Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Nodal downstaging to ypN0 after neoadjuvant chemotherapy positively impacts on survival of cT4N+ GC/GEJ patients.

BACKGROUND: The prognostic value of histomorphologic regression in primary gastric and gastroesophageal cancers (GC/GEJ) has been previously established, however, the impact of lymph node (LN) regression on survival still remains unclear. METHODS: A prospectively maintained database was reviewed to identify cT4N+ gastric and gastroesophageal cancers (GC/GEJ) after NAC (neoadjuvant chemotherapy). Patients were categorized into two groups based on LN status: cN+/ypN0 (downstaged N0) and cN+/ypN+ (persistent N+), long-term survival were analyzed using Kaplan-Meier survival estimates. RESULTS: In total, 125 patients with cT4N+ GC/GEJ underwent NAC followed by surgery were enrolled. A total of 39 patients (31.2%) had cN+/ypN0 (ypN0) disease, 86 patients (68.8%) had cN+/ypN+ (ypN+) disease. Prognosis in ypN+ patients was significantly worse than those in ypN0 group for 3- and 5-year overall survival (OS) (p < 0.05). The 3-year OS was 83%, 44% in ypN0 and ypN+ group, respectively. The 5-year OS was 75%, 35% in ypN0 and ypN+ group, respectively. Multivariable analysis suggested that multivisceral resection (hazard ratio [HR] = 0.33, 95% confidence interval [CI]: 0.14-0.76, p = 0.009), and ypN+ (HR = 3.42, 95% CI: 1.15-10.13, p =0.027) were independent prognostic factors for OS. CONCLUSION: Nodal downstaging is an important hallmark representing the effectiveness of NAC for GC/GEJ, and it positively impacts on survival of these patients.

Clinicopathologic Characteristics and Prognosis of PDGFRA-Mutant Gastrointestinal Stromal Tumors: A Large-Scale, Multi-Institutional, Observational Study in China.

INTRODUCTION: To evaluate clinicopathologic features and prognosis of post-complete resection in patients with PDGFRA-mutant gastrointestinal stromal tumor (GIST), and even to establish a relapse-free survival (RFS) prognostic model for this subgroup. METHODS: This retrospective study used data from patients with primary PDGFRA-mutant GIST who underwent complete resection (2005-2019) at 16 large-scale medical centers in China. Stepwise multivariate Cox regression models were performed to build the prediction model, in which the potential predictors were available in routine clinical practice and using the risk score functions. The prediction model was cross-validated by calibration histogram and time-dependent receiver operating characteristic curves. RESULTS: A total of 280 patients with PDGFRA-mutant (172 D842V-mutant and 108 non-D842V-mutant) GIST after complete resection were enrolled. Most tumors originated in the stomach (89.6%). The 1-, 3-, and 5-year RFS rates were 95.9%, 91.2%, and 89.5%, respectively. The RFS of the non-D842V-mutant group was superior to that of the D842V group (P = 0.033). Multivariate analysis demonstrated that D842V mutation (P = 0.017), non-gastric tumor (P < 0.001), and Ki-67 > 5% (P = 0.005) were the independent variables influencing the prognosis of patients with PDGFRA-mutant GIST. The scoring model showed the predicted and actual cumulative 1-, 3- and 5-year follow-up relapse rates fit well. CONCLUSIONS: PDGFRA-mutant GIST mostly originated in the stomach and had a favorable prognosis after surgery. Non-D842V-mutant patients might have better prognoses than D842V-mutant patients. The prognostic model demonstrated favorable prediction accuracy, suggesting its clinical utility.

The prognostic and diagnostic value of tissue inhibitor of metalloproteinases gene family and potential function in gastric cancer.

