Xiongxiong Lu

Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6

Recent studies have revealed that long non-coding RNAs (lncRNAs) play important roles in cancer biology and that lncRNA gas5 (growth arrest-specific 5) regulates breast cancer cell growth. However, the role of gas5 in pancreatic cancer progression remains largely unknown. In the current study, we assay the expression level of gas5 in pancreatic cancer tissues and define the role of gas5 in the regulation of pancreatic cancer cell proliferation. We verify that the expression level of gas5 is significantly decreased in pancreatic cancer tissues compared with normal control. Overexpression of gas5 in pancreatic cancer cells inhibits cell proliferation, whereas gas5 inhibition induces a significant decrease in G0/G1 phase and an increase in S phase. We further demonstrate that gas5 negatively regulates CDK6 (cyclin-dependent kinase 6) expression in vitro and in vivo. More importantly, knockdown of CDK6 partially abrogates gas5-siRNA-induced cell proliferation. These data suggest an important role of gas5 in the molecular etiology of pancreatic cancer and implicate the potential application of gas5 in pancreatic cancer therapy.

The Interplay Between miR-148a and DNMT1 Might be Exploited for Pancreatic Cancer Therapy

ABSTRACT We discovered the expression level of miR-148a significantly decreased in pancreatic cancer tissues whereas that of DNMT1 increased. In ASPC-1 cancer cells, the overexpression of miR-148a led to a decreased level of DNMT1 and reduced the proliferation and metastasis of ASPC-1 cells. Moreover, the increased expression of miR-148a arrested the UTR methylation of p27, giving rise to an increased level of p27. Interestingly, it was shown that the DNMT1 inhibition enhanced the expression of miR-148a. In vivo studies demonstrated that the tumorigenesis of ASPC-1 was significantly arrested by either the overexpression of miR-148a or the inhibition of DNMT1.

Association between miR34b/c polymorphism rs4938723 and cancer risk: a meta-analysis of 11 studies including 6169 cases and 6337 controls.

Background The functional polymorphism rs4938723 in the promoter region of pri-miR-34b/c is potentially associated with susceptibility to several cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Here we conducted a comprehensive meta-analysis to investigate the association between rs4938723 and cancer risk. Material/Methods Eligible studies extracted from the databases of PubMed, Web of Science, and Cochrane Library were evaluated. Statistical analysis was performed using Revman 5.2 and STATA 12.0 software. Results By characterizing the extracted data, a total of 11 studies reported in 10 publications including 6169 cases and 6337 controls were selected for further analysis. Our results revealed a significant association between the rs4938723 polymorphism and cancer risk in the codominant model (TC vs. TT: OR=1.10, 95% CI=1.02–1.19, P=0.009) but not in other genetic models. In the stratified analysis of different cancer types, a significant association was found in nasopharyngeal cancer, osteosarcoma, and renal cell cancer. Furthermore, stratified analysis of ethnicity indicated that a highly significant association was shown in the Asian population in a codominant model (TC vs. TT: OR=1.13, 95% CI=1.03–1.24, P=0.007) when compared with African-Americans and Caucasians. Conclusions Overall, the current study suggests that the miR-34b/c rs4938723 polymorphism may be associated with the risk of cancers, including nasopharyngeal cancer, osteosarcoma, and renal cell cancer, and to some extent this polymorphism is closely related to cancer susceptibility in Asians.

