Dingzhi Huang

A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis

BACKGROUND Prognosis of patients with gastric cancer (GC) is generally poor due to the lack of non-invasive tools for GC detection. The purpose of present study was to identify a serum microRNA (miRNA) expression profile that can serve as a novel diagnostic biomarker for GC detection and to assess its clinical applications in monitoring disease progression. METHODS Serum samples were taken from 164 GC patients and 127 age- and gender-matched tumour-free controls. An initial screening of miRNA expression by Solexa sequencing was performed using serum samples pooled from 20 patients and 20 controls, respectively. Differential expression was validated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individuals samples, the samples were arranged in two phases. RESULTS The Solexa sequencing results demonstrated that 19 serum miRNAs were markedly upregulated in the GC patients compared to the controls. The qRT-PCR analysis further identified a profile of five serum miRNAs (miR-1, miR-20a, miR-27a, miR-34 and miR-423-5p) as a biomarker for GC detection. The analysis results showed that the expression level of five serum miRNAs was correlated to tumour stage. The areas under the receiver operating characteristic (ROC) curve of this five-serum miRNA signature were 0.879 (95% confidence interval (CI) 0.822-0.936) and 0.831 (95% CI 0.767-0.898) for the two sets of serum samples, respectively, markedly higher than those of the biomarkers carcinoembryonic antigen (CEA) (0.503) and carbohydrate antigen 19-9 (CA19-9) (0.600). CONCLUSIONS We identified five-miRNA signature for GC diagnosis by genome-wide serum miRNA expression profiling. Expression levels of this serum miRNA-based biomarker also indicate tumour progression stages.

The pretreatment platelet and plasma fibrinogen level correlate with tumor progression and metastasis in patients with pancreatic cancer

Abstract Cancer patients frequently present with activated coagulation pathways and thrombocytosis, which are potentially associated with tumor progression and prognosis. However, the prognostic value of abnormal plasma fibrinogen and platelet levels for the treatment of pancreatic cancer is unclear. The purpose of our study was to evaluate the prognostic value of plasma fibrinogen and platelet levels in pancreatic cancer, and to devise a prognostic model to identify the patients with greatest risk for a poor overall survival. One hundred and twenty-five patients diagnosed with pancreatic ductal adenocarcinoma in our hospital between May 2000 and June 2005 were included in this study. The plasma fibrinogen and platelet levels were examined before treatment and analyzed along with patient clinicopathological parameters and overall survival. The foundation of prognostic model was based on the risk factors according to the Cox proportional hazard model. The incidence of hyperfibrinogenemia and thrombocytosis was 24.8% (31/125) and 15.2% (19/125), respectively. The mean fibrinogen concentration differed significantly between the early (I/II) and late (III/IV) stage patients (3.19 ± 0.70 vs. 3.65 ± 0.90 g/l, p = 0.008). Patients with a higher concentration of plasma fibrinogen and platelets had a worse prognosis (p < 0.05). There also existed a significant correlation between higher fibrinogen/platelet levels and distant organ metastasis (p < 0.05, respectively). Bivariate correlation analysis showed that plasma fibrinogen levels correlated significantly with platelet levels (p = 0.000). Multivariate analysis revealed that pretreatment plasma fibrinogen levels (p = 0.027), tumor stage (p = 0.026) and distant metastasis (p = 0.027) were independent prognostic factors. The median survival time for the low-, intermediate-, and high-risk groups was 9.6 months (95% CI 6.2–13.0), 3.8 months (95% CI 2.3–5.3), and 2.3 months (95% CI 0.9–3.7), respectively (p = 0.000). Pretreatment plasma fibrinogen and platelet levels closely correlated with tumor progression, metastasis and overall survival in pancreatic cancer. The foundation of prognostic model may help us identify the greatest risk populations with pancreatic cancer.

