Formin protein FMNL1 is a biomarker for tumor-infiltrating immune cells and associated with well immunotherapeutic response.

Background: Increased studies on the basis of bulk RNA-sequencing (RNA-seq) data of cancer identify numbers of immune-related genes which may play potential regulatory roles in the tumor microenvironment (TME) without in-depth validation. Methods: In the current study, the immunological correlation and cell subpopulation expression pattern of FMNL1 were analyzed using public data. In addition, the cell subpopulation expression pattern of FMNL1 was also deeply validated using single-cell RNA-sequencing (scRNA-seq) and multiplexed quantitative immunofluorescence (mQIF). Results: Bulk FMNL1 mRNA was related to better prognosis in hepatocellular carcinoma (HCC) and was able to identify immuno-hot tumor in not only HCC but also multiple cancer types. Bulk FMNL1 mRNA also predicted the response to immunotherapy in multiple cancers. Further validation using scRNA-seq and mQIF revealed that FMNL1 was a biomarker for immune cells. Conclusions: FMNL1 is a biomarker for immune cells in not only hepatocellular carcinoma, but also multiple cancer types. Moreover, immune infiltration analysis using the bulk RNA-seq data would be further validated using scRNA-seq and/or mQIF to describe the cell subpopulation expression pattern in tumor tissues for more in-depth and appropriate understanding.

GBP2 is a prognostic biomarker and associated with immunotherapeutic responses in gastric cancer.

BACKGROUND: The interferon-induced protein known as guanylate-binding protein 2 (GBP2) has been linked to multiple different cancer types as an oncogenic gene. Although the role of GBP2 in cancer has been preliminarily explored, it is unclear how this protein interacts with tumor immunity in gastric cancer. METHODS: The expression, prognostic value, immune-correlations of GBP2 in gastric cancer was explored in multiple public and in-house cohorts. In addition, the pan-cancer analysis was performed to investigate the immunological role of GBP2 based on The Cancer Genome Atlas (TCGA) dataset, and the predictive value of GBP2 for immunotherapy was also examined in multiple public cohorts. RESULTS: GBP2 was highly expressed in tumor tissues and associated with poor prognosis in gastric cancer. In addition, GBP2 was associated with the immune-hot phenotype. To be more specific, GBP2 was positively related to immuno-modulators, tumor-infiltrating immune cells (TIICs), immunotherapy biomarkers, and even well immunotherapeutic response. In addition to gastric cancer, GBP2 was expected to be an indicator of high immunogenicity in most cancer types. Importantly, GBP2 could predict the immunotherapeutic responses in at least four different cancer types, including melanoma, urothelial carcinoma, non-small cell lung cancer, and breast cancer. CONCLUSIONS: To sum up, GBP2 expression is a promising pan-cancer biomarker for estimating the immunological characteristics of tumors and may be utilized to detect immuno-hot tumors in gastric cancer.

A superficial esophageal cancer with a diverticulum cured by endoscopic submucosal dissection.

Esophageal diverticulum are rare. However, Esophageal cancer that involves diverticula is relatively rare. Here we reported a rare case of a superficial esophageal cancer with an esophageal diverticulum, which was invisible before the endoscopic submucosal dissection. The cancer was successfully removed by ESD with no perforation.

CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA.

BACKGROUND: Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of human malignancies, but the underlying mechanisms remain largely elusive. METHODS: High-throughput sequencing was performed to screen aberrantly expressed circRNAs or miRNAs in colorectal cancer (CRC) and adjacent normal tissues. A series of gain- and loss-of-function studies were conducted to evaluate the biological behaviors of CRC cells. RNA pulldown, mass spectrometry, RIP, qRT-PCR, Western blot, luciferase reporter assays and MeRIP-seq analysis were further applied to dissect the detailed mechanisms. RESULTS: Here, a novel circRNA named circEZH2 (hsa_circ_0006357) was screened out by RNA-seq in CRC tissues, whose expression is closely related to the clinicpathological characteristics and prognosis of CRC patients. Biologically, circEZH2 facilitates the proliferation and migration of CRC cells in vitro and in vivo. Mechanistically, circEZH2 interacts with m6A reader IGF2BP2 and blocks its ubiquitination-dependent degradation. Meanwhile, circEZH2 could serve as a sponge of miR-133b, resulting in the upregulation of IGF2BP2. Particularly, circEZH2/IGF2BP2 enhances the stability of CREB1 mRNA, thus aggravating CRC progression. CONCLUSIONS: Our findings not only reveal the pivotal roles of circEZH2 in modulating CRC progression, but also advocate for attenuating circEZH2/miR-133b/IGF2BP2/ CREB1 regulatory axis to combat CRC.

Dishevelled-Associated Activator of Morphogenesis 2 (DAAM2) Predicts the Immuno-Hot Phenotype in Pancreatic Adenocarcinoma.

Background: DAAM2 participates in the oncogenesis and progression of human cancers. Although the role of DAAM2 in cancers has been preliminarily investigated, its correlations with antitumor immunity are unclear. Methods: A pancancer analysis was conducted to explore the immunological role of DAAM2 based on RNA sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). Next, correlations between DAAM2 and immunological characteristics in the tumor microenvironment (TME) of pancreatic adenocarcinoma (PAAD) were evaluated. In addition, the role of DAAM2 in predicting the clinical characteristics and the response to various therapies in PAAD were also assessed. In addition, the correlations between DAAM2 and the emerging immunobiomarker N6-methyladenosine (m6A) genes were also evaluated. Results: Pancancer analysis revealed that DAAM2 exhibited positive correlations with a majority of immunomodulators, tumor-infiltrating immune cells (TIICs) and inhibitory immune checkpoints in several cancer types, including PAAD. In addition, DAAM2 was associated with an inflamed phenotype in the tumor microenvironment (TME). DAAM2 also predicted significantly higher responses to chemotherapy, anti-EGFR therapy and immunotherapy but lower responses to anti-ERBB2 and antiangiogenic therapy. In addition, DAAM2 was correlated with immune-related microbiota. Conclusion: In PAAD, DAAM2 is associated with an immuno-hot phenotype and can help predict the outcome of various therapeutic options. Overall, DAAM2 is a promising indicator for assessing high immunogenicity in PAAD.

Dietary xylo-oligosaccharide ameliorates colonic mucus microbiota penetration with restored autophagy in interleukin-10 gene-deficient mice.

BACKGROUND: Inflammatory bowel disease (IBD) is, nowadays, highly prevalent and presents a global clinical challenge. The objective of this study is to assess the effects of xylo-oligosaccharide (XOS) on Il10-/- mice, a classic animal model of IBD. METHODS: Male wild-type (WT) mice were assigned to WT group, and Il10-/- mice were assigned to interleukin-10 gene-deficient (IL-10-KO) group and XOS group, respectively. There were 6-8 mice aged 8 weeks in each group. Mice in the XOS group received 1.0 g/kg/day XOS by gavage for 4 weeks. RESULTS: Compared with mice in IL-10-KO group, Il10-/- mice with XOS intervention presented significant mild spontaneous colitis with lower disease activity index, histological scores, and bowel inflammatory cytokine levels. Dietary XOS downregulated bowel mucus bacterial penetration, which occurred as early as the onset of bowel colitis. The effect of XOS was associated with restored expression of LC3II/I and decreased expression of p62 and beclin-1 in colon. CONCLUSIONS: Therefore, XOS decreases colonic mucus microbiota penetration with restored function of antophagy. Our findings suggest that XOS may be a potential dietary supplement or functional food for early management of IBD.

Comprehensive Analysis of Serum Metabolites Profiles in Acute Radiation Enteritis Rats by Untargeted Metabolomics.

