Analysis of serum hepatitis B virus RNA levels among HBsAg and HBsAb copositive patients and its correlation with HBV DNA.

ABSTRACT: There are approximately 2 billion HBV-infected individuals worldwide, and approximately 1.87% to 7% of these individuals are copositive for HBsAg and HBsAb.Our study detected hepatitis B virus pgRNA (HBV RNA) levels in HBsAg and HBsAb copositive patients and then analyzed the correlation with HBV DNA, HBsAg, ALT, and AST levels. A total of 149 HBsAg and HBsAb copositive patients were identified from 66,617 outpatients.HBV RNA, HBV DNA, HBsAg, ALT, and AST serum levels were significantly different in different natural phases of HBV infection (immune tolerance phase, immune clearance phase, low replication phase, and reactivation phase) with statistical significance (P < .01). HBV RNA levels were positively correlated with HBV DNA, HBsAg, ALT, and AST levels. HBV RNA and HBV DNA levels were significantly increased in the HBeAg-positive group (66 patients) compared with the HBeAg-negative group (83 patients) (P < .01). In the HBeAg-positive group, HBV RNA levels were positively correlated with HBV DNA and HBsAg levels. In the HBeAg-negative group, HBV RNA levels were positively correlated with HBV DNA. Serum HBV RNA levels were positively correlated with HBV DNA, HBsAg, ALT, and AST levels.HBV RNA could be used as a virological indicator for antiviral therapy in HBsAg and HBsAb copositive hepatitis B patients.

Clinico-Laboratory Features and Associated Factors of Lupus Mesenteric Vasculitis.

INTRODUCTION: Lupus mesenteric vasculitis (LMV) is a rare but potentially life-threatening clinical entity in systemic lupus erythematosus (SLE) patients. OBJECTIVE: The present study was initiated to explore the clinical features and associated factors of LMV in SLE patients. METHODS: We conducted a retrospective study on 50 cases of SLE patients with lupus mesenteric vasculitis (LMV) from January 2010 to December 2019 and 89 cases of non-LMV-SLE patients with similar demographic and comorbidities were included as control. All the data regarding clinical features, laboratory findings, and treatment were reviewed independently by two experts in the field. Both univariate and multivariate logistic regression analyses were employed to identify the associated factors of LMV. RESULTS: The incidence of LMV was 2.9% among hospitalized SLE patients in the current study. The most frequent symptom and physical sign of LMV were respectively abdominal pain (48, 96%) and abdominal tenderness (45, 90%). Through univariate and subsequent multivariate analysis, oral ulcer (OR, 4.25; P = 0.024), urinary tract involvement (OR, 5.23; P = 0.021), and elevated D-dimer (OR, 1.121; P = 0.008) were demonstrated to be positively associated with LMV, while percentage of lymphocytes (OR, 0.928; P = 0.004) and complement 3 (OR, 0.048; P = 0.008) were negatively correlated with LMV. CONCLUSIONS: Oral ulcer, urinary tract involvement, reduced percentage of lymphocytes and complement 3, elevated D-dimer could be associated factors for LMV in SLE patients.

Rab23 Promotes Hepatocellular Carcinoma Cell Migration Via Rac1/TGF-ß Signaling.

Rab23 is a member of Ras-related small GTPase family, which plays a critical role in the progression of wide range of tumors. However, its biological function in hepatocellular carcinoma still remains unclear. Here, we investigated the effects of Rab23 on proliferation and migration in hepatocellular carcinoma cell and its potential mechanisms. We found over-expression of Rab23 promoted the Hep3B hepatocellular carcinoma cell migration, which could be reversed by Rab23 silencing. Rab23 induced Rac1 activation and followed progression of epithelial-mesenchymal transition (EMT) along with upregulation of N-cadherin, snail as well as vimentin and downregulation of E-cadherin via upregulating Transforming Growth Factor-ß (TGF-ß). Silencing Rac1 significantly attenuated Rab23-induced HepG2 migration and TGF-ß. Moreover, knockdown of TGF-ß effectively attenuated Rab23-induced EMT. Taken together, we demonstrated a mechanistic cascade of Rab23 enhangcing Rac1 activation and subsequent TGF-ß expression, leading to hepatocellular carcinoma cell migration.

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study.