Integrated expression profiles analysis reveals novel predictive biomarker in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a dismal 5-year survival rate of less than 5%. The lack of specific symptoms at early tumor stages and the paucity of biomarkers contribute to the poor diagnosis of pancreatic ductal adenocarcinoma. To improve prognosis, a screening biomarker for early diagnosis of pancreatic cancer is in urgent need. We searched the databases of expression profiling by array on GEO, aiming at comparing gene expression profile of matched pairs of pancreatic tumor and adjacent non-tumor tissues, and we screen out 4 suitable series of gene expression microarray data (“GSE15471”, “GSE18670”, “GSE28735” and “GSE58561”). After carefully analyzing, 13 DEGs (MYOF, SLC6A6, S100P, HK2, IFI44L, OSBPL3, IGF2BP3, PDK4, IL1R2, ERO1A, EGLN3, PLAC8 and ACSL5) are significantly differentially expressed in four microarray databases in common. After analyzing mRNA expression data and clinical follow-up survey provided in the TCGA database and clinicopathological data of 137 pancreatic ductal adenocarcinoma patients, we carefully demonstrated that three of these differentially expressed genes (ERO1A, OSBPL3 and IFI44L) are correlated with poor prognosis of pancreatic ductal adenocarcinoma patients. In addition, we revealed that cell–matrix adhesion and extracellular matrix were top significantly regulated pathways in pancreatic ductal adenocarcinoma and depicted two protein-protein interactions networks of extracellular matrix related Genes which are dysregulated according to 4 gene expression microarray data mentioned above (“GSE15471”, “GSE18670”, “GSE28735” and “GSE58561”), hoping to shed light on the etiology of PDAC and mechanisms of drug resistance in PDAC in this study.

mir-329 restricts tumor growth by targeting grb2 in pancreatic cancer

Pancreatic cancer is one of the most lethal malignancies worldwide. To illustrate the pathogenic mechanism(s), we looked into the expression and function of miR-329 associated with pancreatic cancer development. It was found that miR-329 expression was downregulated in the pancreatic cancer patients who demonstrated significantly shorter overall survival than the patients having upregulated expression. Also, more advanced pT stage cases were observed in the low miR-329 expression group of patients. Interestingly, our studies uncovered that miR-329 overexpression inhibited proliferation and induced apoptosis of pancreatic cancer cells, in contrast the miR-329 inhibitor reversed this phenomenon dramatically. Additionally, overexpression of miR-329 significantly limited tumor growth in the xenograft model. In the mechanistic study, we identified GRB2 as a direct target of miR-329 in pancreatic cancer cells, and expression of GRB2 was inversely correlated with miR-329 expression in pancreatic cancer patients. Furthermore, GRB2 overexpression in cell line and xenograft model dramatically diminished miR-329 mediated anti-proliferation and apoptosis induction, indicating that GRB2/pERK pathway was mainly downregulated by miR-329 expression. In general, our study has shed light on miR-329 regulated mechanism and, miR-329/GRB2/pERK is potential to be targeted for pancreatic cancer management.

Melittin inhibits tumor growth and decreases resistance to gemcitabine by downregulating cholesterol pathway gene CLU in pancreatic ductal adenocarcinoma

Melittin is a Chinese traditional medicine for treating chronic inflammation, immunological diseases and cancers, however, the efficacy of melittin and its mechanism for treating pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here we investigated the anti-cancer activity of melittin and its regulated mechanism(s) in the PDAC models. Melittin was found to suppress tumor growth by promoting cell apoptosis and cell-cycle arrest. Interestingly, the microarray analyses demonstrated that melittin significantly regulated cholesterol biosynthesis pathway during treatment. For instance, the cholesterol pathway gene clusterin (CLU) was highly downregulated by melittin which also enhanced gemcitabine sensitivity in PDAC cells by inhibiting CLU expression. In contrast, overexpression of CLU significantly diminished melittin mediated tumor suppression and gemcitabine sensitization, suggesting that CLU is the target of melittin. Furthermore, in the xenograft mouse model, the combination therapy of melittin and gemcitabine is more efficacious for inhibiting PDAC tumor growth than either single regimen. Taken together, our study has indicated that melittin is capable of suppressing tumor growth and promoting gemcitabine sensitivity in PDAC by downregulating cholesterol pathway.