Acute radiation enteritis is a common complication occurring in patients with pelvic and abdominal tumors who receive radiotherapy. Acute radiation enteritis seriously reduces the life quality, even threatens the lives of patients. Untargeted metabolomics is an emerging strategy to explore the novel biomarkers and uncover potential pathogenesis of acute radiation enteritis. Acute radiation enteritis rat model was established by single abdominal irradiation with a gamma-ray dose of 10 Gy. Serum from 15 acute radiation enteritis rats and 10 controls was extracted for metabolomics analysis by UHPLC-Q-TOF/MS. Clinical manifestations and morphological alterations of intestine confirmed the successful establishment of acute radiation enteritis. According to the metabolomics data, 6,044 positive peaks and 4,241 negative peaks were extracted from each specimen. OPLS-DA analysis and the heat map for cluster analysis showed satisfactory discriminatory power between acute radiation enteritis rats and controls. Subsequent analysis extracted 66 significantly differentially expressed metabolites, which might be potential biomarkers for acute radiation enteritis diagnosis. Moreover, Kyoto Encyclopedia of Genes and Genomes enrichment analyses uncovered the potential mechanisms through which differentially expressed metabolites participated in acute radiation enteritis pathogenesis. To sum up, we summarized several differentially expressed serum metabolites as potential biomarkers for diagnosis of acute radiation enteritis and provide latent clues for elucidating acute radiation enteritis pathology.

Decreased SLC39A1 (Solute carrier family 39 member 1) expression predicts unfavorable prognosis in patients with early-stage hepatocellular carcinoma.

Solute carrier family 39, member 1 (SLC39A1) is a member of the zinc-iron permease family and located to the cell membrane, acting as a zinc uptake transporter. However, the clinical impacts of SLC39A1 in early-stage hepatocellular carcinoma (EHCC) have not been defined. In this research, we compared the differential expression of SLC39A1 in EHCC and normal tissues based on tissue microarray, and the clinical significance of SLC39A1 in EHCC was evaluated as well. Compared with adjacent tissues, SLC39A1 was remarkably decreased in paired EHCC tissues. Besides, decreased SLC39A1 expression was significantly associated with several clinic-pathological features and serum biochemical indicators. Furthermore, Kaplan-Meier analysis exhibited that both overall survival (OS) and relapse-free survival (RFS) of patients with low expression of SLC39A1 were notably poorer than that of patients with high expression. Moreover, Cox regression analyses revealed that low expression of SLC39A1 was an independent prognostic factor for OS in patients with EHCC. Subgroup analysis also revealed beneficiary populations benefiting from the prognostic evaluation using SLC39A1 expression. Collectively, we summarized that downregulated expression of SLC39A1 is a worse prognostic factor for patients with EHCC, which can be used as a promising diagnostic and prognostic biomarker for EHCC.

A Novel Deep Learning System for Diagnosing Early Esophageal Squamous Cell Carcinoma: A Multicenter Diagnostic Study.

INTRODUCTION: This study aims to construct a real-time deep convolutional neural networks (DCNNs) system to diagnose early esophageal squamous cell carcinoma (ESCC) with white light imaging endoscopy. METHODS: A total of 4,002 images from 1,078 patients were used to train and cross-validate the DCNN model for diagnosing early ESCC. The performance of the model was further tested with independent internal and external validation data sets containing 1,033 images from 243 patients. The performance of the model was then compared with endoscopists. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and Cohen kappa coefficient were measured to assess performance. RESULTS: The DCNN model had excellent performance in diagnosing early ESCC with a sensitivity of 0.979, a specificity of 0.886, a positive predictive value of 0.777, a negative predictive value of 0.991, and an area under curve of 0.954 in the internal validation data set. The model also depicted a tremendously generalized performance in 2 external data sets and exhibited superior performance compared with endoscopists. The performance of the endoscopists was markedly elevated after referring to the predictions of the DCNN model. An open-accessed website of the DCNN system was established to facilitate associated research. DISCUSSION: A real-time DCNN system, which was constructed to diagnose early ESCC, showed good performance in validation data sets. However, more prospective validation is needed to understand its true clinical significance in the real world.

miR-224 Regulates the Aggressiveness of Hepatoma Cells Through the IL-6/STAT3/SMAD4 Pathway.