Background: Tissue inhibitor of metalloproteinases (TIMP) gene family, including TIMP1, TIMP2, TIMP3 and TIMP4, was found to be correlated with serval cancers. Still the diagnostic and prognostic study of it in gastric cancer (GC) have few reports. Methods and materials: In this study, the gene expression and clinical data were acquired from the Cancer Gene Atlas (TCGA), function enrichment was used by several databases for verifying known function. Operating characteristic (ROC) curves with area under the curve (AUC) used to assess diagnostic value. Survival analysis and joint-effects survival analysis was performed by the Kaplan-Meier curve. The results were adjusted by cox-regression model. Nomogram is used to directly predict the survival rate for individual GC patient. The potential mechanism for diagnostic and prognostic value was assessed by gene set enrichment analysis (GSEA). Further functions of gene were verified by cell proliferation, migration and invasion assays in human gastric cancer cell line. Results: TIMP1 was expressed in GC tissue was higher than normal gastric tissue. TIMP3 and TIMP4 have expressed in normal gastric tissue were higher than GC tissue. TIMP1, TIMP3 and TIMP4 have potential diagnostic value (AUC=0.842, 0.729, 0.786 respectively; all P<0.01). Low expression of TIMP2 and TIMP3 associated with favorable overall survival (all P<0.05). TIMP2 and TIMP3, which had significantly affection of prognosis were found having some function such as tRNA processing, cell cycle pathway ncRNA processing. The silencing of TIMP3 could inhibit the migration and invasion of gastric cancer cell. Conclusion: We analyzed the TIMP gene family in GC, and the prognostic and diagnostic value. TIMP1 and TIMP2 could be used as diagnostic biomarkers in GC. TIMP2 and TIMP3 could be used as potential biomarkers for GC's prognosis.

Retrospective study of preoperative chemoradiotherapy with capecitabine versus capecitabine plus oxaliplatin for locally advanced rectal cancer.

This study aimed to evaluate whether the addition of oxaliplatin to a neoadjuvant chemoradiotherapy (CRT) regimen could improve survival benefit in locally advanced rectal cancer (LARC) patients. We retrospectively analysed 73 LARC patients (cT2-4 and/or cN1-2) who received preoperative CRT with capecitabine followed by surgery (arm A, 43 patients) or capecitabine plus oxaliplatin followed by surgery (arm B, 30 patients). The main endpoints of the study were pathologic complete response (pCR) rate, overall survival (OS) and disease-free survival (DFS). The secondary endpoints included the sphincter preservation rate and safety. The pCR for arms A and B were 28% and 17% (P = 0.267). In arms A and B, the mean OS was 84.287 months (95% CI 68.413-100.160) and 106.333 months (95% CI 99.281-113.386) (P = 0.185); the mean DFS was 72.812 months (95% CI 56.271-89.353) and 95.073 months (95% CI 83.392-106.754) (P = 0.310); and the sphincter preservation rates were 72% and 67%, respectively (P = 0.619). The incidence of grade 3 toxicity was much higher in arm B than in arm A (57% vs. 21%, P = 0.002). Adding oxaliplatin to a preoperative CRT regimen for LARC did not improve the survival benefits of patients or increase toxicity.

Circular RNA Profiling Reveals That circRNA_104433 Regulates Cell Growth by Targeting miR-497-5p in Gastric Cancer.

BACKGROUND: The role and mechanism of hsa_circRNA_104433 in gastric cancer (GC) are further elucidated. MATERIALS AND METHODS: CircRNA_104433 was selected by circRNA microarrays and GEO database. qRT-PCR was used to analyze the expression of circRNA_104433 in GC. The role of circRNA_104433 in GC cells was evaluated based on cell cycle progression, cell proliferation, cell apoptosis, and tumor xenograft experiment assay. To explore the mechanisms of circRNA_104433 in GC TCGA database, STRING version, qRT-PCR and luciferase assay were performed. Furthermore, the prognostic value of CDC25A in GC was determined based on the GEO database. RESULTS: The level of circRNA_104433 showed upregulation in GC tissues, and the expression of it showed a positive correlation with the degree of differentiation and the size of the tumor. Knockdown of circRNA_104433 inhibited cell cycle transition, and cell proliferation, while promoted cell apoptosis in GC. CircRNA_104433 directly binds to miR-497-5p, which directly regulates CDC25A. The median survival period of GC patients with high expression levels of CDC25A was 21.3 months, which was shorter than those with low group expression of CDC25A (35.9 months). The cell cycle proteins CDK1, CDK2, CCNB1, PKMYT1, CDC20, CHEK1 and CDC25A were coexpressed with CDC25A. CONCLUSION: These findings suggested that knockdown of circRNA_104433 expression suppressed tumor development in GC.

