RUNX1-induced upregulation of PTGS2 enhances cell growth, migration and invasion in colorectal cancer cells.

Colorectal cancer (CRC) arises via the progressive accumulation of dysregulation in key genes including oncogenes and tumor-suppressor genes. Prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2) acts as an oncogenic driver in CRC. Here, we explored the upstream transcription factors (TFs) responsible for elevating PTGS2 expression in CRC cells. The results showed that PTGS2 silencing repressed cell growth, migration and invasion in HCT116 and SW480 CRC cells. The two fragments (499-981 bp) and (1053-1434 bp) were confirmed as the core TF binding profiles of the PTGS2 promoter. PTGS2 expression positively correlated with RUNX1 level in colon adenocarcinoma (COAD) samples using the TCGA-COAD dataset. Furthermore, RUNX1 acted as a positive regulator of PTGS2 expression by promoting transcriptional activation of the PTGS2 promoter via the 1086-1096 bp binding motif. In conclusion, our study demonstrates that PTGS2 upregulation induced by the TF RUNX1 promotes CRC cell growth, migration and invasion, providing an increased rationale for the use of PTGS2 inhibitors in CRC prevention and treatment.

Family-based Helicobacter pylori infection status and transmission pattern in central China, and its clinical implications for related disease prevention.

BACKGROUND: Helicobacter pylori (H. pylori) has characteristics of family cluster infection; however, its family-based infection status, related factors, and transmission pattern in central China, a high-risk area for H. pylori infection and gastric cancer, have not been evaluated. We investigated family-based H. pylori infection in healthy households to understand its infection status, related factors, and patterns of transmission for related disease prevention. AIM: To investigate family-based H. pylori infection status, related factors, and patterns of transmission in healthy households for related disease prevention. METHODS: Blood samples and survey questionnaires were collected from 282 families including 772 individuals. The recruited families were from 10 selected communities in the greater Zhengzhou area with different living standards, and the family members' general data, H. pylori infection status, related factors, and transmission pattern were analyzed. H. pylori infection was confirmed primarily by serum H. pylori antibody arrays; if patients previously underwent H. pylori eradication therapy, an additional 13C-urea breath test was performed to obtain their current infection status. Serum gastrin and pepsinogens (PGs) were also analyzed. RESULTS: Among the 772 individuals examined, H. pylori infection rate was 54.27%. These infected individuals were from 246 families, accounting for 87.23% of all 282 families examined, and 34.55% of these families were infected by the same strains. In 27.24% of infected families, all members were infected, and 68.66% of them were infected with type I strains. Among the 244 families that included both husband and wife, spouse co-infection rate was 34.84%, and in only 17.21% of these spouses, none were infected. The infection rate increased with duration of marriage, but annual household income, history of smoking, history of alcohol consumption, dining location, presence of gastrointestinal symptoms, and family history of gastric disease or GC did not affect infection rates; however, individuals who had a higher education level showed lower infection rates. The levels of gastrin-17, PGI, and PGII were significantly higher, and PGI/II ratio was significantly lower in H. pylori-infected groups than in H. pylori-negative groups. CONCLUSION: In our study sample from the general public of central China, H. pylori infection rate was 54.27%, but in 87.23% of healthy households, there was at least 1 H. pylori-infected person; in 27.24% of these infected families, all members were infected. Type I H. pylori was the dominant strain in this area. Individuals with a higher education level showed significantly lower infection rates; no other variables affected infection rates.

CDC42EP3 is a key promoter involved in the development and progression of gastric cancer.

Gastric cancer (GC) is one of the most prevalent cancers and severely endangers human health. Due to the low rate of diagnosis, most patients with GC are diagnosed as advanced. CDC42 effector protein 3 (CDC42EP3) has been revealed to be involved in several types of human cancers' development and progression. However, the function of CDC42EP3 in GC is not yet clear. CDC42EP3 expression was detected by immunohistochemistry, quantitative real-time PCR and Western blot assay in tumor tissues and cell lines of GC. CDC42EP3 knockdown cell models were constructed by lentivirus transfection. Cell proliferation was evaluated by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound-healing assay and the transwell assay were utilized to assess the cell migration. Also, the cell apoptosis and the cell cycle were evaluated by flow cytometry. Moreover, the mechanism was investigated by Human Apoptosis Antibody Array. The in vivo experiments were conducted to verify the effects of CDC42EP3 knockdown on the tumor growth of GC. The expression level of CDC42EP3 was up-regulated in tumor tissues. High CDC42EP3 expression was positively related to more advanced tumor grade. CDC42EP3 knockdown inhibited cell proliferation and migration, promoted cell apoptosis and suppressed the tumor growth. On the other hand, it was also found that the silencing of CDC42EP3 inhibited HSP27 and IGF-1sR expression as well as promoted Caspase3, p53, TNF-α, TNF-ß, TRAILR-1 and TRAILR-2 expression. CDC42EP3 was revealed to work as a tumor promoter in the development and progression of GC, which could be a promising therapeutic target for the therapy of GC.

circ_SMAD2 regulate colorectal cancer cells proliferation through targeting miR-1258/RPN2 signaling pathway.