BACKGROUND: Previous studies have shown that miR-224 regulates the progression of liver cancer. The aim of this study was to investigate the underlying mechanisms. METHODS: The miR-224, p-STAT3 and SMAD4 expression levels were checked with tissue or/and serum samples of HCC patients by qRT-PCR or IHC methods. The regulatory role of IL-6 in p-STAT3 and SMAD4 was investigated by Western-blot. The targeted gene of miR-224 was verified by both Western-blot and luciferase reporter assay. Furthermore, the carcinogenesis of miR-224 in HCC was investigated by cell experiments in vitro and mouse xenograft model and in vivo imaging in vivo. RESULTS: It was found miR-224 was elevated in both tissue and serum of HCC patients. The p-STAT3 expression was higher but the SMAD4 was lower in the HCC tumor tissues. Moreover, IL-6 can induce the p-STAT3/STAT3 and miR-224 expression in HCC cells and STAT3 played the bridge role between IL-6 and miR-224. Target gene studies found miR-224 targeted the 3'UTR of SMAD4. Finally, the promoting roles of miR-224in the growth, proliferation, invasion and migration of HCC were discovered by in vitro and in vivo studies. CONCLUSION: It implies that miR-224 may potentially represent a new target for developing novel anti-HCC therapeutics.

Carcinoembryonic Antigen Related Cell Adhesion Molecule 6 Promotes Carcinogenesis of Gastric Cancer and Anti-CEACAM6 Fluorescent Probe Can Diagnose the Precancerous Lesions.

The diagnosis of precancerous lesions or early gastric cancer (EGC) is very important for patient survival. Molecular imaging is a visualized method that can easily and precisely diagnose tumors. However, there are currently few studies about molecular imaging diagnosis of EGC. Here, we studied the expression of carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) in the progression of GC. Then, the regulatory roles of CEACAM6 in GC cells were investigated. Furthermore, both the fluorescent-labeled and near infrared molecular-labeled probes were synthesized, and the diagnostic value of anti-CEACAM6 probes in GC was evaluated in vivo using a GC mice model as well as in vitro using fresh dysplastic gastric mucosa obtained from endoscopic submucosal dissection (ESD) operations. Our study showed that CEACAM6 was over expressed in GC tissues compared to adjacent tissues, and the patients with higher CEACAM6 expression had lower survival time. Moreover, the CEACAM6 expression was higher in the dysplastic gastric mucosa than in the adjacent normal mucosa. CEACAM6 accelerated the growth, proliferation, and invasion of GC cells in the in vitro and in vivo studies. Moreover, up regulated CEACAM6 can induce the expression of proteins related to GC progression. Furthermore, the anti-CEACAM6 probes exhibited good affinity with GC cell lines. The probes can track tumors as well as metastases in the mice model in vivo, and can precisely identify the area of dysplastic gastric mucosa using specimens obtained from ESD operations by wide field fluorescent endoscopy. The surface micro features of the mucosa can also be observed using fluorescent micro endoscopy, and the degree of atypia can be distinguished by both the signal intensity and surface micro morphology. CEACAM6 is a key molecular marker in GC progression, and the anti-CEACAM6 probe-assisted fluorescent endoscopy may be a potential option for the diagnosis of precancerous lesions.

Mechanistic Investigation on the Regulation of FABP1 by the IL-6/miR-603 Signaling in the Pathogenesis of Hepatocellular Carcinoma.

BACKGROUND: Abnormal lipid metabolism is closely associated with the invasiveness and metastasis of cancer. Fatty acid-binding proteins (FABPs) play essential roles in lipid metabolism, and miRNAs can affect lipid metabolism by targeting FABPs. However, the exact mechanism is unknown. METHODS: FABP1 expression in HCC tissues was analyzed by immunochemistry with tissue microarrays. The lipid content was detected by Oil Red O staining, and the interaction between FABP1 and free fatty acid (FFA) was studied by a labeling and tracking method. miRNA arrays were used to detect the expression of miRNAs in IL-6-stimulated HCC cells. miR-603 expression was verified by qPCR. The proteins were checked by Western blot analysis. Gain and loss function evaluation was assessed by lentivirus and miRNA mimic transfection in Huh-7 cells, while reactive oxygen species (ROS) were detected by fluorescence. RESULTS: FABP1 expression was significantly decreased in approximately 90% (81/90) of HCC patients. FABP1 expression in adjacent tissues was closely associated with overall survival. Meanwhile, lipid was abundant in the adjacent tissues, yet significantly reduced in HCC tissues. FABP1 and FFA can promote each other for being uptaken by Huh-7 cells. FABP1 overexpression induced apoptosis and inhibited the proliferation, migration, invasion, and metastasis of Huh-7 cells. IL-6 treatment affected the expression of miRNAs, and miR-603 was overexpressed in HCC tissues. Also, miR-603 overexpression promoted the proliferation, migration, invasion, and metastasis of Huh-7 cells. Bioinformatic analysis predicted that miR-603 targets the 3'-UTR region of FABP1. However, miR-603 overexpression inhibited the expression of the FABP1 but increased the CPT1A, PPAR-α, and SREBP1 expressions. FABP1 overexpression reduced ROS in HCC cells, while miR-603 can reverse these effects. CONCLUSION: Our results indicate that in the pathogenesis of HCC, IL-6 induces miR-603 expression, which subsequently inhibits FABP1 expression, promotes the lipid metabolism- and synthesis-related proteins, and finally increases the cellular oxidative stress level and leads to the metastasis of HCC.

