KIF18B as a regulator in microtubule movement accelerates tumor progression and triggers poor outcome in lung adenocarcinoma.

KIF18B is involved in several tumor progression and exerts critical effects on microtubule growth during mitosis, but its role in lung adenocarcinoma still remains rare. Hence, we attempted to explore the biological function of KIF18B in lung adenocarcinoma. We first analyzed the expressional pattern of KIF18B in lung adenocarcinoma, and detected the correlation between KIF18B expression and clinical characteristics in lung adenocarcinoma based on The Cancer Genome Atlas (TCGA) database and Oncomine dataset. Subsequently, cell counting kit-8 (CCK-8) assay, wound-healing analysis, and transwell method were performed to assess the effects of KIF18B in lung adenocarcinoma cells. Quantitative real-time reverse transcription-PCR (qRT-PCR) and western blotting were utilized to measure the mRNA and protein expression levels. Our results illustrated that KIF18B expression was significantly up-regulated in lung adenocarcinoma samples compared to normal specimens. High levels of KIF18B were associated with unfavorable prognosis of lung adenocarcinoma patients. Down-regulation of KIF18B in lung adenocarcinoma cells inhibited cell prolifartion, migration, and invasion. Western blot assay demonstrated that KIF18B knockdown markedly decreased Rac1-GTP expression, an important marker of migration and invasion in tumors. Moreover, the phosphorylation of AKT and mTOR expression levels were attenuated after KIF18B knockdown. Taken together, these data enhanced the point that KIF18B might promote lung adenocarcinoma cell proliferation, migration, and invasion by activating Rac1 and mediating the AKT/mTOR signaling pathway.

Enhanced antiproliferative activity of antibody-functionalized polymeric nanoparticles for targeted delivery of anti-miR-21 to HER2 positive gastric cancer.

MiR-21 is an oncogenic miR frequently elevated in gastric cancer. Overexpression of miR-21 decreases the sensitivity of gastric cancer cells to trastuzumab, which is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2. However, optimization of miRNA or its anti-miRNA oligonucleotides (AMOs) for delivery is a challenge. Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including AMOs. This study is a continuation of our earlier findings involving poly(ε-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target gastric cancer cells with HER2 receptor over-expression using anti-miRNA-21 antisense oligonucleotides (AMO-21). The antibody conjugates (HER-PEG-PCL NPs) act against target cells via antibody-dependent mechanisms and also based on encapsutalated AMO-21. X-ray photoelectron spectroscopy validated the presence of trastuzumab on NP surface. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a stable antibody expression. The cell line specificity, cellular uptake, AMO-21 delivery, and cytotoxicity of the HER-PEG-PCL NPs were investigated. We found that the antibody conjugates significantly enhanced the cellular uptake of NPs. The HER-PEG-PCL NPs effectively suppressed the target miRNA expression in gastric cancer cells, which further up-regulated phosphatase and tensin homolog (PTEN). As a result, the sensitivity of HER2-expressing gastric cancer cells to trastuzumab was enhanced. The approach enhances the targeting by trastuzumab as well as antibody-dependent cellular cytotoxicity of immune effector cells. The antitumor effects of AMO-21-HER-PEG-PCL NPs were compared with trastuzumab in xenograft gastric cancer mice. The results provide insight into the biological and clinical potential of targeted AMO-21 delivery using modified trastuzumab for gastric cancer treatment.

Efficacy of decitabine-loaded gelatinases-stimuli nanoparticles in overcoming cancer drug resistance is mediated via its enhanced demethylating activity to transcription factor AP-2 epsilon.

Hypermethylation of the transcription factor AP-2 epsilon (TFAP2E) gene affects 5-fluorouridine (5-FU) resistance in gastric cancer (GC) patients. The epigenetic inhibitor 5-Aza-2'-deoxycytidine (DAC), which reverses DNA methylation by targeting DNA methyltransferases (DNMTs), has potential to sensitize GC to 5-FU. Nevertheless, DNA demethylation only DAC transiently occurs since DAC is unstable in aqueous solutions, which limits its potential. Here we developed intelligent nanoparticles (NPs) comprising gelatinase with polyethylene glycol (PEG) and poly-ε-caprolactone) (PCL) to specifically deliver DAC (DAC-TNPs) to tumors. DAC-carrying PEG-PCL NPs (DAC-NPs) lacking gelatinase features served as controls. 72 hours after administration of DAC-TNPs or DAC-NPs, 5-FU was sequentially applied to GC cells and human GC xenografts in nude mice. Both in vitro and in vivo evaluations demonstrated that the combination treatment of DAC-TNPs and 5-FU greatly improved tumor suppression in GC cells and mouse xenograft models with hypermethylation TFAP2E (MKN45 cells). We thus propose that the sequential administration of DAC-TNPs and 5-FU could be significant in the development of novel targeted therapies.

