N(6)-methyladenosine-mediated miR-380-3p maturation and upregulation promotes cancer aggressiveness in pancreatic cancer.

N(6)-methyladenosine (m6A)-modified microRNAs (miRNAs) are relevant to cancer progression. Also, although the involvement of miR-380-3p in regulating cancer progression in bladder cancer and neuroblastoma has been preliminarily explored, its role in other types of cancer, such as pancreatic cancer (PC), has not been studied. Thus, this study aimed to investigate the role of miR-380-3p in regulating PC progression. Here, through performing Real-Time qPCR, we evidenced that miR-380-3p was significantly upregulated in the clinical pancreatic cancer tissues and cells compared to their normal counterparts. Interestingly, miR-380-3p was enriched with m6A modifications, and elimination of m6A modifications by deleting METTL3 and METTL14 synergistically suppressed miR-380-3p expressions in PC cells. Next, the gain and loss-of-function experiments verified that knockdown of miR-380-3p suppressed cell proliferation, epithelial-mesenchymal transition (EMT), and tumorigenesis in PC cells in vitro and in vivo, whereas miR-380-3p overexpression had opposite effects. Furthermore, the underlying mechanisms were uncovered, and our data suggested that miR-380-3p targeted the 3' untranslated regions (3'UTRs) of PTEN for its inhibition and degradation, resulting in the activation of the downstream Akt signal pathway. Moreover, the rescuing experiments validated that both PTEN overexpression and Akt pathway inhibitor LY294002 abrogated the promoting effects of miR-380-3p overexpression on cancer aggressiveness in PC cells. Collectively, this study firstly investigated the role of the m6A-associated miR-380-3p/PTEN/Akt pathway in regulating PC progression, which provided novel therapeutic and diagnostic biomarkers for this cancer.

Identification of molecular heterogeneity of hepatocellular carcinoma based on immune gene expression signatures.

Although various molecular subtypes of hepatocellular carcinoma (HCC) have been investigated, most of these studies identify HCC subtype based on genomic profiling. Few studies have investigated the classification based on immune signatures, and none have classified HCC based on Immune activation and immunosuppressive. We performed immune gene expression of tumor tissue in 374 HCC patients from The Cancer Genome Atlas (TCGA) database and used unsupervised consensus clustering to stratify tumors. We then used HCC patients from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) as replication datasets. Based on the expression of 782 immune-related genes, HCC was stratified into four distinct immune subtypes. Tumors in one cluster (high immune activation; high-IA) indicate a higher level of Immune activation, which was characterized by higher anti-tumor immunity, higher pro-tumor immune-suppressive cell types, higher fractions of CD8+ T cells and M0 Macrophages compared with other subtypes. The high-IA also presents higher cancer-related hallmark signatures, such as epithelial-mesenchymal transition (EMT), angiogenesis, and apoptosis. We also found subpopulations of regulatory and exhaustion T lymphocyte were characterized by an opposite trend in high-IA, though samples in high-IA response to immunotherapy with better survival. The comparison of the immune profile in tumor and normal tissue indicates the activation of immune responses which only occurred in high-IA patients, while we conducted comparison of cirrhosis and non-cirrhosis tumor immune signatures, immune response activation was almost occurred in high-IA, but some of immune responses occurred in low-IA (low immune activation).

Comparable prevalence of distant metastasis and survival of different primary site for LN + pancreatic tumor.