High expression of FABP4 in colorectal cancer and its clinical significance.

OBJECTIVES: To investigate the relationship between the fatty acid-binding protein 4 (FABP4) and colorectal cancer (CRC). METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured the expression of FABP4 in plasma of 50 patients who underwent surgery for CRC from October 2017 to May 2018 and 50 healthy controls. The content of the visceral fat area (VFA) as seen with abdominal computed tomography (CT) scanning was measured by ImageJ software. The expression levels of FABP4, E-cadherin, and Snail proteins in CRC and adjacent tissues were determined by immunohistochemistry. RESULTS: The mean concentration of plasma FABP4 of CRC patients was higher than that of the control group (22.46 vs. 9.82 ng/mL; P<0.05). The concentration of plasma FABP4 was related to the tumor, node, metastatis (TNM) stage and lymph node metastasis and was independent of age, body mass index (BMI), tumor size and location, and the degree of differentiation of CRC. The concentration of plasma FABP4 was positively correlated with high VFA and lipoprotein-a (LPA) (P<0.05); but it was not correlated with total cholesterol (TG), total triglyceride (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), or apolipoprotein AI (Apo-AI). The expression of FABP4 protein in CRC tissues was positively correlated with the degree of CRC differentiation, tumor stage, and lymph node metastasis. The level of FABP4 protein was negatively correlated with E-cadherin protein (r=-0.3292, P=0.0196) and positively correlated with Snail protein (r=0.5856, P<0.0001). CONCLUSIONS: High LPA and VFA were risk factors for increased plasma FABP4 in CRC patients. FABP4 protein was highly expressed in CRC tissues and associated with TNM stage, differentiation, and lymph node metastasis of CRC. The level of FABP4 in CRC tissue was correlated with E-cadherin and Snail expression, suggesting that FABP4 may promote CRC progression related to epithelial-mesenchymal transition (EMT).

MicroRNA-23b-3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF-κB signaling pathways.

MicroRNA (miR)-23b-3p plays an important role in tumor growth, proliferation, invasion and migration in pancreatic cancer (PC). However, the function and mechanistic role of miR-23b-3p in the development of PC remains largely unknown. In the present study, the miR-23b-3p levels in the serum of patients with PC were found to be elevated, and the phosphorylation levels of Janus kinase (JAK)2, PI3K, Akt and NF-κВ were found to be upregulated. In addition, miR-23b-3p was induced in response to interleukin-6 (IL-6), which is known to be involved in the progression of PC. Overexpression of miR-23b-3p, on the other hand, activated the JAK/PI3K and Akt/NF-κB signaling pathways in PC cells, as evidenced by miR-23b-3p-induced upregulation of phosphorylated (p-)JAK2, p-PI3K, p-Akt and p-NF-κВ, as well as the downregulation of PTEN; and these effects were found to be reversible by miR-23b-3p inhibition. Furthermore, miR-23b-3p was found to downregulate PTEN by directly targeting the 3'-untranslated region of PTEN mRNA. Notably, in an in vivo xenograft mouse model, overexpression of miR-23b-3p accelerated PC cell-derived tumor growth, activated the JAK/Akt/NF-κВ signaling pathway and promoted liver metastasis. In contrast, knockdown of miR-23b-3p suppressed tumor growth and metastasis as well as JAK/Akt/NF-κВ signaling activity. In vivo imaging of the mice further confirmed the metastasis promoting role of miR-23b-3p in PC. These results suggested that miR-23b-3p enhances PC cell tumorigenesis and metastasis, at least, partially via the JAK/PI3K and Akt/NF-κB signaling pathways. Therefore, targeting miR-23b-3p or the JAK/PI3K and Akt/NF-κB signalings may be potential therapeutic strategy against PC.

