Celastrol induces cell cycle arrest by MicroRNA-21-mTOR-mediated inhibition p27 protein degradation in gastric cancer.

OBJECTIVE: Celastrol has anti-cancer effects by increase of apoptosis of gastric cancer cells. However, its role in gastric cancer cell cycle is still unclear. The aim of this study was to investigate the effect and mechanism of celastrol on gastric cancer cell cycle. METHODS: The effects of celastrol on cell cycle in BGC-823 and MGC-803 cells were assayed via flow cytometry analysis. The expression of p27 and mTOR was detected by real-time PCR and western blot. The activity of mTOR and mTORC2 was measured by mTOR and mTORC2 kinase assays. miR-21 mimic was used to up-regulate miR-21 expression and mTOR expression plasmid was used to increase mTOR level in gastric cancer cells. RESULTS: Celastrol caused G2/M cell-cycle arrest that was accompanied by the down-regulation of miR-21 expression. In particular, miR-21 overexpression reversed cell cycle arrest effects of celastrol. Further study showed that celastrol increased levels of the p27 protein by inhibiting its degradation. miR-21 and mTOR signaling pathway was involved in the increase of p27 protein expression in BGC-823 and MGC-803 cells treated with celastrol. Significantly, miR-21 overexpression restored the decrease of mTOR activity in cells exposed celastrol. CONCLUSIONS: The effect of celastrol on cell cycle arrest of gastric cancer cells was due to an increase of p27 protein level via inhibiting miR-21-mTOR signaling pathway.

Hypertriglyceridemia and hyperglycemia induced by capecitabine: a report of two cases and review of the literature.

BACKGROUND: Capecitabine is a tumor-activated oral fluoropyrimidine used in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature. METHODS: Two patients with colorectal carcinoma who developed capecitabine-induced hypertriglyceridemia (including a patient who developed hyperglycemia concurrently) were described, treatment modalities were discussed, and the literatures were reviewed. RESULTS: The first patient, a 43-year-old man, developed hyperlipidemia and hyperglycemia after two cycles of XELOX regimen chemotherapy for colorectal cancer. His triglyceride was 2.47 mmol/L (normal range 0.34-1.7 mmol/L) and total cholesterol was 6.93 mmol/L (normal range 3.12-5.9 mmol/L), while blood glucose was abnormal (fasting blood glucose was 10.58-11.9 mmol/L and 2 h postprandial glucose was 14.5-17.2 mmol/L) and glucose was positive in the urine(3+). The second patient, a 47-year-old woman, developed abnormalities in the lipid profile after the sixth cycle of XELOX regimen chemotherapy for colorectal cancer. Her serum triglyceride was 2.41 mmol/L (normal range 0.34-1.7 mmol/L), while the cholesterol level was 7.73 mmol/L (normal range 3.12-5.9 mmol/L). The profile of lipid improved gradually with reduced doses of capecitabine and was well restored after chemotherapy without any lipid-lowering agents. The Naranjo score for capecitabine-induced hypertriglyceridemia was 9 (definite). An analysis of the underlying pathogenic mechanisms was provided. CONCLUSION: It is important of physicians and pharmacists to be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia induced by capecitabine.

VEGF +405G/C (rs2010963) polymorphisms and digestive system cancer risk: a meta-analysis.

Vascular endothelial growth factor (VEGF) polymorphisms, specifically +405G/C (rs2010963), reportedly influence the risk for various digestive cancers. However, the consequences of these polymorphisms remain controversial and ambiguous. Therefore, we performed a meta-analysis of 11 studies with VEGF +405G/C genotyping on 2,862 patients and 3,028 controls using the random effects model. We obtained a pooled odds ratio (OR) of 1.04 (95% confidence interval (CI) = 0.86-1.26) for the recessive genetic model, 1.07 (95% CI = 0.81-1.42) for the dominant genetic model, 1.09 (95% CI = 0.81-1.47) for the homozygote comparison, and 1.03 (95% CI = 0.83-1.27) for the heterozygote comparison. In the subgroup analysis of the recessive model, the OR was 1.20 (95% CI = 1.02-1.40) in colorectal cancer. These results show that VEGF +405G/C polymorphisms are unlikely to be a major determinant of susceptibility to digestive cancer. Furthermore, the subgroup analysis of recessive model indicates that VEGF +405G/C polymorphisms increase the risk for colorectal cancer.

Artesunate exerts an anti-immunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expression.

Artesunate (ART), derived from a common traditional Chinese medicine, has beeen used an antimalarial for several years. In this study, the effect and mechanism of ART on anti-human cervical cancer cells was examined. The level of prostaglandin E2 (PGE2 ) and the population of CD4+CD25+Foxp3 regulatory T cells (Treg) in peripheral blood were detected by flow cytometry. In vivo antitumor activity was investigated in mice with cervical cancer by the subcutaneous injection of various concentrations of ART. The concentrations of PGE2 in the supernatants of CaSki cells were measured using an ELISA kit. Cyclooxygenase-2 (COX-2) and Foxp3 expression were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The effect of ART on the viability of CaSki and Hela cells was evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It was identified that the level of PGE2 and the population of CD4+CD25+Foxp3 Treg cells in the peripheral blood were significantly higher in cervical cancer patients and mice with cervical cancer. ART was capable of inhibiting orthotopic tumor growth, which correlated with a decrease in the level of PGE2 and the percentage of Treg cells in mice with cervical cancer. Furthermore, ART decreased COX-2 expression and the production of PGE2 in CaSki and Hela cells. Notably, the supernatants of CaSki cells treated with ART lowered the expression of Foxp3 in Jurkat T cells, which was capable of being reversed by exogenous PGE2 . Our data revealed that ART may elicit an anti-tumor effect against cervical cancer by inhibition of PGE2 production in CaSki and Hela cells, which resulted in the decrease of Foxp3 expression in T cells. Therefore, ART may be an effective drug for immunotherapy of cervical cancer.

Celastrol induces apoptosis of gastric cancer cells by miR-21 inhibiting PI3K/Akt-NF-κB signaling pathway.

OBJECTIVE: Celastrol, a plant triterpene, has anticancer effects by increase of apoptosis. In the present study, the mechanism of celastrol on gastric cancer cell apoptosis was examined. METHODS: The effect of celastrol on PI3K/Akt and the NF-κB signaling pathway was evaluated with Western blot and luciferase reporter assay. miR-21 expression was determined using real-time PCR. miR-21 inhibitor and miR-21 mimic were used to downregulate and upregulate miR-21 expression, respectively. RESULTS: It was identified that celastrol was capable of inducing apoptosis of gastric cancer cells, which was mediated via inhibiting the activation of PI3K/Akt and NF-κB. A strong activator of Akt, IGF-1 restored NF-κB activity in cells treated with celastrol. Celastrol could also significantly suppress miR-21 expression. Furthermore, miR-21 inhibitor could decrease phospho-Akt expression and NF-κB activity. Notably, upregulation of miR-21 expression can increase PI3K/Akt and NF-κB activity and decrease apoptosis of gastric cancer cells treated with celastrol, which could be reversed by PI3K inhibitor. CONCLUSIONS: Our data revealed that the effect of celastrol on apoptosis was due to miR-21 inhibiting the PI3K/Akt-dependent NF-κB pathway.

The effect of CD33 expression on inflammatory response in chronic obstructive pulmonary disease.

OBJECTIVE: In this article, the effects of CD33 expression from peripheral blood granulocytes and monocytes on inflammatory response in chronic obstructive pulmonary disease (COPD) were examined. METHODS: CD33 and CD64 expression on peripheral blood granulocytes and monocytes from patients with acute exacerbation of chronic obstructive pulmonary disease and healthy control were detected by flow cytometry. To evaluate the effect of CD33 on inflammation immunity in COPD, the correlation between CD33 expression and CD64 expression, as well as inflammatory indices were investigated. RESULTS: We found that the expression of CD64 on granulocytes and monocytes, as well as the levels of C-reacting protein (CRP) and myoglobin (MYO) or the proportion of neutrophils (N%) significantly increased in COPD patients compared to normal control group (p < 0.01). The expression of CD33 on granulocytes was significantly and negatively correlated with the level of CRP (r = -0.311, p = 0.012), as well as to the level of MYO (r = -0.295. p = 0.018). CONCLUSIONS: The granulocytes and monocytes in peripheral blood were activated in patients of acute exacerbation in COPD. CD33 on granulocytes had the potential to inhibit inflammation and prevent tissue damage.

Changes in the proportions of CD4(+)T cell subsets defined by CD127 and CD25 expression during HBV infection.

CD4(+)T cell counts are closely related to the progression of HBV infection. Here, we investigated how the proportions of three CD4(+)T cell subsets - CD127(-)CD25(-), CD127(+)CD25(low/-) and CD127(low)CD25(high) - changed during HBV infection, as is little known. Compared with healthy controls, the proportions of CD127(-)CD25(-) in chronic hepatitis B (CHB) patients and HBV carriers significantly increased, while that of CD127(+)CD25(low/-) significantly decreased. The proportion of CD127(low)CD25(high) in CHB patients was significantly higher than those in HBV carriers or healthy controls. Compared with HBV-DNA negative group, the proportion of CD127(-)CD25(-) in positive group significantly decreased and that of CD127(+)CD25(low/-) significantly increased. In the follow-up study for CHB patients treated with interferon-α2b for 12 weeks or 24 weeks, the proportions of CD127(-)CD25(-) significantly decreased, while that of CD127(low/-)CD25(high) significantly increased. The results suggested that specific changes in the fraction of CD4(+)T cell subsets expressing CD127 and/or CD25 were associated with hepatitis B progression.

Elevation of platelet count in patients with colorectal cancer predicts tendency to metastases and poor prognosis.