Immune infiltration of colorectal cancer (CRC) is closely associated with clinical outcome. However, previous work has not accounted for the diversity of functionally distinct cell types that make up the immune response. In this study, based on a deconvolution algorithm (known as CIBERSORT) and clinical annotated expression profiles, we comprehensively analyzed the tumor-infiltrating immune cells present in CRC for the first time. The fraction of 22 immune cells subpopulations was evaluated to determine the associations between each cell type and survival and response to chemotherapy. As a result, profiles of immune infiltration vary significantly between paired cancer and paracancerous tissue and the variation could characterize the individual differences. Of the cell subpopulations investigated, tumors lacking M1 macrophages or with an increased number of M2 macrophages, eosinophils, and neutrophils were associated with the poor prognosis. Unsupervised clustering analysis using immune cell proportions revealed five subgroups of tumors, largely defined by the balance between macrophages M1, M2, and NK resting cells, with distinct survival patterns, and associated with well-established molecular subtype. Collectively, our data suggest that subtle differences in the cellular composition of the immune infiltrate in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and response to treatment.

Nomogram Integrating Genomics with Clinicopathologic Features Improves Prognosis Prediction for Colorectal Cancer.

The current tumor staging system is insufficient for predicting the outcomes for patients with colorectal cancer because of its phenotypic and genomic heterogeneity. Integrating gene expression signatures with clinicopathologic factors may yield a predictive accuracy exceeding that of the currently available system. Twenty-seven signatures that used gene expression data to predict colorectal cancer prognosis were identified and re-analyzed using bioinformatic methods. Next, clinically annotated colorectal cancer samples (n = 1710) with the corresponding expression profiles, that predicted a patient's probability of cancer recurrence, were pooled to evaluate their prognostic values and establish a clinicopathologic-genomic nomogram. Only 2 of the 27 signatures evaluated showed a significant association with prognosis and provided a reasonable prediction accuracy in the pooled cohort (HR, 2.46; 95% CI, 1.183-5.132, P < 0.001; AUC, 60.83; HR, 2.33; 95% CI, 1.218-4.453, P < 0.001; AUC, 71.34). By integrating the above signatures with prognostic clinicopathologic features, a clinicopathologic-genomic nomogram was cautiously constructed. The nomogram successfully stratified colorectal cancer patients into three risk groups with remarkably different DFS rates and further stratified stage II and III patients into distinct risk subgroups. Importantly, among patients receiving chemotherapy, the nomogram determined that those in the intermediate- (HR, 0.98; 95% CI, 0.255-0.679, P < 0.001) and high-risk (HR, 0.67; 95% CI, 0.469-0.957, P = 0.028) groups had favorable responses.Implications: These findings offer evidence that genomic data provide independent and complementary prognostic information, and incorporation of this information refines the prognosis of colorectal cancer. Mol Cancer Res; 16(9); 1373-84. ©2018 AACR.

Prediction and Validation of Hub Genes Associated with Colorectal Cancer by Integrating PPI Network and Gene Expression Data.

Although hundreds of colorectal cancer- (CRC-) related genes have been screened, the significant hub genes still need to be further identified. The aim of this study was to identify the hub genes based on protein-protein interaction network and uncover their clinical value. Firstly, 645 CRC patients' data from the Tumor Cancer Genome Atlas were downloaded and analyzed to screen the differential expression genes (DEGs). And then, the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed, and PPI network of the DEGs was constructed by Cytoscape software. Finally, four hub genes (CXCL3, ELF5, TIMP1, and PHLPP2) were obtained from four subnets and further validated in our clinical setting and TCGA dataset. The results showed that mRNA expression of CXCL3, ELF5, and TIMP1 was increased in CRC tissues, whereas PHLPP2 mRNA expression was decreased. More importantly, high expression of CXCL3, ELF5, and TIMP1 was significantly associated with lymphatic invasion, distance metastasis, and advanced tumor stage. In addition, a shorter overall survival was observed in patients with increased CXCL3, TIMP1, and ELF5 expression and decreased PHLPP2 expression. In conclusion, the four hub genes screened by our strategy could serve as novel biomarkers for prognosis prediction of CRC patients.

Disruption of the c-Myc/miR-200b-3p/PRDX2 regulatory loop enhances tumor metastasis and chemotherapeutic resistance in colorectal cancer.