IL-1ß Pretreatment Improves the Efficacy of Mesenchymal Stem Cells on Acute Liver Failure by Enhancing CXCR4 Expression.

BACKGROUND: Mesenchymal stem cells (MSCs), with the powerful metabolic and functional supporting abilities for inflammatory diseases, may be an effective therapeutic strategy for acute liver failure (ALF). However, the efficacy of MSCs can still be promoted if pretreatment is applied to enhance their poor migration towards the damaged liver. The purpose of this study is to determine the effect of IL-1ß pretreatment on the efficacy and homing ability of MSCs in ALF. METHODS: MSCs were isolated by the whole bone marrow adherence method and characterized. The efficacy and homing ability of IL-1ß-pretreated MSCs (Pre-MSCs) were examined in a rat ALF model and compared with that of MSCs and normal saline. Then, Western blot was performed to detect the c-Met and CXCR4 expression of MSCs and Pre-MSCs and followed by flow cytometry to detect the meaningful indicators. Finally, the migration abilities of different cells and different conditions were tested by the Transwell migration assay. RESULTS: MSCs of ideal purity were successfully isolated and cultured. Comparing with MSCs, Pre-MSCs had significantly better efficacy on improving the survival rate and liver function of ALF rats. Further analyses of damaged liver tissues showed that IL-1ß pretreatment significantly enhanced the efficacy of MSCs on suppressing liver necrosis. Besides, Pre-MSCs exhibited better effects in inhibiting apoptosis and activating proliferation. The results of tracing experiments with CM-Dil-labeled cells confirmed that more cells migrated to the damaged liver in the Pre-MSC group. In terms of mechanism, the CXCR4 expression was significantly enhanced by IL-1ß pretreatment, and an increased migration ability towards SDF-1 that could be reversed by AMD3100 was found in Pre-MSCs. CONCLUSION: IL-1ß pretreatment could enhance the homing ability of MSCs at least partially by increasing the expression of CXCR4 and further improve the efficacy of MSCs on ALF.

Systematic Characterization of the Expression and Prognostic Values of Formin-Like Gene Family in Gastric Cancer.

Formin-like genes (FMNLs) are members of formins family and have been implicated to the development and progression of multiple cancers. This research aims to analyze the expression profiles, prognostic values, and immune infiltrating associations of FMNLs in gastric cancer (GC) using multiple online bioinformatics website, including Oncomine, UALCAN, Kaplan-Meier Plotter, TIMER, GeneMANIA, DAVID, and LinkedOmics databases. The mRNA levels of FMNL1/2/3 were higher in GC tissues than normal. Meanwhile, FMNLs expressions tend to be upregulated in advanced and poorly differentiated GC. Prognostic value analysis suggested that high transcription levels of FMNL1/3 were associated with poor overall survival in GC patients. Correlation analysis between FMNLs expressions and immune infiltrating GC revealed that the expressions of FMNLs were significantly associated with immune infiltrating. Protein-protein interaction network and enrichment analysis of FMNLs in GC showed that FMNLs coexpressed genes mainly participated in organizing actin cytoskeleton through affecting small G proteins activity. Moreover, Gene Set Enrichment Analysis (GSEA) analysis uncovered FMNLs and their coexpressed genes was tightly associated with immune-related cellular functions. These findings demonstrate that FMNLs might play significant immunomodulatory roles in tumor immunity and could be novel therapeutic targets and potential prognostic biomarkers in GC.

Community-Based Pilot Study of a Screening Program for Gastric Cancer in a Chinese Population.

