The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Efficacy of the bromodomain 4 (BRD4) inhibitor JQ1 has been reported for the treatment of various human cancers, but its potential impact on EC remains unclear. We therefore aimed to elucidate the function of BRD4 and the effects of JQ1 in EC in vivo and in vitro. METHODS: The mRNA expression of BRD4 was evaluated using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). BRD4 protein expression in EC tissues was measured using immunohistochemistry (IHC) assays. The effects of JQ1 on EC were determined by using MTT and colony formation assays, flow cytometry and xenograft mouse models. The underlying mechanism was also examined by western blot and small interfering RNA (siRNA) transfection. RESULTS: BRD4 was overexpressed in EC tissues, and the level of BRD4 expression was strongly related to poor prognosis. The BRD4-specific inhibitor JQ1 suppressed cell proliferation and colony formation and triggered cell apoptosis, cell cycle arrest, and changes in the expression of proteins in related signaling pathways. Moreover, JQ1 decreased the protein expression of BRD4 and c-Myc, and knockdown of BRD4 or c-Myc reduced the viability of EC cells. Intraperitoneal administration of JQ1 (50 mg/kg) significantly suppressed the tumorigenicity of EC cells in a xenograft mouse model. CONCLUSION: Our results demonstrate that BRD4 is a potential marker of EC and that the BRD4 inhibitor JQ1 is a promising chemotherapeutic agent for the treatment of EC.

Roles of NPAS2 in circadian rhythm and disease.

NPAS2, a circadian rhythm gene encoding the neuronal PAS domain protein 2 (NPAS2), has received widespread attention because of its complex functions in cells and diverse roles in disease progression, especially tumorigenesis. NPAS2 binds with DNA at E-box sequences and forms heterodimers with another circadian protein, brain and muscle ARNT-like protein 1 (BMAL1). Nucleotide variations of the NPAS2 gene have been shown to influence the overall survival and risk of death of cancer patients, and differential expression of NPAS2 has been linked to patient outcomes in breast cancer, lung cancer, non-Hodgkin's lymphoma, and other diseases. Here, we review the latest advances in our understanding of NPAS2 with the aim of drawing attention to its potential clinical applications and prospects.

Development of Nomogram Models Based on Peripheral Blood Score and Clinicopathological Parameters to Predict Preoperative Advanced Stage and Prognosis for Epithelial Ovarian Cancer Patients.

Purpose: Nutritional and inflammatory states are crucial in cancer development. The purpose of this study is to construct a scoring system grounded on peripheral blood parameters associated with nutrition and inflammation and explore its value in stage, overall survival (OS), and progression-free survival (PFS) prediction for epithelial ovarian cancer (EOC) patients. Patients and Methods: Four hundred and fifty-three EOC patients were retrospectively identified and their clinical data and relevant peripheral blood parameters were collected. The ratio of neutrophil to lymphocyte, lymphocyte to monocyte, fibrinogen to lymphocyte, total cholesterol to lymphocyte and albumin level were calculated and dichotomized. A scoring system named peripheral blood score (PBS) was constructed. Univariate and multivariate Logistic or Cox regression analyses were used to select independent factors; these factors were then used to develop nomogram models of advanced stage and OS, PFS, respectively. The internal validation and DCA analysis were performed to evaluate models. Results: Lower PBS indicated a better prognosis and higher PBS indicated inferior. High PBS is associated with advanced stage, high CA125, serous histological type, poor differentiation, and accompanied ascites. The logistic regression showed age, CA125, and PBS were independent factors for the FIGO III-IV stage. The nomogram models for advanced FIGO stage based on these factors showed good efficiency. FIGO stage, residual disease, and PBS were independent factors affecting OS and PFS, the nomogram models composed of these factors had good performance. DCA curves revealed the models augmented net benefits. Conclusion: PBS can be a noninvasive biomarker for EOC patients' prognosis. The related nomogram models could be powerful, cost-effective tools to provide information of advanced stage, OS, and PFS for EOC patients.

Involvement of oxidative stress in the relapse of acute myeloid leukemia.

The aims of the present study were to determine the level of oxidative stress and the salient factors leading to the relapse of acute myeloid leukemia (AML). Oxidative stress-related parameters and the expressions of specific genes were monitored in 102 cases of AML during a pretreatment period from a primary status to a relapse status. In addition, age-matched healthy subjects were classified as controls. The activities of adenosine deaminase and xanthine oxidase were higher in the relapse condition, whereas those of glutathione peroxidase, monoamine oxidase, and superoxide dismutase, and the total antioxidant capacity (T-AOC) were lower in the primary condition and in controls. Of particular note, levels of advanced oxidation protein products, malondialdehyde, and 8-hydroxydeoxyguanosine were also significantly higher in relapse patients. Furthermore, real-time PCR with SYBR Green revealed that the expression levels of human thioredoxin (TRX) and indoleamine 2,3-dioxygenase were increased in relapse patients. Pearson correlation analysis revealed that the T-AOC was positively correlated with GSH but negatively correlated with 8-OHdG, TRX, and indoleamine 2,3-dioxygenase. Linear regression showed that a low T-AOC and up-regulated TRX expression were the independent factors correlated with relapse. A strong association between oxidative stress and the incidence of disease relapse was observed, which has potential prognosis implications. These results indicate that oxidative stress is a crucial feature of AML and probably affects the development and relapse of AML.