BACKGROUND: Few studies have delved into the prevalence of distant metastasis (DM +) and survival for patients with lymph node metastases (LN +) by primary site. We aimed to detect differences in distant metastasis and prognosis between pancreatic head and bodytail tumors for LN + patients. METHODS: Patients with chemotherapy, histologically diagnosed, primary site between 2004 and 2016 were included from the SEER (Surveillance, Epidemiology, and End Results) database. Pancreatic head tumors were compared with pancreatic bodytail tumors using the odds ratio (OR) for rates of distant metastasis, hazard ratios (HR) for overall survival (OS) and cancer-specific survival (CSS). The competing risk model and propensity score matching (PSM) were performed to further explore. RESULTS: Of 5726 LN + patients identified from the SEER database, pancreatic head tumors account for 85.2% (4877 of 5726) and 14.8% (849 of 5726) were pancreatic bodytail tumors. The incidence of DM was lower in pancreatic head than in pancreatic bodytail tumors (OR, 0.29; 95% CI 0.23-0.37; P < 0.001). The multivariate Cox regression show pancreatic head tumors have a significantly shorter survival rate relative to pancreatic bodytail (HR, 1.12; 95% CI 1.03-1.22; P = 0.008), but the primary site was not a significant independent risk factor for prognosis by log-rank test (P = 0.39) and multivariate competing risk model [subdistribution HR (SHR), 1.08; 95% CI 0.98-1.19; P = 0.087].We then examined our conclusion by 1:1 propensity score matching, and the result reflected pancreatic head tumors have a lower risk of DM compared with pancreatic bodytail tumors (OR, 0.22; 95% CI 0.15-0.34; P < 0.001), but the primary site of pancreatic tumors was not associated with LN + patient survival based on univariate Cox regression (HR, 1.04; 95% CI 0.93-1.17; P = 0.435) and competing risk analysis (SHR, 1.01; 95% CI 0.89-1.12; P = 0.947). CONCLUSIONS: LN + pancreatic head tumors were significantly lower risk of DM relative to pancreatic bodytail tumors. Survival outcome in LN + pancreatic tumors didn't exist significant differences split by primary site, which indicates that the prognosis of LN + patients with chemotherapy isn't associated with the primary site of metastasis, but with the occurrence of metastasis.

Aspirin use and pancreatic cancer risk: A systematic review of observational studies.

OBJECTIVES: Although there is evidence that aspirin might be able to prevent pancreatic cancer, the findings have been inconsistent. In this paper, we conducted a meta-analysis of observational studies to examine the relationship between aspirin use and the risk of pancreatic cancer. METHODS: We identified potential studies by searching the MEDLINE, EMBASE, and Wangfang (Chinese database) database (from 1967 to March 2017) and by reviewing the bibliography of relevant publications. Random effects model was used to calculate odds ratio (OR) and 95% confidence interval. The Cochran Q statistic (significance level at P < .1) was used to assess heterogeneity in this study. The author adopted weighted regression method of Egger to assessed publication bias. RESULTS: A total of 12 studies involving 4748 pancreatic cancer cases, were included in the meta-analysis. The study reflected that there was no signification association between aspirin use and mortality risk of pancreatic cancer. Aspirin use might reduce the incidence of pancreatic cancer. Specifically, there was a high signification association between frequent aspirin use and reduced pancreatic cancer incidence, without heterogeneity. In addition, there was a high signification association between duration of aspirin use more than 5 years and reduced pancreatic cancer incidence, without obvious heterogeneity among the original studies. CONCLUSIONS: In summary, this meta-analysis suggested that the aspirin use might be negatively related to the incidence risk of pancreatic cancer. Specifically, the frequency and duration of aspirin use might play an important role in decreasing the incidence of pancreatic cancer.

Downregulation of miR-21 inhibits the malignant phenotype of pancreatic cancer cells by targeting VHL.

BACKGROUND: MicroRNA (miR)-21 is overexpressed in numerous types of malignancy and participates in the development of cancer. However, the basic mechanism of the influence of miR-21 on the malignant phenotype of pancreatic cancer remains unclear. PURPOSE: The present study aimed to investigate the role of miR-21 in pancreatic cancer development and explore its molecular mechanism. PATIENTS AND METHODS: The tissue samples were collected at the Second Hospital of Tianjin Medical University (Tianjin, China) between January 2013 and December 2015. The expression of VHL in tissue samples was evaluated by IHC staining. The expression of miR-21 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-21 target gene was detected by real-time PCR, Western blot and the luciferase reporter assay. Cell viability, cell proliferation, cell migration and invasion were evaluated by the MTT assays, the colony formation assays and the transwell assays. The nude mouse tumor xenograft model was performed to detect the effect of miR-21 on tumor growth in vivo. RESULTS: Von Hippel-Lindau tumor suppressor (VHL) was downregulated in pancreatic cancer tissues compared with pancreatic non-tumor tissues. VHL was identified as a novel direct target of miR-21, by which it is negatively regulated. In PANC-1 cells, inhibition of miR-21 and upregulation of VHL significantly suppressed cell proliferation, migration and invasion. Knockdown of miR-21 inhibited the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway, while inhibiting the expression of matrix metallopeptidase (MMP)-2 and MMP-9. Silencing of miR-21 inhibited tumor growth in vivo. CONCLUSION: Knockdown miR-21 increased the expression of VHL, and thus modulated the HIF-1α/VEGF pathway and the expression of MMP-2 and MMP-9, which led to the inhibition of the proliferation, migration and invasion of pancreatic cancer cells. All of these results suggest that the miR-21/VHL interaction may be a novel potential target for pancreatic cancer prevention and therapy.