A majority of gastric cancer cases in China are diagnosed at advanced stages, chiefly due to lack of an established routine nationwide screening program. This study evaluated the effectiveness of a novel screening program for gastric cancer. Seven geographic communities were randomly selected, and residents ages 40-69 years were screened. Serologic tests of Helicobacter pylori antibodies and pepsinogens, and positive family history of gastric cancer in first-degree relatives (FDR), were used to differentiate individuals for further gastroscopic examination and gastric mucosal biopsies. Among 7,773 individuals who underwent examination of serum markers, gastric cancer was detected in 14 (1.8%; 10 men). The rate in terms of gastric cancer cases per 100 gastroendoscopies was 1.6% (14/872), which was greater than 0.87% previously reported. Eleven of 14 patients with gastric cancer (78.6%) were FDRs of patients with gastric cancer. Two-thirds of the subjects with cardia gastric cancer were FDRs of individuals with gastric cancer rather than cardia gastric cancer. Comparative analysis indicated that the gastric cancer subjects were significantly more likely to be FDRs of patients with gastric cancer, in contrast to those without gastric cancer. All the individuals with gastric cancer were aged ≥50 years. After conducting a reverse analysis, we propose a novel screening program for gastric cancer. In conclusions, the populations most vulnerable to gastric cancer are those with positive family history of gastric cancer in FDRs, male gender, and aged 50 years or older. This screening program using fewer serum markers combined individual risk factors, mainly FDRs, is novel for identification of high-risk individuals for further gastroscopy in detecting early gastric cancer.

PSMC2 is Up-regulated in Pancreatic Cancer and Promotes Cancer Cell Proliferation and Inhibits Apoptosis.

Objective: The lack of effective therapeutic targets poses a leading challenge to prolong survival and improve the quality of life for pancreatic cancer patients. Proteasome 26S subunit ATPase 2 (PSMC2), a recently discovered gene, has been implicated in certain human carcinogenesis. However, limited data is available concerning the functional significance of PSMC2 in cancer cell growth, and whether it plays a role in pancreatic carcinogenesis remains unknown. Materials and Methods: Quantitative RT-PCR (qRT-PCR) was performed to assess mRNA expression levels of PSMC2 in different pancreatic cancer cell lines. Knockdown of PSMC2 was achieved by using short hairpin RNA (shRNA). The effects of PSMC2 silencing on pancreatic cancer cell proliferation and apoptosis were evaluated by the MTT cell proliferation assay, Celigoassays, Annexin V fluorescence-activated cell sorting (FACS) assay and Caspase-3/7 array. Results: High expression of PSMC2 was detected in three pancreatic cancer cell lines (SW1990, PANC-1, and AsPC-1). Knockdown of PSMC2 in SW1990 cells inhibited proliferation and enhanced apoptosis. Conclusions: Our primary study suggests that PSMC2 might be involved in the progression of pancreatic cancer and may serve as a potential therapeutic target.

Up-regulation of miR-155 contributes to TNF-mediated hepatocyte apoptosis in acute liver failure.

BACKGROUND/AIMS: Acute liver failure (ALF) is due to severe immune response, resulting in massive apoptosis/necrosis of hepatocytes. The precise mechanism has not been explored yet. MATERIALS AND METHODS: The mouse with ALF model was induced by D-GalN/LPS; the hepatic miRNAs expression profile was evaluated by miRNA microarray and verified by RT-PCR. During the ALF in mice, the miR-155 expression was detected in the liver as well as in spleen. Then the correlation between miR-155 and inflammatory cytokines was evaluated. Furthermore, the miR-155 expression in activated Raw264.7 cells and apoptotic hepatocytes was also studied. Finally, the regulatory roles of miR-155 in TNF expression of apoptotic hepatocytes were shown. RESULTS: It was shown that miRNAs changed in the mice with ALF relating to hepatocytes apoptosis/necrosis; the selected miRNAs were confirmed with RT-PCR. miR-155 was up-regulated, but miR-698, -720, and -329 were down-regulated. Moreover, hepatic miR-155 was up-regulated at all-time points in the liver, but only at 7 h in spleen of mice with ALF. A significant correlation was observed between hepatic miR-155 and TNF/IL-6 in mice with ALF, which was supported by the findings in vitro showing up-regulated miR-155 in Raw264.7 cells and Hepa1-6 cells under LPS or D-GalN+TNF induction, respectively. Moreover, a correlation was observed between miR155 and TNF levels in vivo and in vitro. CONCLUSION: These data demonstrate that miR-155 regulates TNF-mediated hepatocyte apoptosis in ALF, which provides some useful information in both basic and clinical researches.