Targeting snoRNAs as an emerging method of therapeutic development for cancer.

The relevance of the dysregulation of snoRNAs in human cancer has been widely investigated and has challenged the view that snoRNAs merely function as house-keeping genes for the posttranscriptional modification of rRNAs. Accumulating evidence has shown the intimate connection between snoRNAs and proliferation, apoptosis, invasion and migration of tumor cells via manual intervention patterns of snoRNA expression. In this review, we focused on how snoRNAs are dysregulated and its regulation of the formation and development of cancer. We summarized the non-classical functions of snoRNAs in the context of their regulations of the signaling pathways involving PI3K-AKT and K-Ras and p53-dependant manner. Under these novel functions and characteristics, snoRNAs can act as potential and feasible biomarkers for diagnosis. Simultaneously, these promising therapeutic strategies should be considered to counteract the perturbations of snoRNAs.

The prognostic value of ADRA1 subfamily genes in gastric carcinoma.

Adrenergic receptor α1 (ADRA1) subfamily members, including ADRA1A, ADRA1B and ADRA1D, are understood to participate in cardiac disease and benign prostatic hyperplasia. In addition, adrenergic signals in cell pathways can promote the development of cancer. However, little is understood regarding the associations between ADRA1 subfamily members and gastric carcinoma (GC). The present study investigated the prognostic value of the ADRA1 subfamily genes in GC. Data from a total of 379 patients with GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Kaplan-Meier analysis and Cox regression analysis were used to determine associations with overall survival (OS) and to evaluate the median survival time using hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate survival analysis revealed that low expression levels of ADRA1A (HR, 0.595; 95% CI, 0.426-0.831; adjusted P=0.002) ADRA1B (HR, 0.576; 95% CI, 0.412-0.805; adjusted P=0.001) and ADRA1D (HR, 0.559; 95% CI, 0.398-0.787; adjusted P=0.001) were associated with a favourable OS. Joint-effects analysis demonstrated that combinations of low expression levels of ARDA1A, ARDA1B and ARDA1D were significantly associated with a favourable OS. Overall, the current results suggested that the mRNA expression levels of ARDA1 subfamily members may serve as potential prognostic markers for GC.

Postoperative morbidity and mortality after neoadjuvant chemotherapy versus upfront surgery for locally advanced gastric cancer: a propensity score matching analysis.

BACKGROUND: Cohort studies have shown that neoadjuvant chemotherapy (NAC) is not associated with increased risk of postoperative complications and mortality as compared to upfront surgery (SURG). OBJECTIVE: The aim of this study was to compare postoperative morbidity and mortality after NAC with SURG. PATIENTS AND METHODS: Patients who underwent gastrectomy with D2 lymphadenectomy for advanced gastric cancer (GC) between 2010 and 2017 were selected. The impact of neoadjuvant chemotherapy on surgical safety was investigated by using propensity score matching. RESULTS: Three hundred and seventy-seven patients were included. After propensity score matching, 86 patients in each group were matched. The percentage of patients with one or more complications was 10.5% in NAC group and 15.1% in SURG group (P=0.361), there was no mortality developed in either group. The total blood loss was significantly more in the NAC group than that in the SURG group (320.79 vs 243.37 ml, P<0.04). In univariate and multivariate of the matched cohort, sex, age (<70), BMI (<24), ASA grade, surgical procedure (open vs laparoscopy), gastrectomy extent, cTNM and Charlson index comorbidity were not associated with postoperative complications (all P>0.05). CONCLUSION: This study showed that postoperative morbidity and mortality were similar for NAC group and SURG group.

Prolonging Gastrointestinal-Stromal-Tumor-free life, an optimal suggestion of imatinib intervention ahead of operation.

Background: Imatinib has been regarded as the first successful synthetic small molecule targeting at blocking tyrosine kinase. Its high efficacy stabilized disease in above 80% of chronic myeloid leukemia (CML) patients over 10 years survival. Due to the similar canceration of gastrointestinal stromal tumor (GIST) as to CML, imatinib has been approved to be used as first-line treatment. Study design: Our retrospective study was proposed to enroll 191 GIST patients with larger tumor size (≥8 cm) who preoperative accepted imatinib from those with direct operation. Analysis included demographics, cancer specific survival and relationship of their risk factors. Results: Male patients and gastrointestinal (GI) tract location took higher proportion in total cases, detection of KIT mutant took 89.7% among all traceable genetic testing. Patients with preoperative imatinib can achieve higher cancer specific survival (CSS) after both in 1 year and 3 years duration than their counterpart. Tumor size above its threshold of 8 cm would be a hazardous factor for poor prognosis. Conclusion: In conclusion, as for regressing tumor progression and creating operative chance, preoperative imatinib should be considered for the patients with high risk, although the precise duration of this intervention needs further validation.