Identification of Three Potential Prognostic Genes in Platinum-Resistant Ovarian Cancer via Integrated Bioinformatics Analysis.

PURPOSE: Ovarian cancer is the most lethal gynecologic malignancy. Resistance to platinum-based chemotherapy affects the overall survival of patients. This study used an integrated bioinformatics to find the poorly understood molecular mechanisms underlying platinum resistance in ovarian cancer. METHODS: Based on the RNA-seq data of tissues in The Cancer Genome Atlas (TCGA) and RNA-seq data of cells from the Cancer Cell Encyclopedia (CCLE), we integrated differentially expressed genes (DEGs) in ovarian cancer tissue and cells. After screening for DEGs related to platinum resistance, we conducted survival analysis and built protein interaction networks to identify genes that may affect prognosis and interact with each other. Least absolute shrinkage and selection operator (Lasso) regression analysis was used to construct a predictive model. Immunohistochemistry and Western blot were used to validate the results. Finally, gene set enrichment analysis (GSEA) was performed on the expression of genes individually. RESULTS: We found that ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) interacted with each other and could predict resistance to platinum-based therapy, correlating negatively with prognosis. Moreover, we constructed a predictive model based on nine genes, including ATP1A2 and CASQ2. Immunohistochemistry and Western blot validated the upregulation of these genes in ovarian cancer tissue samples and cell lines. The immunohistochemistry results also confirmed the prognostic value of ATP1A2, CASQ2 and RYR2. GSEA predicted that ATP1A2, CASQ2 and RYR2 may act on the KRAS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells. CONCLUSION: ATP1A2, CASQ2 and RYR2 were highly expressed in platinum-resistant ovarian cancer. ATP1A2 and CASQ2 were related to the prognosis of platinum-resistant ovarian cancer patients. These genes might act on KARS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells.

Jab1/Csn5-Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress.

Purpose: High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway.Experimental Design: We studied ROS levels and conducted c-Jun activation domain-binding protein-1 (JAB1/COPS5) and thioredoxin (TRX) gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1's regulation of Trx in leukemia cell lines.Results: Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels of TRX and JAB1/COPS5 were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth both in vitro and in vivoConclusions: We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5. Clin Cancer Res; 23(15); 4450-61. ©2017 AACR.

[The research on the expression and localization of multiple myeloma associated antigen MMSA-1].

AIM: To study the expression profile of multiple myeloma associated gene (MMSA-1), explore the relationship between its expression level and MM cells' proliferation as well as its celluler localization. METHODS: The mRNA levels of MMSA-1 and DKK1 genes were detected by RT-PCR in patients with MM, leukemia, non-tumor diseases and in the healthy donors, respectively. Then, their correlation was analyzed. The effects of Ibandronate Sodium on the cell cycle and early apoptosis of 8226 cells were analyzed by flow cytometry, and the effect on its protein expression was analyzed by immunohistochemistry. Construct MMSA-1 eukaryotic expression vector pCMV-Myc-MMSA-1, and antibody immunohistochemistry was applied to study the cellular localization of the protein. RESULTS: MMSA-1 gene was expressed in all of the specimens described above, and the mRNA level in MM was much higher than that in the others, just like DKK1 gene. More than that, their expression exhibited a significant positive correlation. Ibandronate Sodium could inhibit cell proliferation by a cell-cycle arrest in S-phase. By reducing cell maturation promoting factor release, it stopped the cell cycle, promoted their early apoptosis and decreased the protein expression of MMSA-1. MMSA-1 protein principally distributed on cell membranes, however, there are a small quantity in cytalplasm. CONCLUSION: These results revealed that MMSA-1 may play a pivotal role in MM proliferation and osteolysis destruction, which lay the foundation for the further study of biological function and immunotherapy based on MMSA-1.

Peptide-based immunotherapy for multiple myeloma: current approaches.

Multiple myeloma (MM) is a clonal B-cell malignancy with many fatal clinical sequelae. Despite extensive therapeutic approaches, cures remain rare exceptions. A recent promising area of investigation is the development of immunotherapeutic approaches that target and eliminate myeloma cells more selectively. Because of its potential to promote the destruction of cancerous cells via cytotoxic T-cell responses, peptide-based immunotherapy is one of these strategies to have attracted considerable attention. Furthermore, many studies were carried out to identify the best epitope peptides, the optimal vaccine formulation and schedule, and the preferable clinical situation for vaccination. Based on these results, various epitope peptides have been identified that may be selectively targeted by host immunity, and various approaches have been used to enhance the immune responses of peptides. This chapter focuses on reviewing previous immunotherapy trials, describing the current strategies for peptide-based immunotherapy, and discussing the achievable prospects in MM.