ABSTRACT
BACKGROUND: Circulating microRNAs (miRNA) are biomarkers for several neoplastic diseases, including hepatocellular carcinoma (HCC). We performed a literature search, followed by experimental screening and validation in order to establish a miRNA panel in combination with the assessment of alpha-fetoprotein (AFP) levels and to evaluate its performance in HCC diagnostics. METHODS: Expression of miRNAs was quantified by quantitative PCR (qPCR) in 406 serum samples from 118 Vietnamese patients with hepatitis B (HBV)-related HCC, 69 patients with HBV-related liver cirrhosis (LC), 100 chronic hepatitis B (CHB) patients and 119 healthy controls (HC). RESULTS: Three miRNAs (mir-21, mir-122, mir-192) were expressed differentially among the studied subgroups and positively correlated with AFP levels. The individual miRNAs mir-21, mir-122, mir192 or the triplex miRNA panel showed high diagnostic accuracy for HCC (HCC vs. CHB, AUC = 0.906; HCC vs. CHB+LC, AUC = 0.81; HCC vs. CHB+LC+HC, AUC = 0.854). When AFP levels were ≤20ng/ml, the triplex miRNA panel still was accurate in distinguishing HCC from the other conditions (CHB, AUC = 0.922; CHB+LC, AUC = 0.836; CHB+LC+HC, AUC = 0.862). When AFP levels were used in combination with the triplex miRNA panel, the diagnostic performance was significantly improved in discriminating HCC from the other groups (LC, AUC = 0.887; CHB, AUC = 0.948; CHB+LC, AUC = 0.887). CONCLUSIONS: The three miRNAs mir-21, mir-122, mir-192, together with AFP, are biomarkers that may be applied to improve diagnostics of HCC in HBV patients, especially in HBV-related LC patients with normal AFP levels or HCC patients with small tumor sizes.
Subject(s)
Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/etiology , Hepatitis B, Chronic/complications , Liver Neoplasms/diagnosis , Liver Neoplasms/etiology , MicroRNAs/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Case-Control Studies , Disease Susceptibility , Early Detection of Cancer/methods , Female , Gene Expression Profiling/methods , Genetic Testing , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Humans , Male , Middle Aged , Prognosis , ROC Curve , Serologic Tests , Young AdultABSTRACT
The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. ©2016 AACR.
Subject(s)
Adenocarcinoma in Situ/pathology , Carcinoma, Pancreatic Ductal/pathology , Dual-Specificity Phosphatases/metabolism , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Pancreatic Neoplasms/pathology , Adenocarcinoma in Situ/genetics , Adenocarcinoma, Mucinous/genetics , Adenocarcinoma, Mucinous/mortality , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Papillary/genetics , Adenocarcinoma, Papillary/mortality , Adenocarcinoma, Papillary/pathology , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Comparative Genomic Hybridization , Disease Progression , Dual-Specificity Phosphatases/genetics , Heterografts , Humans , Kaplan-Meier Estimate , Mice , Microscopy, Confocal , Mitogen-Activated Protein Kinase Phosphatases/genetics , Neoplasm Invasiveness , Oligonucleotide Array Sequence Analysis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , TranscriptomeABSTRACT
AIM: To revealed the prevalence of Helicobacter pylori (H. pylori) infection in the Bhutanese population. METHODS: We recruited a total of 372 volunteers (214 females and 158 males; mean age of 39.6 ± 14.9 years) from three Bhutanese cities (Thimphu, Punaka, and Wangdue). The status of H. pylori infection was determined based on five different tests: the rapid urease test (CLO test), culture, histology, immunohistochemistry (IHC), and serum anti H. pylori-antibody. RESULTS: The serological test showed a significantly higher positive rate compared with the CLO test, culture, histology and IHC (P < 0.001, P < 0.001, P = 0.01, and P = 0.01, respectively). When the subjects were considered to be H. pylori positive in the case of at least one test showing a positive result, the overall prevalence of H. pylori infection in Bhutan was 73.4%. The prevalence of H. pylori infection significantly decreased with age (P < 0.01). The prevalence of H. pylori infection was lower in Thimphu than in Punakha and Wangdue (P = 0.001 and 0.06, respectively). The prevalence of H. pylori infection was significantly higher in patients with peptic ulcers than in those with gastritis (91.4% vs 71.3%, P = 0.003). CONCLUSION: The high incidence of gastric cancer in Bhutan may be attributed to the high prevalence of H. pylori infection.
