Mammaglobin 1 mediates progression of trastuzumab-resistant breast cancer cells through regulation of cyclins and NF-κB.

Overexpression of human epidermal growth factor receptor 2 (HER2) in various cancers is correlated with poor patient survival. Trastuzumab, a recombinant humanized monoclonal antibody against HER2, has been considered to be a first-line therapy for HER2-positive breast cancer patients, but its usefulness is limited by the development of resistance. In this study, we established resistant cells by long-term treatment with trastuzumab.

Adenovirus infection controls processing bodies to stabilize AU-rich element-containing mRNA.

In the adenovirus-infected cells, virus mRNAs are selectively exported to the cytoplasm by virus early gene products to facilitate virus replication. We previously showed AU-rich elements (AREs) containing mRNAs are exported to the cytoplasm and stabilized in infected cells. Here, we analyzed ribonucleoprotein (RNP) granules in the cytoplasm that are involved in mRNA degradation to elucidate the mechanism of ARE-mRNA stabilization in adenovirus infected cells.

Advantages of Using Paclitaxel in Combination with Oncolytic Adenovirus Utilizing RNA Destabilization Mechanism.

Oncolytic virotherapy is a novel approach to cancer therapy. Ad-ARE is a conditionally replicative adenovirus engineered by inserting AU-rich elements (ARE) in the 3'-untranslated region of the E1A gene. In this study, we examined the oncolytic activity of Ad-ARE and used it in a synergistic combination with the chemotherapeutic agent paclitaxel (PTX) for treating cancer cells.

Conditionally Replicative Adenovirus Controlled by the Stabilization System of AU-Rich Elements Containing mRNA.

AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNAs, including those of genes required for cell growth and proliferation. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the stabilization of ARE-mRNA. The level of HuR in the cytoplasm is up-regulated in most cancer cells, resulting in the stabilization of ARE-mRNA.

The neural ELAVL protein HuB enhances endogenous proto-oncogene activation.

The cytoplasmic distribution of the HuR/ELAVL1 (embryonic lethal abnormal vision 1) protein is recognized as an important prognostic factor of malignant tumors. However, the previous study suggests that exogenous over-expression of HuR is not sufficient for nuclear export. Conversely, the predominantly cytosolic distribution of neuron-specific human ELAV members, including HuB/ELAVL2, HuC/ELAVL3, and HuD/ELAVL4, has been reported.

Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells.

AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNA. The fate of ARE-mRNA is controlled by ARE-binding proteins. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the export and stabilization of ARE-mRNA.

Adenovirus infection induces HuR relocalization to facilitate virus replication.

HuR is an RNA-binding protein of the embryonic lethal abnormal vision (ELAV) family, which binds to the AU-rich element (ARE) in the 3'-untranslated region (UTR) of certain mRNAs and is involved in the nucleo-cytoplasmic export and stabilization of ARE-mRNAs. The cytoplasmic relocalization of ARE-mRNAs with several proteins such as HuR and pp32 increases in cells transformed by the adenovirus oncogene product E4orf6. Additionally, these ARE-mRNAs were stabilized and acquired the potential to transform cells.

Role of ATF5 in the invasive potential of diverse human cancer cell lines.

Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element-binding protein family. Our research group recently revealed that ATF5 expression increases the invasiveness of human lung carcinoma cells. However, the effects of ATF5 on the invasive potential of other cancer cells lines remain unclear.

Involvement of UTR-dependent gene expression in the maintenance of cancer stem cell like phenotypes.

The present study demonstrated the acquisition of additional malignant characteristics in irradiated mouse fibrosarcoma cells compared with the parent cells. Several reporter assays indicated that hypoxia-inducible factor (HIF)-1α, activator protein-1 and Ets-dependent transcription were activated in irradiated cells. The -elements in the 5'-untranslated region (UTR) of these transcription factors plays a major role in their expression in surviving irradiated cancer cells.

Activating transcription factor 5 enhances radioresistance and malignancy in cancer cells.

Radiotherapy is effective for treating various types of tumors. However, some cancer cells survive after irradiation and repopulate tumors with highly malignant phenotypes that correlate with poor prognosis. It is not known how cancer cells survive and generate malignant tumors after irradiation.

Cell type-specific reciprocal regulation of HIF1A gene expression is dependent on 5'- and 3'-UTRs.

In the present study, we demonstrated the reciprocal regulation of hypoxia-inducible factor 1 alpha (HIF1A) gene expression via untranslated region-(UTR) dependent mechanisms. A 151 nucleotide sequence found in the HIF1A 5'-UTR is sufficient for significant translational up-regulation. On the other hand, the 3'-UTR of HIF1A has been implicated in mRNA degradation.

Substrate stiffness regulates temporary NF-κB activation via actomyosin contractions.

Physical properties of the extracellular matrix (ECM) can control cellular phenotypes via mechanotransduction, which is the process of translation of mechanical stresses into biochemical signals. While current research is clarifying the relationship between mechanotransduction and cytoskeleton or adhesion complexes, the contribution of transcription factors to mechanotransduction is not well understood. The results of this study revealed that the transcription factor NF-κB, a major regulator for immunoreaction and cancer progression, is responsive to substrate stiffness.

Lung cancer cells that survive ionizing radiation show increased integrin α2β1- and EGFR-dependent invasiveness.