MiRNA27a is a biomarker for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer

We previously identified five miRNAs (miR‐1, miR‐20a, miR‐27a, miR‐34a, and miR‐423‐5p) that are up‐regulated in gastric cancer. The goal of this study was to investigate the value of these miRNAs as potential biomarkers for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer patients who received first‐line chemotherapy. A total of 82 patients with metastatic or recurrent GC receiving first‐line chemotherapy were included in our study. The expression levels of the five miRNAs were evaluated using hydrolysis probe‐based stem‐loop quantitative reverse transcription polymerase chain reaction (qRT‐PCR) in individual samples before first‐line chemotherapy. Patients receiving first‐line chemotherapy with fluoropyrimidine combined with oxaliplatin or paclitaxel were chosen for the chemosensitivity analysis. The relationships between expression of the five‐miRNAs and clinicopathological parameters, response to chemotherapy and prognosis were analyzed statistically. Patients with higher miRNA1 expression levels tended to have a higher rate of liver metastasis, and higher miRNA34a expression levels occurred more frequently in males (P = 0.022). The expression of the remaining three miRNAs showed no obvious relationship to any of the clinicopathological features. The partial response rates of the patients with high miRNA1 expression and low miRNA1 expression were 11.1% and 23.1%, respectively (P = 0.048). Similar results were observed for miRNA27a (the partial response rate was 7.7% vs. 25.9%, P = 0.018). Patients with up‐regulated miRNA27a expression had a significantly worse overall survival (OS) than patients with lower miRNA27a expression (P = 0.024). In patients with MRGC, miRNA27a is a potential biomarker for predicting resistance to fluoropyrimidine‐based chemotherapy and a novel prognostic marker for gastric cancer. J. Cell. Biochem. 115: 549–556, 2014.

Ramosetron versus Ondansetron in the Prevention of Chemotherapy-Induced Gastrointestinal Side Effects: A Prospective Randomized Controlled Study

Background: This study observed and compared the preventive effects of ramosetron and ondansetron on gastrointestinal side effects caused by cisplatin-containing chemotherapy. Methods: Fifty patients with malignant tumors undergoing their first chemotherapy were randomly divided into two groups, and each group received 0.3 mg of ramosetron and 16 mg of ondansetron in a prospective crossover comparison study. Results: Data were collected for analysis of the therapeutic effect in 47 cases and for adverse events in 50 cases. Both drugs showed similar results in regard to chemotherapy-induced gastrointestinal side effects, emesis and appetite loss on day 1, but by day 5, ramosetron was significantly better than ondansetron in terms of controlling appetite loss. From days 3–5, ramosetron tended to be more effective than ondansetron in its antiemetic action. The incidence of headache, fatigue and constipation was the same for both drugs. Conclusions: Ramosetron is a long-lasting and safe antiemetic agent.

Serum miRNA expression profile as a prognostic biomarker of stage II/III colorectal adenocarcinoma

We sought to identify a serum miRNA expression profile to improve disease surveillance and to predict post-operative disease recurrence for stage II/III colorectal cancer (CRC) patients. Using the TaqMan Low-Density Array (TLDA), we performed an initial survey to analyze 749 miRNAs in the pooled serum of 20 paired pre- and post-operative CRC patients and 20 matched normal subjects. Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001). The area under the ROC curve (AUC) for the three-miRNA panel was 0.886 (95% CI 0.850–0.921) for discriminating between pre-operative CRC patients and normal subjects and 0.850 (95% CI 0.809–0.891) for discriminating between pre- and post-operative CRC patients. Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR-17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a). The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC.