Circular RNAs (circRNAs) are associated with various diseases, including cancers. However, their roles in colorectal cancer (CRC) have not been established. Hsa_circ_0000847 (circ_SMAD2) is a novel circRNA that was found to be elevated in CRC cell lines and tissues. High circ_SMAD2 levels were positively correlated with CRC clinicopathological features. Functional assays revealed that circ_SMAD2 enhanced CRC cell invasion, proliferation, and tumor growth. Mechanistically, circ_SMAD2 elevated Ribophorin II (RPN2) levels by inhibiting miR-1258. Therefore, circ_SMAD2 is a potential indicator for CRC progression.

HOXA10 deteriorates gastric cancer through activating JAK1/STAT3 signaling pathway.

Background: HOXA10 has been reported to be deregulated in many kinds of cancers including gastric cancer. But its role in gastric cancer progression is controversial. Therefore, the current study was performed to explore the role and mechanism of HOXA10 in gastric cancer. Materials and methods: IHC and Western blotting assays were used to assess HOXA10 expression in gastric cancer tissues and cells. Lentivirus infection was used to alter HOXA10, STAT3 and JAK1 expression in gastric cancer NCI-N87 and MKN28 cells. MTT, cloning formation, flow cytometry and in vivo xenotransplantation experiments were carried out to assess cell proliferation, cloning formation, apoptosis and tumorigenesis. Results: HOXA10 expression was obviously increased in gastric cancer tissues and cells when compared with the normal gastric tissue samples and cells. Upregulation of HOXA10 significantly enhanced cell proliferation, cloning formation and tumorigenesis abilities and reduced cell apoptosis in gastric cancer, and promoted the activation of JAK1/STAT3 signaling. In addition, we showed that the effects of HOXA10 on the promotion of cell viability and tumorigenesis and cell apoptosis repression were all weakened when JAK1 or STAT3 was downregulated. Conclusion: This study demonstrates that HOXA10 functions as an oncogene in gastric cancer through activating JAK1/STAT3 signaling.

Downregulation of NGAL is Required for the Inhibition of Proliferation and the Promotion of Apoptosis of Human Gastric Cancer MGC-803 Cells.

BACKGROUND/AIMS: Gastric cancer is considered as a common malignancy with a poor prognosis as well as unsatisfactory treatment. Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to affect multiple aspects of human tumor, including gastric cancer. This study aims to explore the effects of NGAL gene silencing on the proliferation as well as apoptosis of human gastric cancer MGC-803 cells. METHODS: This study included 87 patients with gastric cancer. MGC-803 cells were collected and mainly treated with siRNA against NGAL and recombinant NGAL plasmid. The expression of NGAL mRNA and the expressions of NGAL protein and apoptosis-related proteins were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. Cell cycle and apoptosis were tested by flow cytometry, and cell proliferation was detected by water soluble tetrazolium-1 (WST-1) assay. The effect of NGAL gene silencing on tumorigenicity of MGC-803 cells in vivo was detected through establishment of xenograft in nude mice. RESULTS: NGAL was highly expressed in gastric cancer tissues. The protein and mRNA expressions of NGAL gene in MGC-803 cells treated with NGAL-siRNA were obviously reduced, and the amount of cells in G0/G1 phase was increased. Moreover, MGC-803 cells treated with NGAL-siRNA exhibited inhibited proliferation, enhanced apoptosis, decreased expressions of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) as well as B-cell lymphoma-2 (Bcl-2) and increased expressions of cysteine-aspartic acid specific protease-9 (caspase-9) and Bcl2-associated X (Bax), as well as repressed tumorigenicity in vivo. CONCLUSION: NGAL gene silencing inhibits proliferation and promotes apoptosis of MGC-803 cells, which can provide a novel theory for treatment of gastric cancer.

[Meta-analysis of sacral nerve stimulation for fecal incontinence].

OBJECTIVE: To evaluate the efficacy of sacral nerve stimulation (SNS) therapy for fecal incontinence. METHODS: Clinical researches which evaluated the efficacy of SNS and were published between 1946 and 2016 were systematically searched from electronic databases, including PubMed, Ovid Medline, Web of Science, Wanfang database and Chinese Journal Full-text Database. Grey area literatures were also searched. Influence of SNS therapy on fecal incontinence episodes (FIE) or Wexner incontinence score (WIS) was systematically evaluated. The statistical analysis was performed by RevMan5.2. RESULTS: A total of 6 studies including 270 patients (147 patients in SNS group and 123 patients in control group) with fecal incontinence were enrolled in this systematic review. SNS therapy was associated with a significant reduction in FIE (SMD=-0.69, 95%CI: -0.97 to -0.41, P<0.001) and a significant reduction in WIS (SMD=-5.05, 95%CI: -8.73 to -1.36, P=0.007). Sensitivity analysis showed that the results of this study were stable and the direction and significance of results were not changed (P=0.000 for both). Publication bias was not found by funnel picture in this study. CONCLUSION: SNS significantly improves the outcome of patients with fecal incontinence.

