Yingying Qian

Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer.

Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC.

Gefitinib or Erlotinib as Maintenance Therapy in Patients with Advanced Stage Non-Small Cell Lung Cancer: A Systematic Review

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib have been tested as maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC). The studies are quite heterogenous regarding study size and populations, and a synopsis of these data could give some more insight in the role of maintenance therapy with TKI. Methods In September 2012 we performed a search in the pubmed, EMBASE and Cochrane library databases for randomized phase III trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through a rigorous selection process with specific criteria, five trials (n = 2436 patients) were included for analysis. Standard statistical methods for meta-analysis were applied. Results TKIs (gefitinib and erlotinib) significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50–0.76, I2 = 78.1%] and overall survival (HR 0.84, 95% CI 0.76–0.93, I2 = 0.0%) compared with placebo or observation. The PFS benefit was consistent in all subgroups including stage, sex, ethnicity, performance status, smoking status, histology, EGFR mutation status, and previous response to chemotherapy. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit. Overall survival benefit was observed in patients with clinical features such as female, non-smoker, smoker, adenocarcinoma, and previous stable to induction chemotherapy. Severe adverse events were not frequent. Main limitations of this analysis are that it is not based on individual patient data, and not all studies provided detailed subgroups analysis. Conclusions The results show that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. Given the less toxicity of TKIs than chemotherapy and simple oral administration, this treatment strategy seems to be of important clinical value.

A genetic polymorphism in pre-miR-27a confers clinical outcome of non-small cell lung cancer in a Chinese population.

Background Recent evidence indicates that microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. Our objective was to investigate the association of SNPs in deregulated miRNAs with clinical outcome in patients with non-small cell lung cancer (NSCLC) in a Chinese population. Methods Deregulated miRNAs in NSCLC and their SNPs were identified through public databases. A single SNP, rs895819 in pre-miR-27a, was found suitable for selection. TaqMan assays were performed for genotyping and to assess the effect on the overall survival (OS) and chemotherapy response in 576 NSCLC patients. Results Log-rank test and Cox regression analysis indicated that the G allele of rs895819 was associated with shorter survival and increased risk of death in NSCLC [dominant model: 22.0 vs. 46.0 months, P<0.001; adjusted hazard ratio (HR) = 1.71, 95% confidential interval (CI): 1.12–2.26]. Further stepwise regression analysis suggested that this SNP was an independently unfavorable factor for the prognosis of NSCLC and the effect remained significant in subgroup analysis stratified by clinical parameters and treatment status. Moreover, multivariate logistic regression analysis showed that the subjects with AG/GG genotypes of rs895819 had significantly decreased response rate to platinum-based chemotherapy compared to those with the AA genotype. Conclusion Our results suggest that the pre-miR-27a rs895819 polymorphism may influence NSCLC patients’ clinical outcome. Further large sample studies should be used to validate our findings.

The ERCC1 C118T Polymorphism Predicts Clinical Outcomes of Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy: a Meta-analysis Based on 22 Studies

BACKGROUND Although the predictive value of the excision repair cross-complementing group 1 (ERCC1) C118T polymorphism in clinical outcomes of patients with colorectal cancer (CRC) receiving oxaliplatin-based chemotherapy has been evaluated in numerous published studies, the conclusions are conflicting. Therefore, we performed the present meta-analysis to determine the precise role of the ERCC1 C118T polymorphism in this clinical situation and help optimize individual chemotherapy. MATERIALS AND METHODS A multiple search strategy was used to identify eligible studies. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were used to estimate objective response and oxaliplatin-induced toxicity, with hazard ratios (HRs) with 95%CIs for progression-free survival (PFS) and overall survival (OS). RESULTS A total of 22 studies including 2,846 CRC patients were eligible in the analysis. Overall, no significant correlation was found between the ERCC1 C118T polymorphism and objective response to oxaliplatin-based chemotherapy, in all patients or in the Asian and Caucasian subgroups. However, the pooled analysis showed that the PFS and OS were significantly shorter in patients who carried T/T or T/C genotypes of ERCC1 C118T as compared to the C/C genotype. On stratified analysis by ethnicity, the ERCC1 118T allele was associated with a favorable prognosis in Caucasians (PFS, HR=0.58, 95%CI: 0.24-1.44; OS, HR=0.38, 95%CI: 0.22-0.64) but an unfavorable prognosis in Asians (PFS, HR=2.49, 95%CI: 1.87-3.33; OS, HR=2.63, 95%CI: 1.87-3.69) based on a dominant model. In addition, we failed to find a statistically significant impact of ERCC1 C118T polymorphism on oxaliplatin-induced toxicity. CONCLUSIONS The ERCC1 C118T polymorphism may have prognostic value in patients with CRC undergoing oxaliplatin-based chemotherapy.

Prognostic value of perioperative leukocyte count in resectable gastric cancer

AIM To investigate the prognostic significance of perioperative leukopenia in patients with resected gastric cancer. METHODS A total of 614 eligible gastric cancer patients who underwent curative D2 gastrectomy and adjuvant chemotherapy were enrolled in this study. The relationship between pre- and postoperative hematologic parameters and overall survival was assessed statistically, adjusted for known prognostic factors. RESULTS The mean white blood cell count (WBC) significantly decreased after surgery, and 107/614 (17.4%) patients developed p-leukopenia, which was defined as a preoperative WBC ≥ 4.0 × 10(9)/L and postoperative WBC < 4.0 × 10(9)/L, with an absolute decrease ≥ 0.5 × 10(9)/L. The neutrophil count decreased significantly more than the lymphocyte count. P-leukopenia significantly correlated with poor tumor differentiation and preoperative WBC. A higher preoperative WBC and p-leukopenia were independent negative prognostic factors for survival [hazard ratio (HR) = 1.602, 95% confidence interval (CI): 1.185-2.165; P = 0.002, and HR = 1.478, 95%CI: 1.149-1.902; P = 0.002, respectively] after adjusting for histology, Borrmann type, pTNM stage, vascular or neural invasion, gastrectomy method, resection margins, chemotherapy regimens, and preoperative WBC count. The patients with both higher preoperative WBC and p-leukopenia had a worse prognosis compared to those with lower baseline WBC and no p-leukopenia (27.5 mo vs 57.3 mo, P < 0.001). CONCLUSION Preoperative leukocytosis alone or in combination with postoperative leukopenia could be independent prognostic factors for survival in patients with resectable gastric cancer.

The XPD Lys751Gln polymorphism has predictive value in colorectal cancer patients receiving oxaliplatin-based chemotherapy: a systemic review and meta-analysis.

BACKGROUND The predictive value of the xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism regarding clinical outcomes of patients with colorectal cancer (CRC) receiving oxaliplatin-based chemotherapy has been evaluated in numerous published studies, but the results remain inconclusive. Therefore, we performed a meta-analysis to determine the precise role of the XPD Lys751Gln polymorphism in this clinical situation and optimize individual chemotherapy. MATERIALS AND METHODS A multiple search strategy was used to identify eligible studies. Pooled odds ratios (ORs), generalized odds ratio (ORG) and their 95% confidence intervals (CIs) were used to estimate the objective response, while hazard ratios (HRs) with 95%CIs were used for progression-free survival (PFS) and overall survival (OS). RESULTS A total of 17 studies including 2,286 patients met the inclusion criteria. Overall, the XPD 751Gln allele was associated with a non-significant reduced objective response to oxaliplatin-based chemotherapy in all patients or in the Asian and Caucasian subgroups. However, poor PFS and OS of CRC patients treated with oxaliplatin-based regimens were significantly related to the XPD 751Gln allele in the dominant model (PFS: HR=2.10, 95%CI: 1.65-2.67; OS: HR=3.18, 95%CI: 1.57-6.47). On stratified analysis by ethnicity, these relationships were more pronounced in Asians (PFS: HR=2.49, 95%CI: 1.79-3.47; OS: HR=5.25, 95%CI: 3.46-7.94) than in Caucasians (PFS: HR=1.73, 95%CI: 1.22-2.46; OS: HR=1.78, 95%CI: 1.06-2.99). CONCLUSIONS The XPD Lys751Gln polymorphism may have prognostic value in patients with CRC undergoing oxaliplatin-based chemotherapy.