Gelatinases-stimuli nanoparticles encapsulating 5-fluorouridine and 5-aza-2'-deoxycytidine enhance the sensitivity of gastric cancer cells to chemical therapeutics.

Aberrant methylation of the transcription factor AP-2 epsilon (TFAP2E) has been attributed to 5-fluorouridine (5-FU) sensitivity. 5-Aza-2'-deoxycytidine (DAC), an epigenetic drug that inhibits DNA methylation, is able to cause reactive expression of TFAP2E by demethylating activity. This property might be useful in enhancing the sensitivity of cancer cells to 5-FU. However, the effect of DAC is transient because of its instability. Here, we report the use of intelligent gelatinases-stimuli nanoparticles (NPs) to coencapsulate and deliver DAC and 5-FU to gastric cancer (GC) cells. The results showed that NPs encapsulating DAC, 5-FU, or both could be effectively internalized by GC cells. Furthermore, we found that the NPs enhanced the stability of DAC, resulting in improved re-expression of TFAP2E. Thus, the incorporation of DAC into NPs significantly enhanced the sensitivity of GC cells to 5-FU by inhibiting cell growth rate and inducing cell apoptosis. In conclusion, the results of this study clearly demonstrated that the gelatinases-stimuli NPs are an efficient means to simultaneously deliver epigenetic and chemotherapeutic drugs that may effectively inhibit cancer cell proliferation.

Enhancement of radiotherapy efficacy by miR-200c-loaded gelatinase-stimuli PEG-Pep-PCL nanoparticles in gastric cancer cells.

Radiotherapy is the main locoregional control modality for many types of unresectable tumors, including gastric cancer. However, many patients fail radiotherapy due to intrinsic radioresistance of cancer cells, which has been found to be strongly associated with cancer stem cell (CSC)-like properties. In this study, we developed a nanoparticle formulation to deliver miR-200c, which is reported to inhibit CSC-like properties, and then evaluated its potential activity as a radiosensitizer. miR-200c nanoparticles significantly augmented radiosensitivity in three gastric cancer cell lines (sensitization enhancement ratio 1.13-1.25), but only slightly in GES-1 cells (1.06). In addition to radioenhancement, miR-200c nanoparticles reduced the expression of CD44, a putative CSC marker, and the percentage of CD44(+) BGC823 cells. Meanwhile, other CSC-like properties, including invasiveness and resistance to apoptosis, could be suppressed by miR-200c nanoparticles. CSC-associated radioresistance mechanisms, involving reactive oxygen species levels and DNA repair capacity, were also attenuated. We have demonstrated that miR-200c nanoparticles are an effective radiosensitizer in gastric cancer cells and induce little radiosensitization in normal cells, which suggests that they are as a promising candidate for further preclinical and clinical evaluation.

MicroRNA-155 expression has prognostic value in patients with non-small cell lung cancer and digestive system carcinomas.

OBJECTIVE: Published data have shown that microRNAs (miRNAs) could play a potential role as diagnostic and prognostic indicators in cancers. Data for the predictive value of microRNA-155 are inconclusive. The aim of the present analysis was therefore to evaluate the role of miR-155 in prognosis for patients with a variety of carcinomas. METHODS: Relevant studies were identified by searching PubMed and EMBASE. Data were extracted from studies comparing overall survival (OS), recurrence-free survival (RFS) or cancer-specific survival (CSS) in patients with carcinoma with higher miR-155 expression and those with lower levels. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) of miR-155 for clinical outcome were calculated. RESULTS: A total of 15 studies were included. The pooled hazard ratio (HR) for OS of higher miR-155 expression in cancerous tissue was 1.89 (95% CI: 1.20-2.99, P =0.006), which could markedly predict poorer survival in general cancer. For RFS/CSS, elevated miR-155 was also associated with poor prognosis of cancer (HR= 1.50, 95% CI: 1.10-2.05, P = 0.01). On subgroup analysis, the pooled HR for OS in non-small cell lung cancer (NSCLC) was 2.09 (95% CI: 0.68-6.41, P > 0.05), but for RFS/CSS was 1.28 (95% CI: 1.05-1.55, P = 0.015), with statistical significance; the pooled HRs for OS and RFS/CSS in digestive system neoplasms were 3.04 (95% CI: 1.48-6.24, P =0.003) and 2.61 (95% CI: 1.98-3.42, P<0.05), respectively. CONCLUSIONS: The results indicated that the miR-155 expression level plays a prognostic role in patients with cancer, especially NSCLCs and digestive system carcinomas.