Background: Systemic immune–inflammation index (SII), calculated by immunoinflammatory cell counts of peripheral blood, is considered a predictor of survival outcome in several solid tumors, including gastric cancer (GC). However, there is no study focusing on the prognostic value of SII in the early stage of GC. This study aims to compare prognostic prediction capabilities of several inflammatory indices, nutritional indices, and tumor markers to further verify the superior prognostic value of SII in stage I–II GC patients after surgery. Methods: In this study, 548 patients (358 in the training group and 190 in the validation group) with stage I–II GC after radical surgery were retrospectively analyzed. The peripheral blood indices of interest were SII, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), advanced lung cancer inflammation index (ALI), systemic inflammation score (SIS), prognostic nutritional index (PNI), body mass index (BMI), albumin, carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), carbohydrate-associated antigen 19-9 (CA19-9), and alpha-fetoprotein (AFP). The time-dependent receiver operating characteristic (t-ROC) curves and the area under the curve (AUC) were used to determine the optimal cutoff value and prognostic ability of each parameter. Kaplan–Meier curves and multivariable Cox regression models were used to evaluate independent prognostic factors. The nomogram was constructed based on the result of bidirectional stepwise regression model. Results: The optimal cutoff value of SII was 508.3. The 5-year overall survival rate of the low SII (SII-L) group was significantly higher than that of the high SII (SII-H) group (92% vs. 80%, P < 0.001), especially in the elderly and stage II patients (91% vs. 73%, P = 0.001; 86% vs. 67%, P = 0.003, respectively). The significant prognostic values of SII were consistent in most subgroups. In multivariate analysis, SII and CA19-9 were the only two independent prognostic hematology indices. The AUC value of SII (0.624) was greater than that of CA19-9 (0.528) and other prognostic parameters. Adding SII to the conventional model improved the predictive ability of 5-year overall survival as shown by the significantly increased net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (P = 0.033, P = 0.053, respectively) and modestly improved consistency index (C-index) (increased by 1.6%). External validation of SII-based nomogram demonstrated favorable predictive performance and discrimination. In addition, interactive web dynamic nomogram was published to facilitate clinical use. Conclusion: SII is a simple but powerful index with a high predictive value to predict survival outcome in patients with stage I–II GC after radical operation. The SII-based nomogram can provide intuitive and accurate prognosis prediction of individual patients.

In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double‐membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti‐inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti‐inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53‐dependent G1 cell‐cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti‐inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti‐inflammatory drugs in cancer chemotherapy.

Chemoresistance has been a major problem in cancer chemotherapy. The present study aimed to investigate the effect of Rosmarinic acid (RA) on chemoresistance to 5-Fu and its molecular mechanism in gastric carcinoma. CCK8 cell proliferation and apoptosis assay were used to evaluate the effect of RA on chemoresistance to 5-Fu in GC cells. RNA microarray was used to identify miRNA involved. Expression level of miRNA in GC cells was determined by RT-PCR. Down- or up-regulating of miRNA in the GC cells was performed by transfection of RNA interference or expression vectors in the GC cells. Double luciferase reporter assay was used to verify miRNA target genes. Expression of P-glycoprotein and Bax was analyzed with Western blot. RA treated SGC7901/5-Fu cells showed significant increased chemosensitivity to 5-Fu. The IC50 of 5-Fu was significantly reduced in RA treated SGC7901/5-Fu cells (70.43 ± 1.06 μg/mL) compared to untreated SGC7901/5-Fu cells (208.6 ± 1.09 μg/mL) (P < 0.05). Apoptosis rate was significantly increased in RA+5-Fu treated SGC7901/5-Fu cells compared to 5-FU treatment alone (P < 0.01). Two miRNAs, namely miR-642a-3p and miR-6785-5p, were identified to be involved in the chemo-sensitizing effect of RA in the SGC7901/5-Fu cells. RA treated SGC7901/5-Fu cells showed reduced expression levels of miR-642a-3p and miR-6785-5p compared to untreated SGC7901/5-Fu cells (P < 0.05). Down- or up-regulation of miR-6785-5p increased or reduced chemosensitivity of gastric carcinoma cells to 5-Fu, respectively. RA treated SGC7901/5-Fu and the SGC7901/5-Fu-Si cells showed significantly increased FOXO4 expression (P < 0.01). Double luciferase reporter assay confirmed miR-6785-5p directly targets FOXO4 to regulate its expression. RA significantly reduced P-gp expression and increased Bax expression in SGC7901/5-Fu and the SGC7901/5-Fu-Si cells (P < 0.05). RA enhances chemosensitivity of resistant gastric carcinoma SGC7901 cells to 5-Fu by downregulating miR-6785-5p and miR-642a-3p and increasing FOXO4 expression. These study suggest the potential for RA as a multidrug resistance-reversing agent in GC.

Background: Long noncoding RNAs (lncRNAs) are involved in various human diseases, including cancers. However, their mechanisms remain undocumented. We investigated alterations in lncRNA that may be related to pancreatic cancer (PC) through analysis of microarray data. Methods: In the present study, quantitative real-time PCR analysis was used to examine the expression of taurine upregulated 1 (TUG1) in PC tissue samples and PC cell lines. In PC cell lines, MTT assays, colony formation assays, and flow cytometry were used to investigate the effects of TUG1 on proliferation, cell cycle regulation, and apoptosis. Moreover, we established a xenograft model to assess the effect of TUG1 on tumor growth in vivo. The molecular mechanism of potential target genes was detected through nuclear separation experiments, RNA immunoprecipitation (RIP), chromatin immunoprecipitation assays (ChIP), and other experimental methods. Results: The findings suggest that the abnormally high expression of TUG1 in PC tissues was associated with tumor size and pathological stage. Knockdown of TUG1 blocked the cell cycle and accelerated apoptosis, thereby inhibiting the proliferation of PC cells. In addition, RIP experiments showed that TUG1 can recruit enhancer of zeste homolog 2 (EZH2) to the promoter regions of Rho family GTPase 3 (RND3) and metallothionein 2A (MT2A) and inhibit their expression at the transcriptional level. Furthermore, ChIP experiments demonstrated that EZH2 could bind to the promoter regions of RND3 and MT2A. The knockdown of TUG1 reduced this binding capacity. Conclusion: In conclusion, our data suggest that TUG1 may regulate the expression of PC-associated tumor suppressor genes at the transcriptional level and these may become potential targets for the diagnosis and treatment of PC.

Objective: To investigate the connection between mutant KRAS/NRAS/BRAF and clinicopathological characteristics in therapy-naïve synchronous metastatic colorectal cancer (mCRC) in Chinese populations when compared with all wild type (KRAS/NRAS/BRAF wild type). Patients and Methods: A total of 200 patients with therapy-naïve synchronous mCRC (TNM stage: TanyNanyM1) were retrospectively collected as study objects. Primary tumor tissues from 200 mCRC patients were analyzed through next-generation sequencing panel to assess the mutated regions of KRAS/NRAS/BRAF. Results: The distribution frequency of gene mutation in our study was 41% KRAS, 4% NRAS, 11.5% BRAF, 0.5% both KRAS and BRAF. Tumors with any gene mutations (any gene mutations in KRAS/NRAS/BRAF), KRAS and KRAS codon 12 mutation were more likely to be located in right-sided colon (P=0.007, P=0.008, P=0.026, respectively). For metastasis, tumors with any gene mutations, KRAS and KRAS codon 12 mutation were significantly correlated with peritoneal metastasis (P=0.019, P=0.017, P=0.014, respectively), liver-peritoneum metastases (P=0.004, P=0.003, P=0.002, respectively) and multi-organ metastases (P=0.002, P=0.008, P=0.001, respectively). Tumors with all wild type were significantly correlated with distant lymph node-only metastasis. No statistically significant differences were found between clinicopathological characteristics and KRAS codon 13 and NRAS mutations. Conclusion: Our study suggests that clinicopathological characteristics (specifically for metastasis) are related to KRAS/NRAS/BRAF mutations in therapy-naïve synchronous mCRC population in China. We demonstrated that distant lymph node-only metastasis is visibly linked to all wild-type tumors. We found that patients with any gene mutations, KRAS mutation are more likely to carry peritoneal metastasis, liver-peritoneum metastases and multi-organ metastases than those with all wild type. After stratification, KRAS codon 12 mutation, but not codon 13 mutation, was remarkably associated with peritoneal metastasis, liver-peritoneum metastases, and multi-organ metastases compared to all wild type. These results may be useful for aiding in the prediction of prognosis and choosing the appropriate regimens for therapy.