Soluble interleukin­2 receptor as a factor associated with angiogenesis in gastric cancer.

Angiogenesis serves a role in the growth, metastasis and prognosis of tumors. The aim of the present study was to evaluate the angiogenic ability and clinical significance of the immune biomarker soluble interleukin­2 receptor (sIL­2R) in gastric cancer (GC) patients. Serum levels of sIL­2R were measured in 35 GC patients with different stages of disease and 32 healthy individuals, and it was investigated whether the levels were associated with angiogenesis factors, including vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)­ß1. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without recombinant human (rh)sIL­2R, VEGF and TGF­ß1 for 24 h, and then the HUVECSs were harvested to determine the degree of angiogenesis. The supernatants were also collected for VEGF and TGF­ß1 testing. Serum levels of sIL­2R were higher in GC patients than in healthy individuals, as were the levels of VEGF and TGF­ß1. In addition, serum levels of sIL­2R were positively associated with the levels of VEGF and TGF­ß1. Angiogenesis of HUVECs was also increased by rhsIL­2R pretreatment. VEGF and TGF­ß1 secretion were also incre-ased in supernatants that were pretreated with rhsIL­2R. The results of the present study suggested that serum levels of sIL­2R contributes to the pathophysiology of GC progression and may be used as a prognostic biomarker for GC.

miR-146b-5p regulates cell growth, invasion, and metabolism by targeting PDHB in colorectal cancer.

MiRNA have been found to play a role in a plethora of cellular processes of cancer cells such as cell apoptosis, cell proliferation, invasion, migration metabolism and stem cell differentiation. Dysregulation of miR-146b-5p has been documented in a variety of human malignancies. However, the biological functions and molecular mechanisms of miR-146b-5p in ovarian cancer remain unknown. In this study, our results show that miR-146b-5p was unregulated in colorectal cancer (CRC) tissues compared with the adjacent non-cancerous tissues. Ectopic overexpression of miR-146b-5p in CRC promoted cell growth, invasion and glycolysis, while knockdown of miR-146b-5p inhibited the growth, invasion and glycolysis of CRC cells. The oncogenic effect of miR-146b-5p is also confirmed in vivo. Mechanically, miR-146b-5p targets the 3'-UTR of pyruvate dehydrogenase B (PDHB) and exerts oncogenic effect. Overexpression of PDHB abolished the oncogenic effects of miR-146b-5p on the growth, invasion and glycolysis of CRC cells. Taken together, our results show that miR-146b-5p is an oncogenic miRNA in CRC which exerts its effect by directly targeting PDHB.

Sox4 up-regulates Cyr61 expression in colon cancer cells.

BACKGROUND/AIMS: Genetic changes leading to aberrant activation of oncogenes are viewed as a crucial step in colon cancer. Sox4, a member of Sox (Sry-box) family of transcription factors, plays a critical role in tumorigenesis. METHODS: PCR-based microarrays were used to identify potential transcriptional target of Sox4. siRNA was used to knockdown the expression of Sox4. Luciferase and chromatin immunoprecipitation (ChIP) assays were used to test the transcriptional regulations. RESULTS: PCR-based microarrays found that Cyr61, a secreted extracellular matrix-associated signaling protein, was a transcriptional target of Sox4. Overexpression of Sox4 increased, while its knockdown using small interfering RNA (siRNA) reduced Cyr61 expression. A potential Sox4 binding motif located at the proximal Cyr61 promoter was identified. CONCLUSION: Thus, our results suggest a previously unknown Sox4-Cyr61 molecular network, which may control colon cancer cell proliferation and survival.

Hypoxia-inducible factor-1α (HIF-1α) C1772T polymorphism significantly contributes to the risk of malignancy from a meta-analysis.

Although the association between hypoxia-inducible factor-1α (HIF-1α) C1772T polymorphism and risk of malignancy has been widely studied, results from published studies remained controversial. Therefore, the relationship between them was further assessed in this meta-analysis. The databases of PubMed, Embase, and Wanfang were searched, and odds ratio with 95% confidence interval (OR and 95% CI) were used to assess the strength of the association. A total of 38 case-control studies with 23,876 participants were included. Overall, the T allele of HIF-1α C1772T was significantly associated with increased risk of malignancy development (OR and 95% CI 1.18 (1.00-1.38), P = 0.048 for T carriers vs. CC; 1.22 (1.05-1.41), P = 0.010 for T carriers vs. C carriers). When subgroup analyses were conducted, T allele was further found to be associated with increased risk of malignancy development for Asians rather than Caucasians (OR and 95% CI 1.36 (1.10-1.67), P = 0.004 for Asians) and for population-based studies (OR and 95% CI 1.19 (1.01-1.41), P = 0.040). Between-study heterogeneity existed in genetic comparison models, and meta-regression indicated that the participants' ethnicities and types of malignancy might be the sources of heterogeneity. No publication bias was found. In conclusion, this study indicated that HIF-1α C1772T polymorphism was significantly associated with increased risk of malignancy development for Asians. More studies were further required to focus on the relationship between HIF-1α C1772T polymorphism and risk of a specific type of tumor.