BACKGROUND: Metastasis is a major threat to colorectal cancer (CRC) patients. We have reported that peroxiredoxin-2 (PRDX2) is associated with CRC invasion and metastasis. However, the mechanisms regulating PRDX2 expression remain unclear. We investigate whether microRNAs (miRNAs) regulate PRDX2 expression in CRC progression. METHODS: Quantitative real-time polymerase chain reaction (qPCR) was used to measure microRNA-200b-3p (miR-200b-3p) expression. Immunohistochemistry (IHC) was performed to detect c-Myc and PRDX2 protein levels in CRC tissue samples (n = 97). Western blot was used to quantify PRDX2, c-Myc, AKT2/GSK3ß pathway-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins in CRC cells. Luciferase reporter assays were used to analyze the interaction between miR-200b-3p and 3'untranslated region (3'UTR) of PRDX2 mRNA and AKT2 mRNA as well as c-Myc and the miR-200b-3p promoter. Chromatin immunoprecipitation (ChIP) assay was used to evaluate binding of c-Myc to the miR-200b-3p promoter. Invasive assay and metastatic model were used to assess invasive and metastatic capacities of CRC cells in vitro and in vivo. Moreover, drug-induced apoptosis was measured by flow cytometry. RESULTS: We found that miR-200b-3p was significantly downregulated, whereas c-Myc and PRDX2 were upregulated in metastatic CRC cells and CRC tissues compared to their counterparts. An inverse correlation existed between c-Myc and miR-200b-3p, and between miR-200b-3p and PRDX2. We also found that PRDX2 was a target of miR-200b-3p. Importantly, overexpression of nontargetable PRDX2 eliminated the suppressive effects of miR-200b-3p on proliferation, invasion, EMT, chemotherapeutic resistance and metastasis of CRC cells. Moreover, c-Myc bound to the promoter of miR-200b-3p and repressed its transcription. In turn, miR-200b-3p disrupted the stability of c-Myc protein by inducing c-Myc protein threonine 58 (T58) phosphorylation and serine 62 (S62) dephosphorylation via AKT2/GSK3ß pathway. CONCLUSIONS: Our findings reveal that the c-Myc/miR-200b/PRDX2 loop regulates CRC progression and its disruption enhances tumor metastasis and chemotherapeutic resistance in CRC.

An integrated lncRNA, microRNA and mRNA signature to improve prognosis prediction of colorectal cancer.

Although the outcome of patients with colorectal cancer (CRC) has improved significantly, prognosis evaluation still presents challenges due to the disease heterogeneity. Increasing evidences revealed the close correlation between aberrant expression of certain RNAs and the prognosis. We envisioned that combined multiple types of RNAs into a single classifier could improve postoperative risk classification and add prognostic value to the current stage system. Firstly, differentially expressed RNAs including mRNAs, miRNAs and lncRNAs were identified by two different algorithms. Then survival and LASSO analysis was conducted to screen survival-related DERs and build a multi-RNA-based classifier for CRC patient stratification. The prognostic value of the classifier was self-validated in the TCGA CRC cohort and further validated in an external independent set. Finally, survival receiver operating characteristic analysis was used to assess the performance of prognostic prediction. We found that the multi-RNA-based classifier consisted by 12 mRNAs, 1miRNA and 1 lncRNA, which could divide the patients into high and low risk groups with significantly different overall survival (training set: HR 2.54, 95%CI 1.67-3.87, p<0.0001; internal testing set: HR 2.54, 95%CI 1.67-3.87, p<0.0001; validation set: HR 5.02, 95% CI 2.2-11.6; p=0·0002). In addition, the classifier is not only independent of clinical features but also with a similar prognostic ability to the well-established TNM stage (AUC of ROC 0.83 versus 0.74, 95% CI = 0.608-0.824, P =0.0878). Furthermore, combination of the multi-RNA-based classifier with clinical features was a more powerful predictor of prognosis than either of the two parameters alone. In conclusion, the multi-RNA-based classifier may have important clinical implications in the selection of patients with CRC who are at high risk of mortality and add prognostic value to the current stage system.

Peroxiredoxin 2 is essential for maintaining cancer stem cell-like phenotype through activation of Hedgehog signaling pathway in colon cancer.

Cancer stem cells (CSCs) are a key target for reducing tumor growth, metastasis, and recurrence. Redox status is a critical factor in the maintenance of CSCs, and the antioxidant enzyme Peroxiredoxin 2 (Prdx2) plays an important role in the development of colon cancer. Therefore, we investigated the contribution of Prdx2 to the maintenance of stemness of colon CSCs. Here, we used short-hairpin RNAs and a Prdx2-overexpression vector to determine the effects of Prdx2. We demonstrated that knockdown of Prdx2 reduced the self-renewal and sphere formation and resulted in increased 5-FU-induced apoptosis in human colon CSCs. Prdx2 overexpression induced reversion of the self-renewal and sphere formation. Furthermore, the effects of Prdx2 resulted in an altered expression of stemness associated with the Hh/Gli1 signaling pathway. Finally, knockdown of Prdx2 in CD133+ cells reduced the volume of xenograft tumors in BALB/c-nu mice. Taken together, colon CSCs overexpress Prdx2, which promotes their stem cell properties via the Hh/Gli1 signaling pathway. The results suggest that Prdx2 may be an effective therapeutic target for the elimination of CSCs in colorectal cancer.