miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers.

The TLR7/8/9 Antagonist IMO-8503 Inhibits Cancer-Induced Cachexia.

: Muscle wasting is a feature of the cachexia syndrome, which contributes significantly to the mortality of patients with cancer. We have previously demonstrated that miR-21 is secreted through extracellular vesicles (EV) by lung and pancreatic cancer cells and promotes JNK-dependent cell death through its binding to the TLR7 receptor in murine myoblasts. Here, we evaluate the ability of IMO-8503, a TLR7, 8, and 9 antagonist, to inhibit cancer-induced cachexia.

Circulating Micrornas Predict Survival of Patients with Tumors of Glial Origin.

The World Health Organization has recently introduced molecular prognostic-diagnostic biomarkers in the classification of Central Nervous System (CNS) tumors. In order to characterize subclasses of tumors that cannot find a precise location in the current classification, and, or cannot be tested because of scant material, it is important to find new molecular biomarkers in tissue and, or biological fluid samples. In this study, we identified serum microRNAs that could serve as biomarkers for the diagnosis and prognosis of patients with tumors of glial origin.

miR-130a Deregulates PTEN and Stimulates Tumor Growth.

H-RasV12 oncogene has been shown to promote autophagic cell death. Here, we provide evidence of a contextual role for H-RasV12 in cell death that is varied by its effects on miR-130a. In E1A-immortalized murine embryo fibroblasts, acute expression of H-RasV12 promoted apoptosis, but not autophagic cell death.

Selective targeting of point-mutated KRAS through artificial microRNAs.

Mutated protein-coding genes drive the molecular pathogenesis of many diseases, including cancer. Specifically, mutated KRAS is a documented driver for malignant transformation, occurring early during the pathogenesis of cancers such as lung and pancreatic adenocarcinomas. Therapeutically, the indiscriminate targeting of wild-type and point-mutated transcripts represents an important limitation.

A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy.

Breast cancer is the most common cancer in women worldwide. A new promising anti-cancer therapy involves the use of monoclonal antibodies specific for target tumor-associated antigens (TAAs). A TAA of interest for immunotherapy of Triple Negative Breast Cancer (TNBC) is nucleolin (NCL), a multifunctional protein, selectively expressed on the surface of cancer cells, which regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and drug-resistance.

ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5.

MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497.

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation.

Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12-dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn-sufficient wild-type and Fhit (human or mouse protein) knockout mice.

A Fhit-mimetic peptide suppresses annexin A4-mediated chemoresistance to paclitaxel in lung cancer cells.

We recently reported that Fhit is in a molecular complex with annexin A4 (ANXA4); following to their binding, Fhit delocalizes ANXA4 from plasma membrane to cytosol in paclitaxel-resistant lung cancer cells, thus restoring their chemosensitivity to the drug. Here, we demonstrate that Fhit physically interacts with A4 through its N-terminus; molecular dynamics simulations were performed on a 3D Fhit model to rationalize its mechanism of action. This approach allowed for the identification of the QHLIKPS heptapeptide (position 7 to 13 of the wild-type Fhit protein) as the smallest Fhit sequence still able to preserve its ability to bind ANXA4.

HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide.

Multiple myeloma (MM) is a hematological malignancy of plasma cells in the bone marrow. Despite multiple treatment options, MM is inevitably associated with drug resistance and poor outcomes. Histone deacetylase inhibitors (HDACi's) are promising novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with MM.

A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies.

Central Nervous System malignancies often require stereotactic biopsy or biopsy for differential diagnosis, and for tumor staging and grading. Furthermore, stereotactic biopsy can be non-diagnostic or underestimate grading. Hence, there is a compelling need of new diagnostic biomarkers to avoid such invasive procedures.

Human anti-nucleolin recombinant immunoagent for cancer therapy.

Nucleolin (NCL) is a nucleocytoplasmic protein involved in many biological processes, such as ribosomal assembly, rRNA processing, and mRNA stabilization. NCL also regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and aggressiveness. Interestingly, NCL is expressed on the surface of actively proliferating cancer cells, but not on their normal counterparts.

The long journey of TCL1 transgenic mice: lessons learned in the last 15 years.

The first transgenic mouse of the TCL1 oncogene was described more than 15 years ago, and since then, the overexpression of the gene in T- and B-cells in vivo has been extensively studied to reveal the molecular details in the pathogenesis of some lymphocytic leukemias. This review discusses the main features of the original TCL1 models and the different lines of research successively developed with particular attention to genetically compound mice and the therapeutic applications in drug development.

Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.

Background: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.

Methods: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296).

MicroRNA profiles discriminate among colon cancer metastasis.

MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC).

Fhit delocalizes annexin a4 from plasma membrane to cytosol and sensitizes lung cancer cells to paclitaxel.

Fhit protein is lost or reduced in a large fraction of human tumors, and its restoration triggers apoptosis and suppresses tumor formation or progression in preclinical models. Here, we describe the identification of candidate Fhit-interacting proteins with cytosolic and plasma membrane localization. Among these, Annexin 4 (ANXA4) was validated by co-immunoprecipitation and confocal microscopy as a partner of this novel Fhit protein complex.

Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARβ and tumor regression.

Toll-like receptor 3 (TLR3) is a key effector of the innate immune system against viruses. Activation of TLR3 exerts an antitumoral effect through a mechanism of action still poorly understood. Here we show that TLR3 activation by polyinosinic:polycytidylic acid induces up-regulation of microRNA-29b, -29c, -148b, and -152 in tumor-derived cell lines and primary tumors.

Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas.

T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated.

MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response.

MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs.

Novel insights in molecular mechanisms of CLL.

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia, originates from an expansion of a rare population of CD5+CD19+ mature B-cells. CLL occurs in two forms, aggressive and indolent. For the most part aggressive CLL shows high ZAP-70 expression and unmutated IgH V(H), while indolent CLL is characterized by low ZAP-70 expression and mutated IgH V(H).

Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies.

The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia.