Cyclooxygenase-2 (COX-2) is upregulated in many tumors including neuroblastoma, and its overexpression has been implicated in resistance to p53-dependent apoptosis. Although p53 is rarely mutated in neuroblastoma, the p53 protein is rendered inactive via several mechanisms including sequestration in the cytoplasm. Here, we show that COX inhibitors inhibit the growth of neuroblastoma and when combined with low doses of chemotherapy, exert synergistic effects on neuroblastoma cells. Following COX inhibitor treatment, HDM2, which targets p53 for ubiquitin-mediated degradation, is downregulated, resulting in an attenuation of p53 ubiquitination and an increase in p53 half-life. The level of HDM2 phosphorylation at ser166, which influences both HDM2 and p53 subcellular distribution, is markedly diminished in response to COX inhibitors and is associated with increased p53 nuclear localization. Combining COX inhibitors with low-dose chemotherapy potentiates apoptosis and p53 stability, nuclear localization, and activity. p53 knockdown by siRNA resulted in the rescue of COX-inhibitor-treated cells, indicating that COX inhibitor-induced apoptosis is, at least in part, p53-dependent. Taken together, these results provide the first evidence that COX inhibitors enhance chemosensitivity in neuroblastoma via downregulating HDM2 and augmenting p53 stability and nuclear accumulation.

This study investigates the expression of micro-ribonucleic acid-21 (miRNA-21) and B cell translocation gene 2 (BTG2) in lung cancer cells. We examined the impact of miRNA-21 on biological characteristics of lung cancer cells, such as growth, proliferation, apoptosis, and invasion. The expression of miRNA-21 and BTG2 protein in lung cancer cell lines (A549, HCC827, NCI-H292, and 95-D) was examined using quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. Subsequently, the regulatory role of miRNA-21 on BTG2 was explored by inhibiting miRNA-21 expression in 95-D cells using miRNA-21-antisense oligonucleotides (miRNA-21 ASO). The impact of miRNA-21 on the biological characteristics of 95-D cells was further studied using methylthiazol tetrazolium assays, flow cytometry, and Transwell invasion chamber assays. The impact of miRNA-21 on the expression of cyclin D1, caspase-3, and matrix metalloprotease-9 (MMP9) was also studied. miRNA-21 expression was significantly higher in lung cancer cell lines (A549, HCC827, NCI-H282, and 95-D) than that in normal human bronchial epithelial cells (HBE; p < 0.05). The pattern of BTG2 protein expression was exactly the opposite of miRNA-21 expression in lung cancer cells. BTG2 was highly expressed in HBE cells and was expressed at very low levels in lung cancer cell lines (A549, HCC827, NCI-H292, and 95-D). High miRNA-21 expression may inhibit BTG2 protein expression, whereas the inhibition of miRNA-21 expression may promote BTG2 protein expression in 95-D cells. Cell viability and invasion of 95-D cells were significantly lower in the miRNA-21 ASO-transfected group than that in the control ASO-transfected group and untransfected group (p < 0.05). The number of apoptotic cells was significantly higher in the miRNA-21 ASO-transfected group than that in the control ASO-transfected and untransfected groups (p < 0.05). The expression level of cyclin D1 and MMP9 in 95-D cells was significantly lower in the miRNA-21 ASO-transfected group than in the control ASO-transfected and untransfected groups (p < 0.05). Meanwhile, caspase-3 expression was significantly higher in the miRNA-21 ASO-transfected group than that in the control ASO-transfected and untransfected groups (p < 0.05). miRNA-21 overexpression may inhibit the BTG2 gene in lung cancer cells. miRNA-21 may promote cell proliferation and invasion and inhibit cell apoptosis in 95-D cells.

