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.

Identification of F5 as a Prognostic Biomarker in Patients with Gastric Cancer.

Association of Coagulation factor V (F5) polymorphisms with the occurrence of many types of cancers has been widely reported, but whether it is of prognostic relevance in some cancers remain to be resolved. The RNA-sequencing dataset was downloaded from The Cancer Genome Atlas (TCGA). The potential of F5 genes to predict the survival time of gastric cancer (GC) patients was investigated using univariate and multivariate survival analysis whereas "Kaplan-Meier plotter" (KM-plotter) online tools were employed to validate the outcomes. TCGA data revealed that F5 mRNA levels were significantly upregulated in gastric cancer samples. Survival analysis confirmed that high levels of F5 mRNA correlated with short overall survival (OS) in gastric cancer patients, and the area under the curve (AUC) values of 1-, 2-, and 5-year OS rate were 0.554, 0.593, and 0.603, respectively. Survival analysis by KM-plotter indicated that the high expression of F5 mRNA was significantly associated with a shorter OS compared with the low expression level in all patients with GC, and this was also the case for patients in stage III (hazard ratio (HR) = 1.78, P = 0.017). These findings suggest that the F5 gene is significantly upregulated in GC tumour tissues, and may be a potential prognostic biomarker for GC.

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.

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).

The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis.

BACKGROUND: Recently, accumulated research has found that the expression of telomerase activity (TA) was associated with colorectal cancer (CRC) advancement, whereas the TA prognostic effect in CRC patients is still controversial. AIMS: To investigate relationships between TA and CRC clinicopathological parameters. STUDY DESIGN: Meta-analysis study. METHODS: We searched published studies in databases, such as EMBASE, the Cochrane Library, PubMed, and Ovid databases (last search updated to October 2014) by meeting specified search criteria. The quality of the included studies was usually evaluated and a meta-analysis was implemented by Stata 12.0 software. We used an odds ratio (OR) with a 95% confidence interval (CI) to evaluate relationship strengths between TA and CRC clinicopathological parameters. RESULTS: In total, 11 studies (715 patients) were included to assess the relation between TA and metastasis-related parameters in CRC patients. The results indicate that a senior TA expression was connected with the existence of lymph node metastasis (180 patients; OR=2.85, 95% CI=1.40-5.81, p=0.004), and tumor site (522 patients; OR=2.93, 95% CI=1.29-6.67, p=0.010). However, a senior TA expression was not connected with tumor size (137 patients; OR=1.57, 95% CI=0.71-3.47, p=0.267), histological differentiation (570 patients; OR=1.28, 95% CI=0.78-2.09, p=0.332), depth of invasion (57 patients; OR=3.76, 95% CI=0.61-23.04, p=0.152), distant metastasis (123 patients; OR=1.76, 95% CI=0.54-5.74, p=0.346), and clinical stage of the cancer (543 patients; OR=1.59, 95% CI=0.74-3.38, p=0.232). CONCLUSION: This meta-analysis suggests that a positive TA was correlated with lymph node metastasis progression and tumor site of the CRC but did not correlate with other important clinicopathological parameters. TA can play a useful part in the prognosis and treatment of CRC patients, but further studies are required to confirm this.

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.

Evaluation of miR-29c, miR-124, miR-135a and miR-148a in predicting lymph node metastasis and tumor stage of gastric cancer.

MicroRNAs (miRNAs) are small noncoding RNA that have diverse functions in different biological process. The aim of this study was to evaluate the predictive ability of miR-29c, miR-124, miR-135a and miR-148a for lymph node metastasis (LNM) and tumor stage in gastric cancer. The expression of these miRNAs was detected and quantitated in gastric cancer tissues and in adjacent normal tissues from 60 patients by quantitative real-time reverse transcription-polymerase chain reaction. CT imaging and clinicopathologic characteristics of these patients were performed. The result of this study was that these miRNAs were down-regulated in gastric cancer tissues; The low expression of miR-124 and miR-135a in LNM group and tumor III-IV stages (P < 0.01) presented the potential correlation with LNM and tumor stage; The two miRNAs were highly correlated with r = 0.730. Receiver operating characteristic curve analysis showed that miR-124 had better predictive ability to identify LNM and tumor stage. It could discriminate non-LNM from LNM with 80.0% sensitivity and 80.0% specificity and discriminate tumor Ι-II stages from tumor III-IV stages with 71.9% sensitivity and 75.0% specificity at the best cut-off value of 0.0125. Compared with CT imaging, miR-124 had similar specificity (0.800 versus 0.900, P = 0.508) but higher sensitivity (0.800 versus 0.500, P = 0.022) for lymph node assessment; Combined of miR-124 and CT imaging, The sensitivity and specificity of assessing LNM were raised to 83.3% and 90.0% respectively. Taken together, miR-124 may be a predictor for LNM and tumor stage in gastric cancer.

