MDM2 SNP309 is an ethnicity-dependent risk factor for digestive tract cancers.

Published data on the relationship between T309G polymorphism in the murine double minute 2 (MDM2) gene and susceptibility of digestive tract cancers (DTC) are inconclusive. Thus, the aim of this study is to determine whether MDM2 T309G polymorphism is associated with the risk of diverse DTC, including esophagus, stomach, liver, bile duct, pancreas, and colorectum cancers. Relevant studies were identified up to October 1, 2013. Crude odds ratio (OR) and 95% confidence interval (CI) were used as a measure of the strength of the association. The pooled result based on all studies showed that there was a statistically significant link between MDM2 T309G polymorphism and DTC susceptibility (T vs. G: OR = 0.82, 95%CI = 0.76-0.88). When stratified by race, significant associations were observed for all genetic models among Asians (especially in Chinese population), but not among Caucasians. Subgroup analyses according to tumor location indicated that the genetic variant was associated with esophageal (OR = 0.88, 95%CI = 0.81-0.96 for T vs. G), hepatocellular (OR = 0.69, 95%CI = 0.57-0.84 for T vs. G) and pancreatic cancer risk but not associated with cholangiocarcinoma or colorectum cancer susceptibility. Meanwhile, the G allele was also suggested to be associated with increased gastric cancer risk (OR = 0.68, 95%CI = 0.54-0.87 for TT + TG vs. GG for intestinal type of gastric cancer and OR = 0.18, 95%CI = 0.06-0.50 for TT vs. GG for Helicobacter pylori infection positive stomach cancer). Our study indicates that the MDM2 T309G polymorphism may be an ethnicity-dependent risk factor for DTC, especially for the upper gastrointestinal tract malignancies.

Does gastric stump cancer really differ from primary proximal gastric cancer? A multicentre, propensity score matching-used, retrospective cohort study.

BACKGROUND: Although the location of proximal cancer of the remnant stomach is the same as that of primary proximal cancer of the stomach, its clinical characteristics and prognosis are still controversial. AIM: To evaluate the clinicopathological features and prognosis factors of gastric stump cancer (GSC) and primary proximal gastric cancer (PGC). METHODS: From January, 2005 to December, 2016, 178 patients with GSC and 957 cases with PGC who received surgical treatment were enrolled. Patients in both groups underwent 1:1 propensity score matching analysis, and both clinical and pathological data were systematically collected for statistical purposes. Quality of life was evaluated by the C30 and STO22 scale between GSC-malignant (GSC following gastric cancer) and GSC-benign (GSC following benign lesions of the stomach). RESULTS: One hundred and fifty-two pairs were successfully matched after propensity score matching analysis. Of the 15 demographic and pathological variables collected, the analysis further revealed that the number of lymph nodes and positive lymph nodes were different prognostic and clinicopathological factors between PGC and GSC. Univariate and multivariate analyses showed that gender, differentiation degree and tumor-node-metastasis stage were independent risk factors for patients with GSC. Gender, vascular invasion, differentiation degree, depth of infiltration, positive lymph nodes, and tumor-node-metastasis stage were independent risk factors for patients with PGC. The 5-year overall survival and cancer-specific survival of patients with GSC were significantly lower than those in the PGC group, the scores for overall quality of life in the GSC-malignant group were lower than the GSC-benign, and the differences were statistically significant. CONCLUSION: The differences in clinicopathological characteristics between GSC and PGC were clarified, and PGC had a better prognosis than GSC.

Noninvasive analysis of portal pressure by contrast-enhanced sonography in patients with cirrhosis.

OBJECTIVES: Free portal pressure measurement is a reliable method for assessment of portal pressure in patients with cirrhosis. Intrahepatic circulatory time analysis of a sonographic contrast agent can assess liver fibrosis and its severity. The purposes of this pilot study were to assess the correlation between the intrahepatic circulatory time and free portal pressure and to assess whether intrahepatic circulatory time analysis can be used to predict portal venous pressure severity. METHODS: The intrahepatic circulatory time and free portal pressure were measured in 31 patients with hepatitis B virus-related liver disease. Pearson correlation analysis was used to assess the correlation between the intrahepatic circulatory time and free portal pressure. RESULTS: The hepatic vein-hepatic artery interval times were significantly shorter in the portal hypertension group than the non-portal hypertension group (mean ± SD, 8.26 ± 1.94 and 13.83 ± 1.17 seconds, respectively; P < .001). The portal vein-hepatic artery interval times were significantly longer in the portal hypertension group than the nonportal hypertension group (13.13 ± 2.25 and 7.25 ± 1.81 seconds; P < .001). Considering the whole patient population, there were statistically significant correlations between free portal pressure and the hepatic vein-hepatic artery interval time (r = -0.900; P < .001) and portal vein-hepatic artery interval time (r = 0.808; P < .001). In patients with portal hypertension, there was a statistically significant correlation between free portal pressure and the hepatic vein-hepatic artery interval time (r = -0.804; P = .009) and a weak correlation between free portal pressure and the portal vein-hepatic artery interval time (r = 0.506; P = .036). CONCLUSIONS: Intrahepatic circulatory time measurement is correlated with free portal pressure and has the potential capability to evaluate portal pressure noninvasively in patients with hepatitis B virus-related liver disease.

miR-135b-5p Suppresses Androgen Receptor-Enhanced Hepatocellular Carcinoma Cell Proliferation via Regulating the HIF-2α/c-Myc/P27 Signals in vitro.

