miR-21 induces cell cycle at S phase and modulates cell proliferation by down-regulating hMSH2 in lung cancer

Purpose

MicroRNAs regulate critical genes associated with lung cancer. Human mutS homolog 2 (hMSH2), one of the core mismatch repair genes, is affected in lung cancer development. The aim of this study is to investigate the role of miR-21 in hMSH2 gene expression and the effect of miR-21 on cell proliferation and cell cycle in lung cancer.

Methods

The targets of miR-21 were predicted by a bioinformatics tool, and hMSH2 was validated as a direct target of miR-21 by luciferase activity assay. MiRNA mimics or inhibitors were used to stimulate or attenuate the effect of endogenous miR-21 on hMSH2 expression. MiR-21 and hMSH2 expressions were assessed with real-time RT-PCR and Western blotting. Cell cycle was determined by flow cytometry, and cell growth was analyzed by MTT assay and real-time cell analysis system.

Results

MiR-21 expression was inversely correlated with hMSH2 expression in human lung cancer cell lines. Further validation showed hMSH2 was directly regulated by miR-21. The up-regulation of miR-21 significantly promoted cell proliferation and revealed a higher proportion of cells at S phase. However, knockdown of miR-21 expression resulted in cell cycle arrest at G2/M phase and inhibited cell proliferation.

Conclusions

These data suggest miR-21 is a key regulator of hMSH2 and modulates cell cycle and proliferation by targeting hMSH2 in human lung cancer.     

S-1 combined with oxaliplatin as first line chemotherapy for chinese advanced gastric cancer patients

Background/Aims: To evaluate the efficacy and safety profile of S-1 combined with oxaliplatin (SOX) against unresectable advanced or metastatic gastric cancer. Methodology: Oxaliplatin was administered intravenously at 100mg/m2 for two hours on day 1 and S-1 was administered b.i.d. at 80mg/m2/day on days 1-14 followed by a 7-day rest during the 3-week schedule. Results: All 51 patients were assessed for efficacy and adverse events. The response and disease control rates were 41% and 90%, respectively. The response rate was significantly improved in patients with ECOG performance status of no more than 1, elevated CEA levels or unresected primary cancers. The median follow-up time was 11.8 months, the median time to progression was 6.8 months, the median overall survival was 11.8 months and the 1-year survival rate was 47.4%. Patients with diffused type exhibited significantly decreased time to progression and overall survival. The grade 3/4 adverse events were hematological toxicities, including neutropenia (13.7%), thrombocytopenia (13.7%) and anemia (11.8%). The incidence of grade 3/4 non-hematological events was low (≤2%). Conclusions: The SOX regimen (oxaliplatin, 100mg/m2 d1; S-1, 80mg/m2/day, b.i.d. d1-14, q3w) provided a favorable efficacy and safety profile in Chinese patients with advanced gastric cancer.     

Roles of Kupffer cells in liver transplantation

Kupffer cells, the resident macrophages of the liver, not only exert phagocytosis but also excrete proinflammatory cytokines. Large amounts of cytokines, produced by activated Kupffer cells, can induce aggravate liver ischemia/reperfusion (I/R) injury. Also, Kupffer cells that express protective genes protect from I/R injury after liver transplantation. Due to their key location, Kupffer cells might function as antigen-presenting cells and participate in transplantation immunity. They also seem to play a key role in innate immune responses and host defence through the expression and secretion of soluble inflammatory mediators. With this review we want to assist in improving the understanding of the contribution of Kupffer cells in liver I/R injury and the development of the transplantation immune. We hope that the delineation of the complex mechanisms of dysregulation may inspire the design and development of novel treatment approaches.     

Idarubicin-intensified BUCY2 regimens may lower relapse rate and improve survival in patients undergoing allo-SCT for high-risk hematological malignancies: a retrospective analysis

We conducted a retrospective study to evaluate the outcome of 94 consecutive patients with high-risk hematological malignancies who received allo-PBSCT, following idarubicin (IDA)-intensified BUCY2 (IDA-BUCY2) myeloablative conditioning regimens (n=53) and BUCY2 conditioning regimens (n=41). IDA 15?mg/m(2) once daily was administered by continuous infusion on days -11 to -9, followed by BU, 3.2?mg/kg in divided doses daily, on days -6 to -4, and i.v. injection of CY, 1.8?g/m(2) once daily on days -3 to -2 in the IDA-BUCY2 group. The relapse rate in patients in the IDA-BUCY2 and BUCY2-conditioning regimens group was 18.9 and 39%, respectively (P=0.030). There was no significant difference in terms of TRM. The cumulative probabilities of OS and disease-free survival at 2 years for patients conditioned with the IDA-BUCY2 and BUCY2 regimens were 65.3% vs 46.8% (P=0.038), and 63.5% vs 43.4% (P=0.025), respectively. Multivariate analysis showed that IDA-BUCY2 regimens and limited chronic GVHD were the only two factors resulting in improved survival and reduced relapse rate. This retrospective study suggests that IDA-intensified BUCY2 may be substituted for BUCY2 as conditioning regimen for patients with high-risk hematological malignancies.