Long noncoding RNA CBR3-AS1 mediates tumorigenesis and radiosensitivity of non-small cell lung cancer through redox and DNA repair by CBR3-AS1 /miR-409-3p/SOD1 axis.

The long noncoding RNA CBR3-AS1 has important functions in various cancers. However, the biological functions of CBR3-AS1 in non-small cell lung cancer (NSCLC) remain unclear. This study aimed to investigate the roles and molecular mechanisms of CBR3-AS1 in NSCLC tumorigenesis and radiosensitivity. Here, we demonstrate CBR3-AS1 overexpression in NSCLC tissue compared with adjacent normal tissue. CBR3-AS1 downregulation reduced proliferation, invasion, and migration; inhibited cell cycle progression; and promoted apoptosis of NSCLC cells. CBR3-AS1 also promoted tumor growth in vivo. CBR3-AS1 may regulate the expression and functions of the miR-409-3p target gene SOD1. CBR3-AS1 expression was negatively correlated with radiosensitivity. CBR3-AS1 downregulation decreased post-irradiation SOD1 expression, increased γH2AX formation, raised levels of reactive oxygen species, and promoted apoptosis. Our results suggest that CBR3-AS1 functions as an oncogene through the CBR3-AS1/miR-409-3p/SOD1 pathway, and may represent a new therapeutic target, especially to regulate radiosensitivity in NSCLC.

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop.

Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.

Effect of receptor for hyaluronan-mediated motility inhibition on radiosensitivity of lung adenocarcinoma A549 cells.

BACKGROUND: Receptor for hyaluronan-mediated motility (RHAMM), one of the major hyaluronic acid (HA) receptors, is upregulated in several forms of cancer and is a poor prognostic factor for non-small cell lung cancer (NSCLC) adenocarcinoma. RHAMM is also a potential therapeutic target for inhibition of tumor metastasis in NSCLC. However, its role in the radiosensitivity of NSCLC has yet to be determined. The aim of this study was to examine the inhibitory effect of RHAMM on the radiosensitivity of lung adenocarcinoma cell line A549 and its potential mechanism. METHODS: Expression of the RHAMM gene in NSCLC cell lines A549 and H460 was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Colony formation assays were used to analyze radiosensitivity of the two cell lines. Transfection with small interfering (si) RNA was used to inhibit expression of the RHAMM gene in the A549 cell line. A cell counting kit assay was used to analyze the cell proliferation rate; flow cytometry was used to evaluate the cell apoptosis and cell cycle; and Western blot was used to investigate the expression of phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and ERK1/2 proteins. RESULTS: Expression of the RHAMM gene was negatively correlated with the radiosensitivity of NSCLC cell lines; inhibition of RHAMM gene expression enhanced the radiosensitivity of A549 cells. The mechanism for this inhibition was associated with reduced proliferation, increased apoptosis induced by radiotherapy, reduced ERK1/2 phosphorylation, and regulation of the ERK1/2 signaling pathway. Inhibition was not associated with increased G2/M phase arrest. CONCLUSIONS: RHAMM is a potential target for radiosensitization of lung adenocarcinomas.

MicroRNA-198 inhibition of HGF/c-MET signaling pathway overcomes resistance to radiotherapy and induces apoptosis in human non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the most common cause of death from cancer worldwide. MicroRNAs (miRNAs) are a group of important regulators in NSCLC, including miR-198. However, the underlying molecular mechanisms of miR-198 involvement in intrinsic resistance to radiotherapy in NSCLC remain to be elucidated. In this study, to investigate the clinical significance of miR-198 in NSCLC in relation to the response to radiotherapy, we determined the expression patterns of miR-198 between responders and nonresponders after 2 months of radiotherapy and found that decreased expressions of miR-198 were associated with radiotherapy resistance. In addition, we altered the endogenous miR-198 using mimics or inhibitors to examine the effects of miR-198 on 4-Gy-irradiated A549 and SPCA-1 cells in vitro. Upregulating miR-198 was shown to inhibit cell proliferation, migration, and invasion and induce apoptosis. MiR-198 inhibition produced a reciprocal result. PHA665752, a selective small-molecule c-Met inhibitor, potently inhibited hepatocyte growth factor (HGF)-stimulated and constitutive c-Met phosphorylation and rescued 4-Gy-irradiated A549 and SPCA-1 cells from miR-198 inhibition. Most importantly, we established tumor xenografts of 4-Gy-irradiated A549 and SPCA-1 cells in nude mice and found that miR-198 could suppress tumor formation. Hence, our data delineates the molecular pathway by which miR-198 inhibits NSCLC cellular proliferation and induces apoptosis following radiotherapy, providing a novel target aimed at improving the radiotherapeutic response in NSCLC.

Spatio-temporal distribution of meiofaunal assemblages and its relationship with environmental factors in a semi-enclosed bay.

In order to reveal the spatio-temporal distribution of meiofaunal assemblages and its relationship with environmental factors in semi-enclosed bay habitats, meiofaunal and sediment samples were collected in February (winter), May (spring), August (summer) and November (autumn) 2014 in Jiaozhou Bay, China. A total of 20 meiofaunal taxa were identified. The most dominant group was free-living marine nematode, followed by benthic copepod. During the four sampling seasons, the values of meiofaunal average abundance were (912.3 ±â€¯603.1), (1576.4 ±â€¯659.5), (1074.6 ±â€¯417.6), (2152.4 ±â€¯1062.3) ind./10 cm2 while those of biomass were (575.0 ±â€¯398.5), (874.3 ±â€¯518.4), (617.9 ±â€¯337.8), (1203.6 ±â€¯719.6) µg dwt/10 cm2, respectively. In terms of vertical distribution, meiofauna were mainly found in the (0-2) cm sediment layer (59.92%), followed by (2-5) cm layer (28.25%) and (5-8) cm layer (11.82%). Results of correlation analysis showed that bottom water temperature was the main factor influencing meiofaunal distribution and food source (sediment organic matter content) was the main factor influencing meiofaunal assemblages.

Assessing benthic ecological impacts of bottom aquaculture using macrofaunal assemblages.

Bottom aquaculture of bivalves is a high-yield culture method, which is increasingly adopted by shellfish farmers worldwide. However, the effects of bottom aquaculture on benthic ecosystems are not well-known. Manila clam (Ruditapes philippinarum), is a widely distributed bottom aquaculture mollusk species. To assess the ecological impacts of Manila clam bottom aquaculture, clams and other macrofaunal assemblages were investigated during four cruises (July and November 2011, February and May 2012) at six sampling sites in Jiaozhou Bay, China. Correlation analysis showed that macrofaunal assemblages had significant negative correlations with the abundance of Manila clams. However, according to the results of several biotic indices, a low disturbance was detected by Manila clam bottom aquaculture. In conclusion, AMBI (AZTI'S Marine Biotic Index) and M-AMBI (Multivariate AZTI Marine Biotic Index) indices are more suitable for assessing ecological quality than polychaete/amphipod ratios when the disturbance is slight, such as at a bivalve bottom aquaculture.

Sensitization of Radiation or Gemcitabine-Based Chemoradiation Therapeutic Effect by Nimotuzumab in Pancreatic Cancer Cells.

This study was performed to observe the effect of the combination of nimotuzumab with radiation or gemcitabine-based chemoradiation on antipancreatic cancer cell therapy. Pancreatic cancer cells (PANC-1) were treated with nimotuzumab alone or combined with radiation (2, 4, or 8 Gy), which was either with or without gemcitabine chemotherapy. Cell proliferation, cell cycle distribution, and apoptosis were observed. The inhibition rate, the percentage of G2/M phase arrest, and the apoptosis rate of the combined nimotuzumab with radiation group was significantly higher than the group without nimotuzumab (P < .001). The inhibition rate, the percentage of G2/M phase, and the apoptosis rate of the nimotuzumab therapy combined with gemcitabine-based chemoradiation group were obviously higher than that in gemcitabine-based chemoradiation group (P < .001). In conclusion, nimotuzumab could enhance the anticancer effect of radiation and gemcitabine-based chemoradiation in PANC-1 cancer cells because of the enhancement of cell cycle arrest and apoptosis.

Sensitisation of human lung adenocarcinoma A549 cells to radiotherapy by Nimotuzumab is associated with enhanced apoptosis and cell cycle arrest in the G2/M phase.

The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and maintenance of cancers, making it a possible therapeutic target for cancer treatment. Nimotuzumab (h-R3), a humanised monoclonal antibody against EGFR, sensitises human lung adenocarcinoma A549 cells to radiotherapy. We have investigated the underlying molecular mechanism by treating A549 cells with Nimotuzumab (100 µg/mL) alone or in combination with a single dose of 2 Gy irradiation, and analysing apoptosis and cell cycle distribution by flow cytometry. Nimotuzumab significantly enhanced radiation-induced apoptosis of A549 cells as evidenced by increased cell apoptosis (7.15 ± 0.30%) compared with the control group (1.08 ± 0.25%), Nimotuzumab alone group (4.89 ± 0.30%) and irradiation alone group (5.90 ± 0.15%). Combining Nimotuzumab with irradiation significantly arrested cells in the G2/M phase (43. ± 0.36%) compared radiotherapy alone (18.7 ± 0.35%) and single Nimotuzumab treatment (27.2 ± 0.17%). A combination of Nimotuzumab with radiation increased apoptosis and G2/M phase arrest in human lung adenocarcinoma A549 cells, suggesting potential development of combinatorial therapy of Nimotuzumab with radiotherapy for lung cancer.