Postoperative morbidity and mortality in patients receiving neoadjuvant chemotherapy for locally advanced gastric cancers: A systematic review and meta-analysis.

AIM: To investigate the postoperative morbidity and mortality for neoadjuvant chemotherapy (NAC) plus surgery compared with surgery alone. METHODS: PubMed and Embase were searched to capture the incidence of any postoperative complications, pulmonary complications, anastomotic leakage, surgical site infections, and postoperative mortality in randomized clinical trials comparing NAC plus surgery with surgery alone. The meta-analyses were performed with a random effects model. RESULTS: Nine relevant studies were included. Comparing NAC with surgery alone, there were no increases in any postoperative complications, pulmonary complications, anastomotic leakage, surgical site infections, or postoperative mortality attributable to NAC. Sensitivity analysis suggested a possible increased risk of any postoperative complications compared with surgery alone: the risk difference 0.056 (95% confidence interval -0.032 to 0.145). Severe complications such as anastomotic leakage and pulmonary complications were similar in the 2 groups. CONCLUSIONS: NAC for gastric cancer does not increase the risk of postoperative morbidity and mortality compared with surgery alone.

The accuracy of magnifying narrow band imaging (ME-NBI) in distinguishing between cancerous and noncancerous gastric lesions: A meta-analysis.

BACKGROUND: Previous clinical trials have demonstrated the diagnostic accuracy of magnifying narrow-band (ME-NBI) for gastric cancerous lesions, but the results are inconsistent. The purpose of this meta-analysis is to investigate the accuracy of ME-NBI in distinguishing between cancerous and noncancerous gastric lesions. METHODS: Systematic literature searches were conducted until October 2016 in PubMed, Embase by 2 independent reviewers. Meta-analysis was performed to calculate the pooled sensitivity, specificity. Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data. Meta-analytic method was used to construct summary receiver operating characteristic curves, and pooled sensitivity, specificity were calculated. RESULTS: Nine studies enrolling 5398 lesions were included. The pooled sensitivity, specificity were 88% (95% confidence interval [CI]: 78-93%), 96% (95% CI: 91-98%), respectively. The area under the curve (AUC) was 0.97. There was a large heterogeneity between the included studies. Studies with lesions ≤ 10 mm still had a high pooled sensitivity of 81% (95% CI: 73-90%) and specificity of 97% (95% CI: 95-100%). Studies which analyzed resected specimens had a sensitivity of 91% (95 CI: 82-99%) and specificity of 88% (95% CI: 83-94%), and studies which analyzed biopsied specimens had a sensitivity of 85% (95 CI: 74-96%) and specificity of 99% (95% CI: 98-99%). CONCLUSIONS: ME-NBI is highly accurate and consistent to distinguish between gastric cancerous and noncancerous lesions.

Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients.

Despite extensive progress in treatment for cancer in recent decades, the early diagnosis for gastric cancer (GC) and colorectal cancer (CRC) remains poor. In this study, we explore the diagnostic value of joint detection of thymidine kinase 1 (TK1), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9) and carbohydrate antigen 72-4 (CA 72-4) in the diagnosis of GC and CRC, and to evaluated the relationship between TK1 expression and clinical pathological characteristics in the patients. Serum TK1, CA 19-9, CA 72-4 and CEA levels were measured in 169 patients with GC, 344 patients with CRC and 75 healthy controls using electro-chemiluminescence. The TK1 concentration was significantly higher in patients with cancer than in healthy controls and patients with clinical stage Ⅲ+Ⅳ had higher TK1 levels than clinical stage Ⅰ+Ⅱ (P<0.05). The levels of TK1 is significantly associated with tumor stage, lymph node metastasis, distant metastasis, tumor differentiation and age (P<0.05). When the tumor markers (TK1, CA 19-9 and CA 72-4) were detected respectively, the area under receiver operating characteristics curve (AUC) of TK1 for three cancers was the highest (0.823-0.895). However, the combination of AUC was higher than that for each tumor marker detected respectively (0.934-0.953), and the Hosmer-Lemeshow test showed an adequate model of calibration (P>0.05). Moreover, the AUCs varied significantly between the combination tests and single biomarker tests (Z test, P<0.01). In conclusion, serum TK1 may be an independent tumor marker for GC and CRC patients, and the combination of TK1, CA 19-9 and CA 72-4 and CEA performed even better. This study suggests that combination detection of four tumor markers may prove to be useful for the diagnosis of GC and CRC.

Systematic review and meta-analysis of single-incision versus conventional multiport laparoscopic splenectomy.

BACKGROUND: There is no consensus that single-incision laparoscopic surgery splenectomy (SILS-SP) is on a par with conventional multiport laparoscopic surgery splenectomy (CMLS-SP). AIMS: The aim of this systematic review and meta-analysis was to assess feasibility and safety of SILS-SP when compared with CMLS-SP. MATERIALS AND METHODS: Eligible articles were identified by searching several databases including PubMed, EMBASE, CNKI (China) and the Cochrane Library, up until February 2016. Studies were reviewed independently and rated by Newcastle-Ottawa Quality Assessment Scale. Evaluated outcomes were complications, operative time, post-operative hospital stay, blood loss, starting diet, post-operative pain scores, conversion and analgesic requirements. RESULTS: Ten retrospective studies met the eligibility criteria. Overall, there was no significant difference between SILS-SP and CMLS-SP in complications, operative time, post-operative hospital stay, blood loss, starting diet, post-operative pain scores, conversion and analgesic requirements. CONCLUSIONS: SILS-SP is feasible and safe in certain patients, with no obvious advantages over CMLS-SP. Therefore, it may be considered an alternative to CMLS-SP. We await high-quality, double-blind RCTs. These should include clear statements on standard scores of post-operative pain and cosmetic results, longer follow-up assessment and cost-benefit analysis.

Single-Incision Laparoscopic Inguinal Hernioplasty Versus Conventional Laparoscopic Inguinal Hernioplasty.

PURPOSE: Additional studies comparing single-incision laparoscopic inguinal hernioplasty (SILH) and conventional laparoscopic inguinal hernioplasty (CLH) have been published, and this study updates the meta-analysis of this subject. METHODS: Two reviewers independently searched the PubMed, Embase, Google Scholar, and Cochrane Library electronic databases to locate original articles that compared SILH and CLH for inguinal hernia that were published until October 2015. Operative time, conversions, complications, length of hospital stay, recurrence, postoperative pain at 24 hours, and postoperative pain at 7 days were compared using Stata software, version 12.0. RESULTS: Sixteen studies were selected for this analysis, which included a total of 1672 patients (907 in SILH and 765 in CLH). SILH showed a longer operative time; however, conversions, complications, length of hospital stay, recurrence, postoperative pain at 24 hours, and postoperative pain at 7 days were similar between the 2 groups. CONCLUSIONS: Our meta-analysis has shown that inguinal hernia repair using SILH is as safe as CLH. However, based on our evidence, we currently believe that SILH is not an efficacious surgical alternative to CLH for inguinal hernias due to the fact that it does not provide significant benefit in postoperative pain and cosmetic outcomes. However, large-scale, well-designed, and multicenter studies will be needed to further confirm the results of this study.

Comparison of efficacy of simo decoction and acupuncture or chewing gum alone on postoperative ileus in colorectal cancer resection: a randomized trial.

To compared the ability of chewing gum or simo decoction (SMD) and acupuncture to reduce incidence of postoperative ileus (POI) after colorectal cancer resection, patients with colorectal cancer undergoing open or laparoscopic resection were randomized to receive SMD and acupuncture (n = 196), chewing gum alone (n = 197) or no intervention (n = 197) starting on postoperative day 1 and continuing for 5 consecutive days. Patients treated with SMD and acupuncture experienced significantly shorter hospital stay, shorter time to first flatus and shorter time to defecation than patients in the other groups (all P < 0.05). Incidence of grade I and II complications was also significantly lower in patients treated with SMD and acupuncture. Patients who chewed gum were similar to those who received no intervention in terms of hospital stay, incidence of complications, and time to first bowel motion, flatus, and defecation (all P > 0.05). The combination of SMD and acupuncture may reduce the incidence of POI and shorten hospital stay for patients with colorectal cancer after resection. In contrast, chewing gum does not appear to affect recovery of bowel function or hospital stay, though it may benefit patients who undergo open resection. (Clinicaltrials.gov registration number: NCT02813278).

MicroRNA-1284 inhibits proliferation and induces apoptosis in SGC-7901 human gastric cancer cells.

OBJECTIVES: To explore the functional effects of miR-1284 on gastric cancer cells. RESULTS: Overexpression of miR-1284 significantly reduced SGC-7901 cell proliferation, but improved apoptosis. However, miR-1284 suppression displayed the inversed impacts. Furthermore, the protein levels of p27, Bax, procaspase-3 and active caspase-3 were up-regulated by miR-1284 overexpression, but were down-regulated by miR-1284 suppression. The level of Bcl-2 was down-regulated by miR-1284 overexpression, while it was up-regulated by miR-1284 suppression. The level of p21 was unaffected. CONCLUSION: These results suggest that miR-1284 overexpression might be a suppressor for gastric cancer via controlling of cell proliferation and apoptosis.

E2F-1 promotes DAPK2-induced anti-tumor immunity of gastric cancer cells by targeting miR-34a.

Activation of the transcription factor E2F-1 gene is a negative event in dendritic cell (DC) maturation process. Down-regulation of E2F1 causes immaturity of DC thereby stopping antigen production which in turn leads to inhibition of immune responses. E2F-1-free stimulates the NF-kB signaling pathway, leading to activation of monocytes and several other transcription factor genes. In the study, we report that down-regulation of E2F-1 in DCs promote anti-tumor immune response in gastric cancer (GC) cells through a novel mechanism. DCs were isolated from peripheral blood mononuclear cells. E2F-1 small interfering RNA (E2F-1-shRNA) induced down-regulation of E2F-1 mRNA and protein expression in DCs. Furthermore, we identified the E2F-1-shRNA targeted the CD80, CD83, CD86, and MHC II molecules, promoted their expression, and induced T lymphocytes proliferation activity and up-regulation of IFN-I³ production and GC cell killing effect, which significantly correlated with the cytotoxic T lymphocytes activated by E2F-1-shRNA DCs. The higher expression of miR-34a was found which was significantly correlated with the DC enhancing anti-tumor immunity against gastric cancer cell, and miR-34a potently targeted DAPK2 and Sp1, both of which were involved in the deactivation of E2F-1. Moreover, in E2F-1-DC-down-regulation in mice, GC transplantation tumors displayed down-regulation of Sp1, DAPK2, Caspase3, and Caspase7 and progressed to anti-tumor immunity. Collectively, our data uncover an E2F-1-mediated mechanism for the control of DC anti-tumor immunity via miR-34a-dependent down-regulation of E2F-1 expression and suggest its contribution to GC immunotherapy.

miR-135a promotes gastric cancer progression and resistance to oxaliplatin.

Resistance to oxaliplatin (OXA)-based chemotherapy regimens continues to be a major cause of gastric cancer (GC) recurrence and metastasis. We analyzed GC samples and matched non-tumorous control stomach tissues from 280 patients and found that miR-135a was overexpressed in GC samples relative to control tissues. Tumors with high miR-135a expression were more likely to have aggressive characteristics (high levels of carcino-embryonic antigen, vascular invasion, lymphatic metastasis, and poor differentiation) than those with low levels. Patients with greater tumoral expression of miR-135a had shorter overall survival times and times to disease recurrence. Furthermore, miR-135a, which promotes the proliferation and invasion of OXA-resistant GC cells, inhibited E2F transcription factor 1 (E2F1)-induced apoptosis by downregulating E2F1 and Death-associated protein kinase 2 (DAPK2) expression. Our results indicate that higher levels of miR-135a in GC are associated with shorter survival times and reduced times to disease recurrence. The mechanism whereby miR-135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPK2 pathway signaling.