A clinical prognostic scoring system for resectable gastric cancer to predict survival and benefit from paclitaxel- or oxaliplatin-based adjuvant chemotherapy

Background Gastrectomy with D2 lymphadenectomy is a standard procedure of curative resection for gastric cancer (GC). The aim of this study was to develop a simple and reliable prognostic scoring system for GC treated with D2 gastrectomy combined with adjuvant chemotherapy. Methods A prognostic scoring system was established based on clinical and laboratory data from 579 patients with localized GC without distant metastasis treated with D2 gastrectomy and adjuvant chemotherapy. Results From the multivariate model for overall survival (OS), five factors were selected for the scoring system: ≥50% metastatic lymph node rate, positive lymphovascular invasion, pathologic TNM Stage II or III, ≥5 ng/mL preoperative carcinoembryonic antigen level, and <110 g/L preoperative hemoglobin. Two models were derived using different methods. Model A identified low- and high-risk patients for OS (P<0.001), while Model B differentiated low-, intermediate-, and high-risk patients for OS (P<0.001). Stage III patients in the low-risk group had higher survival probabilities than Stage II patients. Both Model A (area under the curve [AUC]: 0.74, 95% confidence interval [CI]: 0.69–0.78) and Model B (AUC: 0.79, 95% CI: 0.72–0.83) were better predictors compared with the pathologic TNM classification (AUC: 0.62, 95% CI: 0.59–0.71, P<0.001). Adjuvant paclitaxel- or oxaliplatin-based or triple chemotherapy showed significantly better outcomes in patients classified as high risk, but not in those with low and intermediate risk. Conclusion A clinical three-tier prognostic risk scoring system was established to predict OS of GC treated with D2 gastrectomy and adjuvant chemotherapy. The potential advantage of this scoring system is that it can identify high-risk patients in Stage II or III who may benefit from paclitaxel- or oxaliplatin-based regimens. Prospective studies are needed to confirm these results before they are applied clinically.

Long Noncoding RNA EGFR-AS1 Promotes Cell Proliferation by Increasing EGFR mRNA Stability in Gastric Cancer

Background/Aims: LncRNA EGFR-AS1 is an antisense transcript of EGFR, which plays a key role in gastric cancer progression. This study was aimed to explore the effects of lncRNA EGFR-AS1 on GC and the underling mechanisms. Methods: The silencing of EGFR-AS1 expression was performed by using EGFR-AS1 shRNA lentivirus in MGC803 and SGC-7901 GC cell. The levels of lncRNA EGFR-AS1 and EGFR were detected by qPCR and western blot. Cell proliferation was assessed by CCK-8, EdU, and colony formation assays. The EGFR mRNA stability was explored by using RNA synthesis inhibitor α-amanitin. Results: In our study, EGFR-AS1 significantly up-regulated in GC tissues and correlated with tumor size. And the expression of EGFR-AS1 positively correlated with EGFR in tissues. Moreover, knock-down of EGFR-AS1 inhibited the proliferation of GC cells via suppressing EGFR-dependent PI3K/AKT pathway in vitro and in vivo. Mechanismly, depletion of EGFR-AS1 was found to decrease EGFR expression by reduction of EGFR mRNA stability. Conclusion: Our findings suggested that EGFR-AS1 might have an oncogenic effect on GC and serve as a potential target of GC.