular field and discusses the future perspectives this technology holds, to tame this notorious virus. Day by day, various areas of this technology are being explored and the day is not far when this chemical entity will reach from “bench to bedside”.

Cervical cancer is the second leading gynecological malignancy threat to the health of women in the world. However, few improvements in the efficacy of treatments of cervical cancer have been reported for the recurrent and metastasis patterns. As an endogenous antitumor agent, pigment epithelium derived factor (PEDF) has attracted wide attention, and its sensitivity to estrogen suggests a special role in female tumors, including cervical cancer. This review aims to summarize recent findings, the role of PEDF in cervical cancer treatment, and enhance the current understanding of the antitumor properties of PEDF such as inhibiting angiogenesis and metastasis, inducing tumor cell apoptosis and differentiation, and modulating cellular immunity against cervical cancer. The production and delivery of PEDF, as well as derived short peptides and their respective receptors will also be discussed.

Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disease characterized by the production of a large number of autoantibodies, but the etiology is complex and poorly understood. A range of different platforms have served as screening methods for the determination of autoantibody specificities over the past few decades. Proteomic microarray is a relatively new high-throughput technology which is playing an increasingly important role in autoantibody diagnostics. In this article, we review different platforms for assaying autoantibodies in SLE, and highlight the use of autoantigen arrays as powerful tools for autoantibody exploration in SLE.

Tumor-derived autologous antigenic peptides when bound to endogenous 70 kDa family heat shock proteins (HSP70) are able to induce effective T-cell responses against tumors. However, efficacy of HSPbased vaccines in clinical practical stand point still has a number of certain limitations including an activation of immune responses against alien non-human HSPs. In this study we reconstructed the complexes of human recombinant HSPs70 (human recombinant HSP70A1B and HSC70 mixture; hrHSPs70) with antigenic lowweight peptides derived from mice B16F10 melanoma cell lysate (PepMCL) in vitro and investigated the prophylactic potential of these complexes to activate anti-tumor immunity in melanoma mouse model. Our results demonstrate that the developed prophylactic vaccine elicits melanoma-specific immune responses and anti-tumor effects against melanoma. These results suggest that hrHSPs70 has capability to reconstitute complexes with peptides obtained from tumor cells lysates in vitro and, therefore, can be used for delivery of multiple antigenic peptides into antigen-presenting cells (APCs) to activate effectors cells. Designed in such a way hrHSPs70-based prophylactic vaccines induce immune responses resulting in a significant efficient prevention of tumor growth and metastases.

FOXQ1 is an oncogene for a variety of tumors and encodes the forkhead boxrelated transcription factor FoxQ1. However, little is known about the role of FoxQ1 in pancreatic cancer (PC). In this study, we examined FoxQ1 expression in PC cell lines and human PC tissues by quantitative PCR and tissue microarray based immunohistochemical staining (IHC), and investigated the clinical correlation between FoxQ1 tissue levels and the clinicopathological characteristics of PC patients. We found that FoxQ1 mRNA expression was up-regulated both in PC cell lines and tumor tissues. IHC results revealed that FoxQ1 was mainly expressed in the cytoplasm, and to a lesser extent in the nucleus of PC cells. FoxQ1 protein levels were significantly higher in PC tissues when compared with matched non-cancerous tissues, and associated positively with the degree of tumor differentiation. Univariate and multivariate survival analysis revealed that patients with high FoxQ1 expression and advanced TNM stage had poor prognosis (HR=1.856, 95%CI 1.065- 3.234, P=0.029; HR=2.091, 95%CI 1.181-3.705, P=0.01). These data indicate that FoxQ1 expression is negatively associated with the overall survival of PC patients, and that this protein may therefore represent a novel molecular target and new prognostic biomarker for PC.

The fact that the phosphatidylinositol 3 kinase (PI3K) signaling pathway is one of the most frequently deregulated signaling networks has triggered intensive efforts in the development of PI3K pathway inhibitors. However, recent clinical trial data have shown only limited activity of PI3K inhibitors at tolerated doses. Thus, there is an urgent need to identify rational combination therapy to improve the efficacy of PI3K-targeted cancer treatment. In this study, we investigated if dietary compound ellagic acid (EA) could improve the therapeutic efficacy of PI3K inhibitor GDC-0941 in breast cancer. Specifically, using a panel of breast cancer cell lines, we showed that combined use of EA and GDC-0941 significantly inhibited cell growth under attached and detached conditions, blocked migration and invasion in vitro as well as tumor initiation and metastasis in vivo. Furthermore, we found that EA promoted apoptosis and further reduced AKT/mTOR activation in GDC-0941- treated breast cancer cells. Together, our data suggest that EA may be a safe and effective agent to boost the efficacy of PI3K-directed breast cancer therapy and that such drug combination may merit further clinical investigation.

Studies have shown that TNFR1 is a key factor in the tumor microenvironment that is dependent on the TNF-α-initiated cascade for tumorigenesis. In this present study, we found that TNFR1 is over-expressed in ovarian cancer, which is relevant to both clinical survival and disease free status. Knockdown of TNFR1 dramatically attenuates malignant phenotypes, including proliferation and colony growth in soft agar, as well as glycolysis in ovarian cancer cells. Unexpectedly, knocking down TNFR1 blocks EGF-induced p-AKT and p-p70S6K expression and EGF-induced cell transformation through PIK3-p110beta rather than p110alpha expression. Taken together, our data provide evidence that TNFR1 plays a critical role in ovarian cancer and show that the EGF induced signaling pathway is independent of the TNF-α triggering cascade signal. Therefore, TNFR1 may serve as a prognostic molecule in ovarian cancer.

Epigenetic regulation of long interspersed nucleotide element-1 (LINE-1) retrotransposition events plays crucial roles during early development. Previously we showed that LINE-1 hypomethylation in neuronal tissues is associated with pathogenesis of neural tube defect (NTD). Herein, we further evaluated LINE-1 Homo sapiens (L1Hs) methylation in tissues derived from three germ layers of stillborn NTD fetuses, to define patterns of tissuespecific methylation and site-specific hypomethylation at CpG sites within an L1Hs promoter region. Stable, tissue-specific L1Hs methylation patterns throughout three germ layer lineages of the fetus, placenta, and maternal peripheral blood were observed. Samples from maternal peripheral blood exhibited the highest level of L1Hs methylation (64.95%) and that from placenta showed the lowest (26.82%). Between samples from NTDs and controls, decrease in L1Hs methylation was only significant in NTD-affected brain tissue at 7.35%, especially in females (8.98%). L1Hs hypomethylation in NTDs was also associated with a significant increase in expression level of an L1Hs-encoded transcript in females (r = -0.846, p = 0.004). This could be due to genomic DNA instability and alternation in chromatins accessibility resulted from abnormal L1Hs hypomethylation, as showed in this study with HCT-15 cells treated with methylation inhibitor 5-Aza.