Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

AIM:To investigate M2 isoform of pyruvate kinase(PKM2) expression in gastric cancers and evaluate its potential as a prognostic biomarker and an anticancer target.METHODS:All tissue samples were derived from gastric cancer patients underwent curative gastrectomy as a primary treatment.Clinical and pathological information were obtained from the medical records.Gene expression microarray data from 60 cancer and 19 noncancer gastric tissues were analyzed to evaluate the expression level of PKM2 mRNA.Tissue microarrays were constructed from 368 gastric cancer patients.Immunohistochemistry was used to measure PKM2 expression and PKM2 positivity of cancer was determined by proportion of PKM2-positive tumor cells and staining intensity.Association between PKM2 expression and the clinicopathological factors was evaluated and the correlation between PKM2 and cancer prognosis was evaluated.RESULTS:PKM2 mRNA levels were increased more than 2-fold in primary gastric cancers compared to adjacent normal tissues from the same patients(log transformed expression level:7.6 ± 0.65 vs 6.3 ± 0.51,P < 0.001).Moreover,differentiated type cancers had significantly higher PKM2 mRNA compared to undifferentiated type cancers(log transformed expression level:7.8 ± 0.70 vs 6.7 ± 0.71,P < 0.001).PKM2 protein was mainly localized in the cytoplasm of primary cancer cells and detected in 144 of 368(39.1%) human gastric cancer cases.PKM2 expression was not related with stage(P = 0.811),but strongly correlated with gastric cancer differentiation(P < 0.001).Differentiated type cancers expressed more PKM2 protein than did the undifferentiated ones.Well differentiated adenocarcinoma showed 63.6% PKM2-positive cells;in contrast,signet-ring cell cancers showed only 17.7% PKM2-positive cells.Importantly,PKM2 expression was correlated with shorter overall survival(P < 0.05) independent of stage only in signet-ring cell cancers.CONCLUSION:PKM2 expression might be an adverse prognostic factor for signet-ring cell carcinomas.Its function and potential as a prognostic marker should be further verified in gastric cancer.

Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype

AIM:To identify molecular biologic differences between two gastric adenocarcinoma subgroups presenting different prognoses through the analysis of microRNA and protein expression.METHODS:Array technologies were used to generate1146 microRNAs and 124 proteins expression profiles of samples from 60 patients with gastric cancer.For the integrative analysis,we used established mRNA expression data published in our previous study.Whole mRNA expression levels were acquired from microarray data for 60 identical gastric cancer patients.Two gastric adenocarcinoma subgroups with distinct mRNA expression profiles presented distinctly different prognoses.MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal gastric tissue and between two different prognostic groups.Aberrantly expressed microRNA,associated mRNA,and protein in patients with poor-prognosis gastric cancer were validated by quantitative reverse transcription polymerase chain reaction and immunochemistry in independent patients.RESULTS:We obtained the expression data of 1146microRNAs and 124 cancer-related proteins.Four microRNAs were aberrantly expressed in the two prognostic groups and in cancer vs non-cancer tissues(P<0.05).In the poor-prognosis group,miR-196b,miR-135b,and miR-93 were up-regulated and miR-29c*was down-regulated.miR-196b expression positively correlated with Homeobox A10(HOXA10)expression(r=0.726,P<0.001),which was significantly increased in poor-prognosis patients(P<0.001).Comparing gastric cancer with non-cancer tissues,46/124 proteins showed differential expression(P<0.05);COX2(P<0.001)and cyclin B1(P=0.017)were clearly overexpressed in the poor-prognosis group.CONCLUSION:Co-activation of miR-196b and HOXA10characterized a poor-prognosis subgroup of patients with gastric cancer.Elucidation of the biologic function of miR-196b and HOXA10 is warranted.

Targeted therapy in gastric cancer:Personalizing cancer treatment based on patient genome

Gastric cancer is the second leading cause of cancerrelated deaths worldwide.Conventional cytotoxic chemotherapy has limited efficacy for metastatic gastric cancer,with an overall survival of approximately ten months.Recent advances in high-throughput technologies have enabled the implementation of personalized cancer therapy for high-risk patients.The use of such high-throughput technologies,including microarray and next generation sequencing,have promoted the discovery of novel targets that offer new treatment strategies for patients lacking other therapeutic options.Many molecular pathways are currently under investigation as therapeutic targets in gastric cancer,including those related to the epidermal growth factor receptor family,the mesenchymal-epithelial transition factor axis,and the phosphatidylinositol 3-kinase-AKTmammalian target of rapamycin factors.Advances in molecular diagnostic tools further support the discovery of new molecular targets.Limitations exist,however;not all patients can be tested for biomarkers,and numerous challenges hamper implementation of targeted therapy in clinical settings.Indeed,the scale of tumor genomic profiling is rapidly outpacing our ability to appropriately synthesize all the information in order to optimally refine patient care.Therefore,clinicians must continue to educate themselves regarding new tools and frameworks,and to utilize multidisciplinary team science,comprised of oncologists,geneticists,pathologists,biologists and bioinformaticians,to successfully implement this genomic approach therapeutically.

Thioredoxin and thioredoxin-interacting protein as prognostic markers for gastric cancer recurrence

AIM:To evaluate the potential of thioredoxin (TXN) and thioredoxin-interacting protein (TXNIP) expression as biomarkers for predicting gastric cancer recurrence. METHODS:TXN and TXNIP expression levels were acquired from gene expression microarray data for 65 human gastric cancer tissues. We determined whether each gene expression level was associated with cancer recurrence and investigated the relationship between the two genes. For validation, the expression levels of TXN and TXNIP were measured by quantitative real- time reverse transcription polymerase chain reaction in 68 independent stage Ⅲ gastric cancer patients. The correlation between gene expression and cancer prognosis was evaluated. Immunohistochemical staining was performed to investigate the protein expression levels of TXN and TXNIP and to characterize the expression patterns of each protein. RESULTS:TXN was a prognosis-related gene (P = 0.009), whereas TXNIP, a TXN inhibitor, demonstrated a negative correlation with TXN in the gene expression microarray data. In the 68 stage Ⅲ patients, the expression levels of both TXN and TXNIP had a statistically significant effect on recurrence-free survival (RFS, P = 0.008 and P = 0.036, respectively). The low TXN and high TXNIP expression group exhibited a better prognosis than the other groups, and the high TXN and low TXNIP expression group exhibited a poorer prognosis (P < 0.001 for RFS and P = 0.001 for overall survival). More than half of the patients in the simulta-neously high TXN and low TXNIP expression group ex- perienced a recurrence within 1 year after curative surgery, and the 5-year survival rate of the patients in this group was 29%, compared with 89% in the low TXN and high TXNIP expression group. The TXN protein was overexpressed in 65% of the gastric cancer tissues, whereas the TXNIP protein was underexpressed in 85% of the cancer cells. In a correlation analysis, TXN and TXNIP were highly correlated with many oncogenes and tumor suppressors as well as with genes related to energy, protein synthesis and autophagy. CONCLUSION:TXN and TXNIP are promising prognostic markers for gastric cancer, and performing personalized adjuvant treatment based on TXN and TXNIP expression levels would be an effective practice in the treatment of gastric cancer.

Survival analysis based on human epidermal growth factor 2 status in stage Ⅱ-Ⅲ gastric cancer

AIM To investigate human epidermal growth factor 2(HER2) overexpression and validate its prognostic effect in stage Ⅱ-Ⅲ gastric cancer.METHODS We reviewed the data of patients who were diagnosed with gastric cancer between March 2008 and October 2013 at the Yonsei University Medical Center. Among these patients, 384 patients who met the inclusion criteria were analyzed retrospectively. RESULTS Thirty-two(8.3%) of the 384 stage Ⅱ-Ⅲ gastric cancer patients exhibited HER2 overexpression. The median follow-up duration was 26.0 mo. HER2-negative patients had superior recurrence-free survival(RFS) compared to HER2-positive patients(HR = 0.52, 95%CI: 0.30-0.89; P = 0.015). The median overall survival(OS) was significantly prolonged in the HER2-negative group compared with the HER2-positive group(55.0 mo vs 38.0 mo, HR = 0.43, 95%CI: 0.21-0.88, P = 0.021). OS was also prolonged in HER2-negative patients who received adjuvant chemotherapy compared to HER2-positive patients(55.0 vs 38.0mo, HR = 0.42, 95%CI: 0.18-1.00, P = 0.051). In patients who did not receive adjuvant chemotherapy,the median RFS was prolonged in the HER2-negative group compared to the HER2-positive group(not reached vs 12.0 mo, HR = 0.17, 95%CI: 0.06-0.49, P= 0.001). In a multivariate analysis, HER2 status(HR= 0.421, 95%CI: 0.206-0.861, P = 0.018) and Eastern Cooperative Oncology Group performance status(HR = 2.002, 95%CI: 1.530-2.618, P < 0.001) were independent predictors of OS.CONCLUSION Our findings showed that HER2-positive patients had inferior OS and RFS. Stage Ⅱ-Ⅲ HER2-positive patients might be potential candidates for targeted therapies involving trastuzumab.

基于辣椒基因组测序探究辣味在种群中的进化

辣椒(Capsicum annuum)是美洲最古老的驯化作物之一,在全世界被广泛种植。本研究对CM334(墨西哥地方品种)进行了全基因组测序和组装(覆盖度为186.6×),同时还对另外两个栽培种和一个野生种分别进行了重测序和从头(de novo)测序。结果表明辣椒基因组大小约为番茄的4倍,辣椒基因组上存在大量gypsy转座子和花椰菜病毒家族元件的积累。结合转录组综合分析认为,辣椒素合成酶基因表达模式的改变及新功能化是导致辣椒素生物合成的原因,研究还发现辣椒与番茄在乙烯合成及果实成熟调控方面存在明显不同的分子模式。辣椒参考基因组的发布为辣椒营养品质和药用价值的改善提供了重要平台。