FOXO3a expression and its diagnostic value in pancreatic ductal adenocarcinoma.

FOXO3a (FKHRL1) is an important regulator of cell apoptosis, proliferation, metabolic state and longevity. FOXO3a expression can be measured and has been regarded as a tumor suppressor factor in many cancers. However, the expression and role of FOXO3a in PDAC have not been defined. We evaluated the expression of FOXO3a in PDAC and the relationship of its expression with clinicopathological features and patient outcomes. We found that compared with normal tissues, the expression of FOXO3a was significantly higher in tumor tissues (P<0.001). FOXO3a expression correlates significantly with tumor differentiation and with the primary location of the tumor (P<0.001 and P=0.005, respectively). In a univariate analysis, we found that FOXO3a expression has a strong relationship with survival (P=0.013). In addition, Kaplan-Meier survival curves indicated that a low expression of FOXO3a in tumor tissues has a significantly shorter OS compared with patients with high expression of FOXO3a (P=0.013). In conclusion, the expression of FOXO3a is significantly higher in PDAC compared with normal pancreatic tissues and has a low expression or negative staining in poorly differentiated PDAC, which seems to indicate that FOXO3a expression in tumor tissues may be related to the pathological progression stage and may be used as a diagnostic indicator with early tumors.

Castleman's disease combined with choledocholithiasis: a case report and review of literature.

Castleman's disease (CD) is a rare lymphoproliferative disease with unclear pathogenesis. CD is divided into unicentric and multicentric according to clinical classification, and is usually successfully treated with surgical resection alone. CD is also classified into hyaline vascular, plasma cell, or mixed cell type according to histopathological type. CD can occur in any part of the lymphatic tissue, but most occur in mediastinal lymph node, followed by the neck, armpit, and abdominal lymph nodes. Here, we have reported a case of Castleman disease which was accidently discovered during the operation of common bile duct calculi. The histological presentation of the lymph nodes was corresponded to the plasma cell type of CD. To our knowledge, there is no report about the plasma cell type of Castleman's disease coexistence with common bile duct calculi. Finally we also review the literature.

Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia.

INTRODUCTION: After decades of research, pancreatic cancer is still a devastating disease. The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and S-1 (GS) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: Relevant trials were identified by searching databases. Five trials were selected in this article. The indicators we used were overall response rate, disease control rate, 1-year survival rate and haematological toxicities. RESULTS: Meta-analysis of the pooled data demonstrated that the overall response rate (risk ratio, RR = 2.52, 95% confidence interval, CI: 1.85-3.42, P < 0.00001) and disease control rate (RR = 1.24, 95% CI: 1.12-1.37, P < 0.0001) were significantly different for the GS and GEM alone chemotherapies. Among the group of patients, 43.4% in the GS group and 31.4% in the GEM group survived more than a year. According to this, patients who use the GS regiment may have a better prognosis than the GEM regiment (RR = 1.62, 95% CI: 1.12-2.33, P = 0.04). The combination chemotherapy with GEM and S-1 group had higher haematological toxicities including neutropaenia (RR = 1.58, 95% CI: 1.17-2.14, P = 0.003) and thrombocytopaenia (RR = 1.85, 95% CI: 1.28-2.67, P = 0.001). The incidence of anaemia was much the same in the two groups (RR = 1.22, 95% CI: 0.87-1.70, P = 0.24). DISCUSSION: Overall response rate and disease control rate as well as 1-year survival rate in patients who received GS were superior to those treated with GEM alone. Combination chemotherapy with GEM and S-1 may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. Combination chemotherapy with GEM and S-1 might be an option of first-line chemotherapy for pancreatic cancer patients, at least in Asia. Mini Abstract: This systematic review analysing randomized controlled trials (RCTs) comparing S-1 combination chemotherapy versus GEM alone for locally advanced and metastatic pancreatic cancer demonstrated greater efficacy for S-1 combination in term of response, disease control and 1-year survival proportion.