INTRODUCTION: Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers and is ranked as the fifth most common malignancy. Androgen receptor (AR) may promote the progression of HCC at an early stage of the disease. However, this study identified miR-135b-5p as an AR upstream regulator can suppress AR protein expression and inhibit HCC proliferation, consistent with the idea that AR expression is negatively correlated with HCC progression. METHODS: The target microRNAs were predicted using online databases (TargetScan, miRDB, and MicroCosm Targets). Cell proliferation ability was measured by MTT and colony formation assay. Western blot was performed to analyze the expression levels of AR, HIF-2α, c-Myc, and p27, which are related to HCC proliferation. Chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay were carried out to investigate the mechanism by which miR-135b-5p decreases AR expression. RESULTS: miR-135b-5p suppresses HCC cell proliferation and AR expression. Downregulation of AR expression by miR-135b-5p may in turn transcriptionally modulate HIF-2α expression via direct binding of AR to the androgen response element (ARE) in the HIF-2α promoter. Further dissection of the mechanism revealed that AR-modulated HIF-2α could suppress c-Myc expression resulting in increased p27 expression that likely contributes to the suppression of proliferation in HCC cells. CONCLUSION: miR-135b-5p suppresses HCC cell proliferation via targeting AR-modulated HIF-2α/c-Myc/p27 signals, which may help to develop more effective therapies to prevent HCC progression.

A critical analysis of the relationship between aldehyde dehydrogenases-2 Glu487Lys polymorphism and colorectal cancer susceptibility.

Studies investigating the association between genetic polymorphism of aldehyde dehydrogenases-2 (ALDH-2) Glu487Lys and colorectal cancer (CRC) risk have reported conflicting results. Given this uncertainty, we carried out a critical analysis of published case-control studies to derive a more precise estimation of this relationship. Published literature from PubMed, EMBASE and China Knowledge Resource Integrated Database were retrieved, and the literature search was updated in June 2014. Eleven studies comprising 6965 subjects were selected (2300 cases and 4665 controls). Overall, our study showed no statistical significance for CRC risk associated with any of the genetic models of ALDH-2 Glu487Lys polymorphism. When studies were stratified for control source, a decreased risk of CRC for participants with Lys/Lys was observed in population based case-control studies [Lys/Lys vs. (Glu/Lys + Glu/Glu): odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38-0.87]. Furthermore, we also confirmed the significant correlation between Glu487Lys polymorphism and the influence on the risk of rectal cancer in males [Glu/Glu vs. (Glu/Lys + Lys/Lys): OR = 1.52, 95%CI = 1.10-2.08]. The combined effects of the two gene polymorphisms [ALDH-2 and alcohol dehydrogenase 1B (ADH-1B)] were also studied. Compared with subjects having ALDH-2 Lys+ with ADH-1B His/His, ORs and 95%CIs for those with ALDH-2 Glu/Glu and ADH-1B His/His was 3.42(0.57-20.38). Similar trends were observed for the other two types of comparisons. Our study supports that ALDH-2 Glu487Lys polymorphism is associated with significant reduced risks of CRC in population-based samples, and of rectal cancer in males.

A novel retinoic acid analog, 4-amino-2-trifluoromethyl-phenyl retinate, inhibits gastric cancer cell growth.

Retinoic acid (RA) analogs have been used in the treatment of a variety of cancers; however, their application is limited due to serious therapy-related sequelae. In the present study, the effects of a novel RA analog, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), on the growth of gastric cancer cells were evaluated. Three gastric cancer cell lines, AGS, MKN-74 and SC-M1, were treated with either all­trans retinoic acid (ATRA) or ATPR, and their growth and distribution in different cell cycle phases were assessed using an MTT assay and propidium iodide (PI) staining followed by flow cytometry. The binding affinity of ATPR to the retinoic acid receptors, retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α), was determined using ligand-binding assays. Activator protein-1 (AP-1) activity was measured using a luciferase reporter assay. Western blot analysis was used to determine cyclin E, Bcl-2 and Bax protein expression. ATPR preferentially bound RXR-α (0.04 nM) as compared with RAR-α (20.96 nM). Although both ATRA and ATPR inhibited the growth of AGS, MKN-74 and SC-M1 cells in a dose-dependent manner, a significantly greater inhibitory effect was observed with treatment with 5 and 500 µM ATPR for 3 days (P<0.05). In addition, ATPR (50 µM), but not ATRA, significantly increased the population of AGS and MKN-74 cells in the subG1 phase and decreased the Bcl-2/Bax ratio (P<0.05). Furthermore, in MNK-74 and SC-M1 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and 5 or 10 µM of ATPR significantly suppressed the activity of the AP-1 reporter as compared to treatment with ATRA (P<0.05). Thus, ATPR inhibits cancer cell proliferation to a greater extent compared to ATRA, possibly through the RXR-mediated inhibition of AP-1 activity.

Retinoid receptors in gastric cancer: expression and influence on prognosis.

BACKGROUND: Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatment approaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation, proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors, each with three subclasses, α, ß and γ. At present, little is known about retinoid expression and influence on prognosis in gastric cancers. PATIENTS AND METHODS: We retrospectively analyzed the expression of the subtypes RARα, RARß, RARγ, RXRα, RXRß, RXRγ by immunohistochemistry in 147 gastric cancers and 51 normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the results with clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using real- time PCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80 patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA). RESULTS: RARα, RARß, RARγ and RXRγ positively correlated with each other (p<0.001) and demonstrated significantly lower levels in the carcinoma tissue sections (p<0.01), with lower RARß, RARγ and RXRα expression significantly related to advanced stages (p<=0.01). Tumors with poor histopathologic grade had lower levels of RARα and RARß in different histological types of gastric carcinoma (p<0.01). Patients whose tumors exhibited low levels of RARa expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor (p<0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment had significantly longer median survival times (p=0.007, HR=0.41, 95.0% CI 0.21-0.80). CONCLUSIONS: Retinoic acid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression and RARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic use of retinoids against gastric cancer.