Cell-derived microvesicles mediate the delivery of miR-29a/c to suppress angiogenesis in gastric carcinoma

Microvesicles (MVs) secreted from cells have been found to mediate signal transduction between cells. In the tumor microenvironment, VEGF released from cancer cells plays a key role in promoting tumor angiogenesis. In this study, we characterized the inhibitory effect of MV-delivered miR-29a/c on angiogenesis and tumor growth in gastric cancer (GC). We found that the downregulation of miR-29a/c increases VEGF expression and release in GC cells, promoting the growth of vascular cells. By simulating the tumor microenvironment, the MV-delivered miR-29a/c significantly suppresses VEGF expression in GC cells, inhibiting vascular cell growth, metastasis, and tube formation. We also used a tumor implantation mouse model to show that secreted MVs containing overexpressed miR-29a/c significantly reduced the growth rate of the vasculature and tumors in vivo. To conclude, our results contribute to a novel anti-cancer strategy using miRNA-containing MVs to control tumor cell growth by blocking angiogenesis.

Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer

ABSTRACTGastric cancer is one of the most common malignancies worldwide; however, the molecular mechanism in tumorigenesis still needs exploration. BCL2L11 belongs to the BCL-2 family, and acts as a central regulator of the intrinsic apoptotic cascade and mediates cell apoptosis. Although miRNAs have been reported to be involved in each stage of cancer development, the role of miR-24 in GC has not been reported yet. In the present study, miR-24 was found to be up-regulated while the expression of BCL2L11 was inhibited in tumor tissues of GC. Studies from both in vitro and in vivo shown that miR-24 regulates BCL2L11 expression by directly binding with 3′UTR of mRNA, thus promoting cell growth, migration while inhibiting cell apoptosis. Therefore, miR-24 is a novel onco-miRNA that can be potential drug targets for future clinical use.

Systemic therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer with high incidence and mortality worldwide. The main treatments for HCC include radical hepatectomy, liver transplant, locoregional therapies, and systemic therapies. Systemic treatments include targeted agent treatment, chemotherapies, antiviral therapies, and nutritional treatments. According to the results of SHARP and ORIENTAL study, sorafenib became the standard first-line therapy since 2008 because of nearly three months of survival improvement in patients with advanced HCC. Subsequent studies on targeted agents found that neither sunitinib nor brivanib were superior to sorafenib as first-line therapy. After progression or intolerance of sorafenib, brivanib did not improve the overall survival (OS) compared with placebo as second-line therapy. Randomized controlled EACH study and retrospective AGEO study for systemic chemotherapy showed that oxaliplatin-based or gemcitabine-based regimen was effective for advanced HCC patients. Randomized controlled trial for adjuvant chemotherapy in China showed that capecitabine could reduce the risk of recurrence and improve postoperative survival of HCC. Comparing sorafenib with other treatments, several retrospective studies found that other treatments were not inferior to sorafenib in terms of OS. In the systemic treatment of HCC, antiviral treatment can decrease the recurrence of HBV-related HCC postoperation and prolong the survival of patients. Based on the etiology, symptoms, complications, and treatment-related side effects, nutritional treatment is also very important for HCC patients. Systemic chemotherapy, newer targeted agents, and immune therapy are the new directions in future research.

Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer

MicroRNAs (miRNAs) have been proved to play crucial roles in tumorigenesis. TGFβ signal pathway abnormality is found in various cancers and correlates with tumor proliferation and metastasis. However, the mechanisms underlying the dys-regulation of TGFβR2 expression in GC have not been investigated yet. In this study, we found that the TGFβR2 protein was clearly repressed in tumor tissues, while miR-130 expression level was dramatically increased in GC tissues. Firefly luciferase activity assay revealed that miR-130 could directly bind to 3′UTR of TGFβR2 mRNA. Meanwhile, miR-130 mimics lead to the decreased TGFβR2 protein levels, while miR-130 inhibitors enhanced TGFβR2 expression in SGC7901 cells. Subsequent functional experiments showed that overexpressed miR-130 could promote proliferation and migration of SGC7901 cells. And siRNA-mediated TGFβR2 down-regulation could simulate the effects of miR-130 mimics on phenotypes of SGC7901 cells. Furthermore, there existed intense relationship between the expression level of miR-130 and epithelial-mesenchymal markers. Our results demonstrated that miR-130 was an oncogene by directly targeting TGFβR2 in GC.

The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma

miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down-regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR-24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC.