Phosphatase and Tensin Homolog (PTEN) Represses Colon Cancer Progression through Inhibiting Paxillin Transcription via PI3K/AKT/NF-κB Pathway.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) is frequently mutated in colon cancer. However, the potential contribution of loss of PTEN to colon cancer progression remains unclear. In this study, we demonstrated that PTEN overexpression or knockdown in Lovo colon cancer cells decreased or increased paxillin expression, respectively. Moreover, paxillin reversed PTEN-mediated inhibition of Lovo cell invasion and migration. Overexpression of PTEN in an orthotropic colon cancer nude mice model inhibited tumor formation and progression. In addition, PTEN protein level was negatively correlated with that of paxillin in human colon cancer tissues. Mechanistically, we identified three NF-κB binding sites on paxillin promoter and confirmed that paxillin was a direct transcriptional target of NF-κB. Our findings reveal a novel mechanism by which PTEN inhibits the progression of colon cancer by inhibiting paxillin expression downstream of PI3K/AKT/NF-κB pathway. Thereby, PTEN/PI3K/AKT/NF-κB/paxillin signaling cascade is an attractive therapeutic target for colon cancer progression.

TRIM26 functions as a novel tumor suppressor of hepatocellular carcinoma and its downregulation contributes to worse prognosis.

Hepatocellular carcinoma (HCC) is the one of the most common malignancies worldwide and its prognosis is extremely poor. Tripartite motif (TRIM) proteins play crucial roles in cancer cell biology but the function of tripartite motif 26 (TRIM26) has not been investigated. We demonstrated that low expression level of TRIM26 in tumor samples was significantly correlated with worse prognosis in HCC patients. We also demonstrated its expression level was associated with several clinicopathologic features such as AFP level and T stage of HCC patients. Furthermore, we validated that TRIM26 was significantly downregulated in HCC tissue compared with normal liver tissue. To further clarify the functional role of TRIM26 in HCC, We confirmed that TRIM26 silencing can promote cancer cell proliferation, colony forming, migration and invasion in vitro with HCC cell lines HepG2 and Bel-7402. Then we utilized bioinformatic tool to predict gene influenced by TRIM26, showing TRIM26 could modulate gene sets about cancer cell metabolism. In conclusion, we proved that TRIM26 is a novel tumor suppressor modulating multiple metabolism-related pathways in HCC. To our best knowledge, this is the first study to investigate the function of TRIM26 in cancer biology. Our findings provide useful insight into the mechanism of HCC origin and progression. Moreover, TRIM26 may represent a novel therapeutic target for HCC.

Sequence analysis of the HBV S protein in Chinese patients with coexisting HBsAg and anti-HBs antibodies.

The coexistence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in patients with hepatitis B virus (HBV) infection has been discovered and explained for several decades, but debate still exists. This study was to explore the relationship between this special serological pattern and mutations in S gene region. Fifteen patients with coexisting HBsAg and anti-HBs were selected as the experimental group, and 27 patients with HBsAg positive only were selected as the control group. The S gene region was amplified and sequenced. No significant differences were observed between the two groups with regard to age, gender, alanine aminotransferase level, HBsAg titer, genotype, and HBV DNA level. The patients from the two groups were infected with HBV of the genotype B and C. Compared with the control group, the experimental group showed a higher variability in amino acid within the N-terminal region and the MHR, especially the "a" determinant. The most frequent change in patients from the experimental group was located at positions s126. The coexistence of HBsAg and anti-HBs might be associated with the increased amino acid mutations in the "a" determinant. Further studies should be performed to determine the clinical implication of this serological pattern, including the binding of anti-HBs to HBsAg, escape from immune system, and efficacy of antiviral therapy.

Downregulation of TRIM21 contributes to hepatocellular carcinoma carcinogenesis and indicates poor prognosis of cancers.

The aim of our work is to clarify the clinical implication and functional role of tripartite motif 21 (TRIM21) in hepatocellular carcinoma (HCC). We validated that TRIM21 was downregulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that its downregulation was associated with several clinicopathologic features such as tumor numbers, T stage, Barcelona Clinic Liver Cancer (BCLC) stage, and Cancer of the Liver Italian Program (CLIP) stage of HCC patients. Importantly, the expression of TRIM21 in tumor samples is significantly correlated with the prognosis of the patients. We further silenced TRIM21 in HCC cell HepG2 and LM3 and confirmed that TRIM21 silencing will promote cancer cell proliferation (CCK-8 assay), colony forming (plate colony-forming assay), migration (transwell assay), and the ability of antiapoptosis (annexin V-FITC/PI staining) in vitro. Then, we predicted gene sets influenced by TRIM21 by using bioinformatic tools. For the first time, we prove that TRIM21 is a potential tumor suppressor in HCC and its low expression indicates poor prognosis. Our findings provide useful insight into the mechanism of HCC origin and progression and offer clues to novel HCC therapies.

Association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease risk in Caucasian: a meta-analysis.