BACKGROUNDS/AIMS: Thrombocytosis had been found to be associated with tumor metastasis and poor prognosis in malignant tumors including colorectal cancer (CRC). In the present study, we investigated the relationship between the platelet and the biological features in patients with CRC in China. METHODOLOGY: The correlation of platelet counts of 150 cases with CRC with their clinicopathological characteristics was explored. Furthermore, the survival impact of preoperative platelet count was also investigated. RESULTS: Statistically significant correlations between the platelet count and the lymph node and distance metastasis (p=0.016 and 0.014), vascular and perinural invasion (p=0.025 and 0.016) as well as TNM clinical stages (p=0.014) except for the age, gender and grades (p=0.245, 0.276 and 0.324, respectively) were found. In addition, 5-year survival of patients with high platelet count and normal platelet count were 13.30% and 56.30%, respectively (p=0.000). Meanwhile, concurrent with lymph node and distance metastasis, perinural invasion and clinical stages (p=0.000, 0.022, 0.034 and 0.000), platelet count (p=0.010) was also found to be an independent prognostic factor in CRC in our study through multivariate analysis. CONCLUSIONS: Elevated platelet might play some role in the progress of CRC and preoperative platelet count might be a prognostic indicator in the CRC patients.

Tissue microarrays in Chinese human rectal cancer: study of expressions of the tumor-associated genes.

BACKGROUNDS/AIMS: The cellular basis for rectal cancer development is still unclear. The aim of this study was to evaluate the relationship between the expression of p53, cyclinD1, bcl-2, ß-catenin, c-myc, cyclooxygenase-2 (COX-2) and nm23-H1 and the clinicopathological characteristics of rectal cancer. METHODOLOGY: Expressions of p53, cyclinD1, bcl-2, ß-catenin, c-myc, COX-2 and nm23-H1 proteins were detected by immunohistochemical staining to two tissue microarrays containing tissues accumulated from 54 human rectal cancers and 40 para-cancer mucosa. RESULTS: Significant differences were demonstrated between the rectal cancers and their benign para-cancer counterparts according to the expressions of p53, cyclinD1, bcl-2, ß-catenin, c-myc, COX-2 and nm23-H1 (p<0.05). Additionally, positive correlations of ß-catenin with cyclinD1 and c-myc (r=0.412, p=0.002; r=0.447, p=0.000) and of p53 with bcl-2 (r=0.332, p=0.001) were found. Cancer tissues with overexpression of ß-catenin or bcl-2 were less likely to differentiate to advanced grade. Expression of cyclinD1 had a correlation with clinical stages (p=0.039). In addition, a negative correlation was found between nm23-H1 expression and the histological grades, distance metastasis and Duke's stages. CONCLUSIONS: Aberrant expression of p53, cyclinD1, bcl-2, ß-catenin, c-myc, COX-2 and nm23-H1 might attribute to the carcinogenesis of human rectal cancer. Furthermore, cyclinD1 and nm23-H1 might be involved in rectal cancer progression. This study recommends the application of tissue microarrays in rectal cancer research for its reliable quick throughput.

LncRNA-ECM is overexpressed in esophageal squamous cell carcinoma and promotes tumor metastasis.

The aim of the present study was to investigate the expression of long non-coding(lnc) RNA-extracellular matrix (ECM) in esophageal squamous cell carcinoma (ESCC) and its effect on ESCC metastasis. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the expression of lncRNA-ECM in ESCC tissues was investigated and compared with that in corresponding adjacent tissues. In addition, the expression of lncRNA-ECM in the human ESCC cell lines TE-1, EC9706, KYSE150, Eca109 and KYSE30 was also detected and compared with that in the normal esophageal mucosal epithelial cell line HET-1A. The clinicopathological association between lncRNA-ECM and ESCC was assessed. Silencing and overexpression of lncRNA-ECM in ESCC TE-1 and Eca109 cells determined the correlation between lncRNA-ECM expression and ESCC invasion and metastasis. The possible target genes of lncRNA-ECM were predicted and verified by bioinformatics analysis and experimental results. The expression level of intercellular adhesion molecule 1 (ICAM1) was detected in ESCC tissues by RT-qPCR and the correlation between the expression of ICAM1 and lncRNA-ECM was analyzed. Changes in the expression of ICAM1 in ESCC TE-1 and Eca109 cell lines were evaluated after knocking down lncRNA-ECM and transfection of lncRNA-ECM overexpression plasmids. The expression level of lncRNA-ECM in the tissues of ESCC with lymph node metastasis were significantly increased compared with ESCC with no lymph metastasis (P<0.05). LncRNA-ECM silencing notably reduced the invasion and metastasis of TE-1 and Eca109 cells, while lncRNA-ECM overexpression promoted the invasion and metastasis of the two cell lines. The expression level of ICAMI was directly correlated with the expression of lncRNA-ECM, suggesting that ICAM1 may be the downstream target gene of lncRNA-ECM. LncRNA-ECM was revealed as being overexpressed in ESCC. LncRNA-ECM expression was positively correlated with metastasis and may affect the metastasis of ESCC through ICAMI regulation. These findings indicate that lncRNA-ECM may be promising as a novel biomarker for the diagnosis and prediction of prognosis for ESCC, and it may also serve as a novel therapeutic target for ESCC.