Screening and preliminary validation of miRNAs with the regulation of hTERT in colorectal cancer.

The overexpression of human telomerase reverse transcriptase (hTERT) has been associated with the invasion and metastasis of colorectal cancer (CRC) and has received extensive attention, although the underlying mechanism involved remains unclear. The aim of the present study was to screen and preliminarily validate new tumor­suppressor microRNAs (miRNAs) that potentially inhibit hTERT expression and to assess its clinical significance. Screening for downregulated miRNAs in CRC tissues was performed by retrieving and analysing microRNA microarray data. miRNA candidates were then filtered by bioinformatics analysis. The expression of miRNAs candidates was verified by quantitative polymerase chain reaction in the CRC and corresponding normal tissues. Immunohistochemistry (IHC) was used for the detection of hTERT protein expression. Spearman's correlation coefficient between miRNA candidates and hTERT protein expression was calculated (r) to identify hTERT-targeting miRNAs. A survival analysis was performed to assess the prognostic significance of hTERT-targeting miRNAs in CRC. Eight miRNAs with the potential to interact with hTERT were predicted: miR­29c-3p, miR­124-3p, miR­133a-3p, miR­133b, miR-138-5p, miR-150-5p, miR-378a-3p and miR-422a, respectively. Following detection of the miRNAs using RT-qPCR, miR-29c-3p was excluded. miR-138-5p and miR-422a were observed to potentially interact with hTERT (r=-0.362, P=0.001; r=-0.306, P=0.005, respectively). The Kaplan-Meier survival curves demonstrating high- vs. low-expression group of miR­422a showed a highly significant difference in CRC patients (P=0.024), which suggests that the downregulation of miR-422a was associated with a poorer prognosis. The results indicated that miR-138-5p and miR-422a potentially inhibited hTERT expression in CRC, and suggest a potential application of miR­422a in prognosis prediction and CRC treatment.

Consumptive hypothyroidism due to a gastrointestinal stromal tumor expressing type 3 iodothyronine deiodinase.

CONTEXT: Gastrointestinal stromal tumors (GISTs) are responsive to sunitinib (the tyrosine kinase inhibitor), this agent is widely used in prevention relapse of GISTs and neo-adjuvant chemotherapy in GIST patients without operation opportunity. The use of these agents has both advantages and disadvantages. On the one hand, it can improve the outcome for patient. On the other hand, it may lead to consumptive hypothyroidism, a rare syndrome caused by increased catabolism of T4 and T3 by increased type 3 iodothyronine deiodinase (D3) activity. D3 is the major physiologic inactivator of thyroid hormone, this selenoenzyme catalyzes the inner-ring deiodination of T(4) to reverse T(3) and T(3) to 3, 3;-diiodothyronine, both of which are biologically inactive [1]. Increased monitoring and supernormal thyroid hormone supplementation are required for affected patient. OBJECTIVE: The aim of the study was to report the first case of consumptive hypothyroidism in an athyreotic patient after surgical resection of gastrointestinal stromal tumor. DESIGN, SETTING, AND PATIENT: A 60-year-old athyreotic male was presented and he was euthyroid when receiving a stable therapeutic dose of thyroid hormone which was used to treat consumptive hypothyroidism resulting from the side effects of sunitinib, which is used for treatment of neo-adjuvant chemotherapy in gastrointestinal stromal tumor. With a discovery of large D3-expressing gastrointestinal stromal tumor, this patient suffered from marked Hyperthyrotropinemia, which instantly worsened after surgical resection of the gastrointestinal stromal tumor and then continued for 12 weeks after the surgical resection, in spite of further increases in levothyroxine therapy. The patient also had low serum T3 and elevated serum reverse T3 (rT3). INTERVENTION: The patient's consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating D3 within the gastrointestinal stromal tumor and adjacent normal gastrointestinal tissue. MAIN OUTCOME MEASURES AND RESULTS: D3 immunostaining of the patient's gastrointestinal stromal tumor was positive, with no significant immunoreactivity in adjacent normal gastrointestinal tissue. The expression levels of CD34, CD117, and DOG1 in peri-tumor tissue samples was lower than that in tumor tissue. The mRNA expression level of KIT exon17 in peri-tumor tissue was higher than that in tumor tissue. CONCLUSIONS: This is the first case report of consumptive hypothyroidism in an adult after surgical partial resection of the gastrointestinal stromal tumor. This case demonstrates that hyperthyrotropinemia may worsen after surgical resection of the gastrointestinal stromal tumor.