dehydroxymethylepoxyquinomicin and Stomach-Neoplasms

MicroRNA‑301a (miRNA/miR‑301a) and nuclear factor (NF)‑κB signaling play important roles in tumor invasion, migration and progression. However, the role of miRNA‑301a‑3p in human gastric cancer (GC), and specifically in the activation of NF‑κB signaling, remains unclear. The aim of the present study was to investigate miRNA‑301a‑3p expression in GC progression and the molecular mechanisms as regards the regulation of NF‑κB signaling. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect miRNA‑301a‑3p expression in GC and paired normal tissues. The association between the expression of miRNA‑301a‑3p and patient pathological parameters and the prognosis of GC was statistically analyzed using an in situ hybridization (ISH) assay. An MTS assay and a Transwell assay were performed to evaluate the effects of miRNA‑301a‑3p on the proliferation, invasion and migration of GC cells. RT‑qPCR and western blot analysis were used to analyze the association between miRNA‑301a‑3p and nuclear factor‑κB repressing factor (NKRF) expression and the corresponding downstream NF‑κB signaling molecules. A luciferase assay was used to verify the target effect of miRNA‑301a‑3p and NKRF. It was found that miRNA‑301a‑3p expression was significantly higher in 30 cases of primary GC compared with matched normal tissues. Additionally, the ISH assay indicated that the high expression of miRNA‑301a‑3p in GC was associated with tumor invasion depth, lymph node metastasis, lymph node invasion and tumor metastasis stage. Patients whose tumors had a higher miRNA‑301a‑3p expression level exhibited a poorer prognosis. The in vitro assay indicated that miRNA‑301a‑3p affected the proliferative and invasive ability of GC cells by targeting the expression of NKRF, which then affected NF‑κB signaling. Therefore, it was hypothesize that miRNA‑301a‑3p promotes GC progression and affects the prognosis of patients with GC by targeting NKRF, which in turn, directly influences NF‑κB activation.

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclohexanones; Female; Gastrectomy; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; MicroRNAs; Middle Aged; Neoplasm Invasiveness; NF-kappa B; Prognosis; Repressor Proteins; Signal Transduction; Stomach; Stomach Neoplasms; Up-Regulation

Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-κB) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-κB blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-κB activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (α2, α3, β1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination.

Topics: Animals; Antineoplastic Agents; Benzamides; Cell Adhesion; Cell Line, Tumor; Cell Separation; Cyclohexanones; Flow Cytometry; Humans; Male; Mice; Mice, Nude; Neoplasm Invasiveness; NF-kappa B; Peritoneal Neoplasms; Stomach Neoplasms; Xenograft Model Antitumor Assays