Research ArticleKaempferol modulates the metastaKaempferol modulates the metastaKaempferol modulates the metastasis of human non sis of human non sis of human non---small cell lung small cell lung small cell lung cancer cells by inhibiting epithelial cancer cells by inhibiting epithelial cancer cells by inhibiting epithelial---mesenchymal transition mesenchymal transition mesenchymal transition BJP IntroductionLung cancer is the most commonly diagnosed cancer type worldwide and a leading cause of cancer-related deaths. It can be categorized into two sub-types: nonsmall cell lung cancer (Koh et al., 2012) and small cell lung cancer. Despite many efforts to improve lung cancer outcome, long-term survival has not improved significantly over the last 20 years, with a 5-year cumulative survival rate that remains very dismal at only 15% (Ghosal et al., 2009). Current standard therapies limited to chemotherapy and radiotherapy or both rarely cure this disease, thus accentuating the need for more effective and alternate therapeutic strategies.Metastasis is a complex, multistep process and involves the invasion of cells from primary tumors into the circulation, migration to distant organs and finally infiltration into tissues referred to as secondary metastatic sites (Gupta and Massagué, 2006). Epithelial-mesenchymal transition (EMT), a developmental program plays an important role in this process and involves downregulation of epithelial markers like E-cadherin and upregulation of mesenchymal markers like vimentin and fibronectin (Borthwick et al., 2009;Kalluri and Neilson, 2003). As a result, the epithelial cells acquire fibroblastlike properties, thus losing their defined cell-cell and cell-extracellular matrix contacts (Thiery et al., 2010). Thus, the EMT becomes a target to prevent tumor progression.Flavonoids are polyphenolic natural compounds present in a wide variety of fruits and vegetables (Bosetti et al., 2007) and in recent years their anti-tumor activities have been widely studied and recognized (Gonzalez and Riboli, 2006). Kaempferol (3,4',5,7-tetrahydroxyflavone), is a natural polyphenol of the flavonoid family and exhibits various biological properties including anti -tumor activities. It induces apoptosis and cell cycle arrest in various cancer cell lines, including lung cancer cells (Nguyen et al., 2003), breast cancer cells (Kang et al., 2010), colon cancer cells (Li et al., 2009), besides inhibiting the migration and invasiveness of glioma cells (Shen et al., 2006). The effect of kaempferol on the growth and invasiveness of lung cancer is not yet determined and the mechanism involved needs to be defined. The present study examined the effects of kaempferol on the metastasis and invasion of A549 non-small cell lung cancer cells. It was found that kaempferol markedly inhibited cell proliferation besides overcoming EMT and cell migration. AbstractThe present study was done to determine whether kaempferol, a natural polyphenol of the flavonoid family, affects Epithelial-Mesenchymal Transition (EMT) in no...

Irinotecan plus capecitabine was a relatively active and tolerable regimen as a second-line chemotherapy for AGC. Further investigation of this regimen is warranted, including the addition of new biological agents such as bevacizumab or cetuximab to improve the salvage regimen.

Hepatocellular carcinoma (HCC) is hardly curable with present treatment modalities, especially for those in advanced disease stage. Several chronic hepatic disorders, including alcoholic liver disease, cirrhotic and viral hepatitis, can ultimately lead to occurrence of HCC. This study investigated the effects of curcumin on natural killer (NK) cell-based immunotherapies being applied to restrain the progress of HCC, and disclose valid message for better clinical application of curcumin. After receiving curcumin treatment, the HCC cells were co-cultured with NK cells to study cytotoxicity of NK cells. After the in vitro cytotoxicity assay, we determined the function of curcumin in modulating the cytotoxicity of NK cells. Additionally, the mechanism of curcumin on HCC cells was investigated by utilizing the following techniques: lentiviral infection/transfection, qPCR and Western-blot, thereby exploring the genetic alterations of differently treated HCC cells. HCC cell lines (SK-Hep1 and SUN423) were studied, and findings confirmed that curcumin significantly strengthened the cytotoxic NK cells to kill HCC cells. This effect was mainly achieved through regulating androgen receptor (AR)/UL162 signal, which led to efficacy enhancement of NK cell-based immunotherapy. Moreover, secretion of interferon-γ which is an immunoregulator executing an anti-tumor effect was also elevated. In addition, curcumin strengthened the expression of ULBP2 in SK-Hep1 and SUN423 cells, while relatively weakening the expression of androgen receptor. The findings from this study can provide a theoretical base for further research and development of curcumin as a beneficial suppressor of HCC progression. We found that the cytotoxicity of NK cells towards HCC cells was gradually elevated as the HCC cells were treated with increased concentration of curcumin. Meanwhile, the secretion of interferon-γ, which was an immunoregulator exerting an anti-tumor effect, was also gradually elevated. In addition, the expression levels of ULBP2 in SK-Hep1 and SUN423 cells were continuously enhanced with increased concentration of curcumin in the pre-treatment of HCC cells, while the expression of androgen receptor was relatively weakened. Similar results were also obtained after the overexpression or knockdown of androgen receptor (AR) gene in SK-Hep1 and SUN423 cells. Therefore, this study found that curcumin can boost the NK cell-based immunotherapy in impeding progression of HCC through the androgen receptor/ULBP2 signal.

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