OBJECTIVE: Published studies on the association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease (IBD) risk in Caucasian have yielded conflicting results. The present study aimed to provide more reliable conclusions by conducting a meta-analysis. METHODS: All eligible studies were extracted from Wiley Online Library, Chinese National Knowledge Infrastructure and PubMed databases. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations between rs4821544T/C polymorphism and IBD risk in Caucasian. RESULTS: A total of 13 case-control studies comprising 7441 Crohn's disease (CD) patients, 2565 ulcerative colitis (UC) patients and 8315 controls were included in this meta-analysis. Significant associations were found between CD and the rs4821544T/C polymorphism in three genetic models (C vs T: OR = 1.11, 95 % CI: 1.06, 1.16, P = 0.000; CC vs TT: OR = 1.31, 95 % CI: 1.18, 1.45, P = 0.000; CC/TC vs TT: OR = 1.07, 95 % CI: 1.01, 1.13, P = 0.014; CC vs TC/TT: OR = 1.28, 95 % CI: 1.16, 1.42, P = 0.000). However, significant associations were not found in UC under any genetic models (C vs T: OR = 1.04, 95 % CI: 0.97, 1.11, P = 0.264; CC vs TT: OR = 1.10, 95 % CI: 0.93, 1.30, P = 0.284; TC vs TT: OR = 1.04, 95 % CI: 0.95, 1.13, P = 0.429; CC/TC vs TT: OR = 1.04, 95 % CI: 0.95, 1.13, P = 0.390; CC vs TC/TT: OR = 1.07, 95 % CI: 0.91, 1.26, P = 0.409). CONCLUSION: This meta-analysis suggested that the rs4821544T/C polymorphism was associated with CD, but not UC in Caucasian.

Mutations in the S gene and in the overlapping reverse transcriptase region in chronic hepatitis B Chinese patients with coexistence of HBsAg and anti-HBs.

BACKGROUND: The mechanism underlying the coexistence of hepatitis B surface antigen and antibodies to HBsAg in chronic hepatitis B patients remains unknown. AIMS: This research aimed to determine the clinical and virological features of the rare pattern. METHODS: A total of 32 chronic hepatitis B patients infected by HBV genotype C were included: 15 carrying both HBsAg and anti-HBs (group I) and 17 solely positive for HBsAg (group II). S gene and reverse transcriptase region sequences were amplified, sequenced and compared with the reference sequences. RESULTS: The amino acid variability within major hydrophilic region, especially the "a" determinant region, and within reverse transcriptase for regions overlapping the major hydrophilic region in group I is significantly higher than those in group II. Mutation sI126S/T within the "a" determinant was the most frequent change, and only patients from group I had the sQ129R, sG130N, sF134I, sG145R amino acid changes, which are known to alter immunogenicity. CONCLUSIONS: In chronic patients, the concurrent HBsAg/anti-HBs serological profile is associated with an increased aa variability in several key areas of HBV genome. Additional research on these genetic mutants are needed to clarify their biological significance for viral persistence.

AGXT2L1 is down-regulated in heptocellular carcinoma and associated with abnormal lipogenesis.

AIMS: To clarify the clinical implications and functional role of the alanine-glyoxylate aminotransferase 2-like 1 (AGXT2L1) gene in hepatocellular carcinoma (HCC). METHODS AND RESULTS: We confirmed that AGXT2L1 was down-regulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that this down-regulation was associated with several clinicopathological features such as alpha fetoprotein (AFP) serum level and T stage. Furthermore, we showed with Kaplan-Meier analysis that expression of AGXT2L1 in tumour samples was significantly correlated with patient prognosis. The bioinformatic tool indicated that AGXT2L1 plays a role in the lipid metabolic process of HCC tissue, while siRNA silenced the expression of AGXT2L1 in HCC 97H and LM3 cells, confirming that down-regulation of AGXT2L1 promotes the lipogenesis of cancer cells. CONCLUSIONS: For the first time, we have shown that AGXT2L1 is down-regulated in HCC and its low expression indicates a poor prognosis. Our findings also demonstrated that AGXT2L1 is a crucial gene in the abnormal lipogenesis of HCC tissue.

Mutations in the S gene and in the overlapping reverse transcriptase region in chronic hepatitis B Chinese patients with coexistence of HBsAg and anti-HBs

Abstract Background The mechanism underlying the coexistence of hepatitis B surface antigen and antibodies to HBsAg in chronic hepatitis B patients remains unknown. Aims This research aimed to determine the clinical and virological features of the rare pattern. Methods A total of 32 chronic hepatitis B patients infected by HBV genotype C were included: 15 carrying both HBsAg and anti-HBs (group I) and 17 solely positive for HBsAg (group II). S gene and reverse transcriptase region sequences were amplified, sequenced and compared with the reference sequences. Results The amino acid variability within major hydrophilic region, especially the “a” determinant region, and within reverse transcriptase for regions overlapping the major hydrophilic region in group I is significantly higher than those in group II. Mutation sI126S/T within the “a” determinant was the most frequent change, and only patients from group I had the sQ129R, sG130N, sF134I, sG145R amino acid changes, which are known to alter immunogenicity. Conclusions In chronic patients, the concurrent HBsAg/anti-HBs serological profile is associated with an increased aa variability in several key areas of HBV genome. Additional research on these genetic mutants are needed to clarify their biological significance for viral persistence.