Ionizing radiation (IR)-enhanced tumor invasiveness is emerging as a contributor to the limited benefit of radiotherapy; however, its mechanism is still unclear. We previously showed that subcloned lung adenocarcinoma A549 cells (P cells), which survived 10 Gy IR (IR cells), acquired high invasiveness in vitro. Here, we tried to identify the mechanism by which IR cells increase their invasiveness by examining altered gene expression and signaling pathways in IR cells compared with those in P cells.

Irradiation-tolerant lung cancer cells acquire invasive ability dependent on dephosphorylation of the myosin regulatory light chain.

Radiotherapy is one of the major treatment modalities for malignancies. However, cells surviving irradiation often display high levels of invasiveness. This study shows that irradiation-tolerant lung adenocarcinoma demonstrates high invasive capability depending on dephosphorylation of the myosin regulatory light chain (MRLC).

High prevalence of multiple human papillomavirus infection in Japanese patients with invasive uterine cervical cancer.

Objective: Multiple human papillomavirus (HPV) infection of the uterine cervix has been suggested as a risk factor for persistent HPV infection, resulting in the development of invasive cervical cancer. The aim of this study was to reveal the actual state of multiple HPV infection in Japanese patients with invasive cervical cancer.

Methods: Sixty fresh-frozen invasive cervical cancer tissues were examined for genotyping of HPV.

Radiation-induced cancer cell repopulation: a possible mechanism implied by experiments using transplantable mouse-derived sarcoma cell line.

Purpose: Treatment with any cytotoxic agent can trigger surviving cells in a tumor to divide faster than before. This phenomenon is widely recognized as "repopulation". To better clarify the mechanism, gene expression profiling and pathological experiments were performed.

Integrin beta1-dependent invasive migration of irradiation-tolerant human lung adenocarcinoma cells in 3D collagen matrix.

Radiotherapy is one of the effective therapies used for treating various malignant tumors. However, the emergence of tolerant cells after irradiation remains problematic due to their high metastatic ability, sometimes indicative of poor prognosis. In this study, we showed that subcloned human lung adenocarcinoma cells (A549P-3) that are irradiation-tolerant indicate high invasive activity in vitro, and exhibit an integrin beta1 activity-dependent migratory pattern.

Increased motility and invasiveness in tumor cells that survive 10 Gy irradiation.

Radiotherapy is an important noninvasive treatment for many types of cancer. However, it has been reported that the proliferative, invasive, and metastatic capacities of tumor cells can be increased in the repopulated tumors that survive radiotherapy. We have previously established a radiation-surviving cell model for the human non-small cell lung cancer cell line H1299 by harvesting relic cells 14 days after irradiation (IR cells).

Value of fluorodeoxyglucose positron emission tomography before radiotherapy for head and neck cancer: does the standardized uptake value predict treatment outcome?

Purpose: The aim of this study was to determine if the standardized uptake value (SUV) of fluorodeoxyglucose positron emission tomography (FDG-PET) for head and neck cancer can predict the outcome of radiotherapy and if the SUV is correlated with histological grade, mitosis, and apoptosis.

Materials And Methods: The study included 45 head and neck cancer patients who underwent FDG-PET scanning before radiotherapy. The maximum SUV (SUVmax) of their primary lesions were measured.

Novel function of transcription factor ATF5: blockade of p53-dependent apoptosis induced by ionizing irradiation.

Purpose: To find a new molecule that affects p53-dependent radiosensitivity.

Methods And Materials: A mouse sarcoma cell line, QRsP(p53+/+), was used. From this cell line, we established a radiosensitive clone and a radioresistant one.

Resveratrol modulates phagocytosis of bacteria through an NF-kappaB-dependent gene program.

Many studies have shown that the pharmacological effects of resveratrol, a phytoalexin polyphenolic compound, include protective effects against cancer and inflammation as well as enhancement of stress resistance. In this study, we examined whether resveratrol affected the phagocytosis of bacteria by macrophages and the activation of the transcription factor NF-kappaB after stimulation with or without the ligand FSL-1 for Toll-like receptor 2 (TLR2). Phagocytosis of Escherichia coli and of Staphylococcus aureus by THP-1 cells and RAW264.

The diacylated lipopeptide FSL-1 enhances phagocytosis of bacteria by macrophages through a Toll-like receptor 2-mediated signalling pathway.

A significant amount of evidence has been accumulated to show that Toll-like receptors (TLRs) function as sensors for microbial invasion. However, little is known about how signalling triggered by TLRs leads to the phagocytosis of pathogens. This study was designed to determine whether stimulation of TLR2 mainly with the lipopeptide FSL-1 plays a role in the phagocytosis of pathogens by macrophages.

The diacylated lipopeptide FSL-1 induces TLR2-mediated Th2 responses.

The diacylated lipopeptide FSL-1 enhanced the generation of IgG antibodies in TLR2(+/+) mice, but not in TLR2(-/-) mice, when administered together with hen egg lysozyme as an antigen. Escherichia coli lipopolysaccharide enhanced the generation of antigen-specific antibodies in both TLR2(-/-) and TLR2(+/+) mice. In TLR2(+/+) mice, the level of enhancement due to FSL-1 was similar to that caused by lipopolysaccharide.