Genomic signatures of pancreatic adenosquamous carcinoma (PASC)

In pancreatic cancer, pancreatic adenosquamous carcinoma (PASC) containing both ductal adenocarcinoma and squamous carcinoma in the same tumour represents ∼4% of the total incidence. To date, the genomic features of this mixed tumour are still unknown. We analysed the genomes of 17 PASCs and 34 pancreatic ductal adenocarcinomas (PDACs), and showed that PASC carried highly enriched TP53 mutations and 3p loss as compared with PDAC. We also showed that adenomatous and squamous components of PASC harboured comparable genomic alterations, suggesting that the two cellular components develop from the same progenitor cancer cells. Our study has updated genomic knowledge to help with understanding mixed cancers of the pancreas. Copyright

Capture-based next-generation sequencing reveals multiple actionable mutations in cancer patients failed in traditional testing.

Targeted therapies including monoclonal antibodies and small molecule inhibitors have dramatically changed the treatment of cancer over past 10 years. Their therapeutic advantages are more tumor specific and with less side effects. For precisely tailoring available targeted therapies to each individual or a subset of cancer patients, next‐generation sequencing (NGS) has been utilized as a promising diagnosis tool with its advantages of accuracy, sensitivity, and high throughput.

Systematic Review and Meta-Analysis of Pancreatic Amylase Value on Postoperative Day 1 After Pancreatic Resection to Predict Postoperative Pancreatic Fistula.

Abstract Early detection of postoperative pancreatic fistula (POPF) may help to improve the outcome following pancreatic surgery, and exclusion of POPF may allow early drain removal which can accelerate recovery. The aim of this study was to evaluate the diagnostic accuracy of drain/plasma pancreatic amylase values on postoperative day 1 (DPA1/PPA1) in POPF by means of a systemic review and meta-analysis. Online journal databases and a manual search up to March 2015 were used. Studies clearly documenting DPA1 or PPA1 in predicting overall POPF (Grade 0 vs A+B+C) or clinically relevant POPF (Grade 0+A vs B+C) following pancreatic surgery were selected. Pooled predictive parameters were performed using STATA 12.0. Fifteen studies were finally identified with a total of 4331 patients. The pooled sensitivity and specificity of DPA1 were 0.92 (95% confidence interval (CI) 0.81–0.96) and 0.77 (95% CI 0.64–0.86) for predicting overall POPF and 0.79 (95% CI 0.61–0.90) and 0.83 (95% CI 0.74–0.89) for predicting clinically relevant POPF. The pooled sensitivity and specificity of PPA1 were 0.74 (95% CI 0.63–0.82) and 0.62 (95% CI 0.55–0.70) for overall POPF. After the DPA1 at/over cutoff values for overall POPF or clinically relevant POPF, corresponding post-test probability (Post-test (+)) (if pretest probability was 50%) was 80% and 82% respectively, while, if values were below the cutoff values, the post-test probability (Post-test (−)) was 10% and 20% respectively. Post-test (+) and Post-test (−) of PPA1 for overall POPF were 66% and 30% respectively. In subgroup analysis, the summary sensitivities of cutoff <1000 group and cutoff >1000 group were 0.96 (0.92–0.98) and 0.85 (0.64–0.95), respectively; the summary specificities were 0.59 (0.44–0.72) and 0.86 (0.80–0.91) respectively. Positive LR were 2.3 (1.7–3.3) and 6.2 (3.7–10.2) respectively. Negative LR were 0.06 (0.03–0.14) and 0.18 (0.07–0.47) respectively. DPA1 is a useful predictive test for overall POPF and clinically relevant POPF which has good sensitivity and specificity based on the current studies. Meanwhile, it should be cautiously applied to clinical practice because cutoffs had a wide range between studies.

Clinical significance of RECK promoter methylation in pancreatic ductal adenocarcinoma

The aim of this study was to analyze the clinical significance of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (P < 0.001). RECK methylation status was significantly associated with clinical stage (P = 0.017), histological differentiation (P = 0.046), and lymph node metastasis (P = 0.003), but was not associated with gender, age, and tumor location (all P > 0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis.