SIGIRR suppresses hepatitis B virus X protein-induced chronic inflammation in hepatocytes.

Although antiviral drugs can effectively inhibit hepatitis B virus (HBV) replication, the maintenance of chronic inflammation in the liver is still considered to be an important cause for the progression of HBV-related liver disease to liver fibrosis and advanced liver disease. As an endogenous inhibitory receptor of IL-1R and TLR signaling pathways, single immunoglobulin interleukin-1-related receptor (SIGIRR) has been proven to reduce inflammation in tissues to maintain system homeostasis. However, the relationship between SIGIRR expression and HBV replication and inflammatory pathway activation in hepatocytes remains unclear. In this study, hepatitis B virus X protein (HBx) upregulated MyD88 in liver cells, promoting NF-κB signaling and inflammatory factor production with LPS treatment, and the cell supernatant accelerated the activation and collagen secretion of hepatic stellate cells. However, SIGIRR overexpression suppressed HBx-mediated MyD88/NF-κB inflammatory signaling activation and inflammatory cytokine production induced by LPS in hepatocytes and HBV replication hepatocytes. Although we did not find any effect of SIGIRR on HBV replication in vitro, this study investigated the role of SIGIRR in blocking the proinflammatory function of HBx, which may provide a new idea for the treatment of chronic hepatitis B.

MALAT1 knockdown alleviates myocardial injury in mice with severe acute pancreatitis via the miR-374a/Sp1/Wnt/ß-catenin pathway.

BACKGROUND: Severe acute pancreatitis (SAP) contributes to high mortality (as high as 30%) and multiple organ injuries. In this study, we established a mouse model with SAP to detect biomolecules implicated in myocardial injury and to expound the signal transduction pathway involved. METHODS: A SAP mouse model was established to assess inflammation- and myocardial injury-related markers. Also, pancreatic and myocardial injuries and cardiomyocyte apoptosis were evaluated. Microarray analysis was implemented to filter differentially expressed long non-coding RNAs (lncRNAs) in myocardial tissues of normal and SAP mice. Then, miRNA-based microarray analysis and bioinformatics prediction were performed to probe the downstream molecules of MALAT1, followed by rescue experiments. RESULTS: SAP mice showed pancreatic and myocardial injuries and increased apoptosis of cardiomyocytes. MALAT1 was expressed highly in SAP mice, and inhibition of MALAT1 reduced myocardial injury and cardiomyocyte apoptosis in SAP mice. MALAT1 was found to localize to the cytoplasm of cardiomyocytes and bind to miR-374a. Inhibition of miR-374a inhibited the alleviating effects of MALAT1 knockdown on the myocardial injury. miR-374a targeted Sp1, and Sp1 silencing reversed the promoting effects of miR-374a inhibitor on myocardial injury. Sp1 regulated myocardial injury in SAP via the Wnt/ß-catenin pathway. CONCLUSION: MALAT1 promotes myocardial injury complicated by SAP via the miR-374a/Sp1/Wnt/ß-catenin pathway.

The role of circulating microRNAs for the diagnosis of hepatitis B virus-associated hepatocellular carcinoma with low alpha-fetoprotein level: a systematic review and meta-analysis.

BACKGROUND: Alpha-fetoprotein (AFP) has been widely used for many years as a serum marker for hepatocellular carcinoma (HCC). However, AFP has been recognized as having poor sensitivity. More and more studies have concluded that circulating microRNAs (miRNAs) might be a promising biomarker that could complement AFP. However, the diagnostic ability of circulating miRNAs has varied among the studies. Therefore, we performed the present meta-analysis to appraise the diagnostic performance of circulating miRNAs as a biomarker for hepatitis B virus-associated HCC (HBV-HCC) patients with low AFP levels. METHODS: We performed a systematic review and meta-analysis of the published literature to assess the diagnostic accuracy of circulating miRNAs in differentiating HBV-HCC patients with low AFP levels from non-HCC controls. RESULTS: Circulating miRNAs showed promising potential in the diagnosis of HBV-HCC patients with low AFP levels. In the low-AFP HBV-HCC patients, the area under the curve (AUC) was 0.88 (95% confidence interval [CI]: 0.84-0.90). The pooled sensitivity and specificity were 0.84 (95% CI: 0.78-0.88) and 0.76 (95% CI: 0.69-0.83), respectively. CONCLUSIONS: The detection of circulating miRNAs provides a valuable method for the diagnosis of HBV-HCC in patients with low AFP levels.

Long Noncoding RNA DIO3OS Hinders Cell Malignant Behaviors of Hepatocellular Carcinoma Cells Through the microRNA-328/Hhip Axis.

BACKGROUND: The decline of a long non-coding RNA (lncRNA) DIO3OS was implicated in a plethora of cancers, while the relevance in hepatocellular carcinoma (HCC) has not been mentioned. Accordingly, we set to determine the functional role of DIO3OS and the molecular mechanism in HCC progression. MATERIALS AND METHODS: The differentially expressed lncRNAs, mRNAs, and microRNAs (miRNAs) were obtained through the datasets GSE101728 and GES57555. Afterwards, DIO3OS was enhanced in HCC cells to examine the behavior changes. Subcellular localization of DIO3OS was determined through website prediction and experimental validation. The expression of Hedgehog (Hh) signaling pathway-related genes was detected. The effects of DIO3OS overexpression on tumor growth were evaluated as well. RESULTS: DIO3OS was lower in HCC tissues and cells, while upregulation of DIO3OS repressed malignant biological behavior both in vitro and in vivo. DIO3OS, localized in the cytoplasm, inhibited the occurrence of HCC by disrupting the Hh pathway by sponging miR-328 to mediate Hh interacting protein (Hhip). CONCLUSION: All in all, the obtained data suggested that DIO3OS interacted with Hhip-dependent Hh signaling pathway to inhibit HCC progression through binding to miR-328, which may be a potent therapeutic target for HCC.

Expression of Carboxypeptidase X M14 Family Member 2 Accelerates the Progression of Hepatocellular Carcinoma via Regulation of the gp130/JAK2/Stat1 Pathway.

BACKGROUND: Carboxypeptidase X, M14 family member 2 (CPXM2) has been reported to be involved with several human malignancies. However, the impact of CPXM2 on human hepatocellular carcinoma (HCC) tumorigenesis has not been studied. MATERIALS AND METHODS: Using immunohistochemistry, the detailed CPXM2 expression patterns were examined in HCC cell lines and tissues. Additionally, a hepatic stellate cell line overexpressing CPXM2 and an HCC CPXM2-knockdown cell line were established by lipofection of an expression plasmid or short hairpin RNA, respectively. The transfection efficiencies were confirmed by reverse transcription-quantitative PCR, Western blotting and immunofluorescence. Moreover, Western blotting was conducted to determine the phosphorylation levels of the tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (Stat1) pathway. Furthermore, gp130-specific hairpin RNA was used to knockdown gp130 expression in hepatic stellate cells overexpressing CPXM2. The malignant phenotype of cultured HCC cells was assessed by a Cell Counting Kit-8 (CCK8) assay, plate cloning assay, Matrigel invasion assay and wound-healing assay in vitro. RESULTS: It was demonstrated that CPXM2 was upregulated in HCC, and its upregulation predicted a poor prognosis. Besides, the upregulation of CPXM2 markedly enhanced the metastatic potential of HCC via the gp130/JAK2/Stat1 signaling pathway in vitro. CONCLUSION: In summary, this evidence suggests a positive role for CPXM2 in HCC progression via modulation of the gp130/JAK2/Stat1 signaling pathway in HCC.

Giant simple hepatic cyst with multiple elevated serum tumor markers: A case report.

BACKGROUND: Simple hepatic cysts are relatively common in adults, and mostly appear as asymptomatic incidental radiologic findings. Occasionally, a large cyst will cause symptoms. Elevations in the serum biomarkers protein induced by vitamin K absence (PIVKA)-II, cancer antigen (CA) 12-5, and CA19-9 are often associated with malignant tumors in the liver or bile ducts. This is the first report to describe a case of hepatic cyst with elevated levels of PIVKA-II and CA12-5. CASE SUMMARY: An 84-year-old Chinese woman was admitted with gradual abdominal distension. Her symptoms started 1 year ago, and she had poor appetite and a weight loss of 5 kg within the past 2 wk. She denied any symptoms associated with abdominal pain, fever and chills, nausea and vomiting, etc. The abdomen was enlarged, more in the right upper quadrant, without tenderness. Laboratory examination showed significantly increased serum levels of PIVKA-II, CA12-5, and CA19-9. A computed tomography scan revealed multiple round cysts in the liver with clear boundaries. The largest cyst was 20.1 cm × 12.2 cm × 19.6 cm in size, located in the right lobe of the liver with mild dilatation of the intrahepatic bile duct, but there was no contrast enhancement. Percutaneous drainage on the largest hepatic cyst and polycinnamol sclerosing agent injection into the cyst cavity were performed. After treatment, the patient's symptoms relieved and the elevated serum tumor makers reduced to the normal levels dramatically. CONCLUSION: The present report identifies an unusual case of a giant hepatic cyst with marked elevation of serum tumor marker levels of PIVKA-II, CA12-5, and CA19-9. After treatment, these three serum markers dramatically decreased to normal levels. The mechanisms for the elevation of these tumor markers may be as follows: (1) A giant hepatic cyst compresses the liver, causing injury to the hepatocytes, which may lead to secretion of a large amount of PIVKA-II; and (2) Some tumor-associated antigens, such as carcinoembryonic antigen, CA19-9, CA12-5, and CA15-3, are expressed on inflammatory cells.

Perspectives of Molecular Therapy-Targeted Mitochondrial Fission in Hepatocellular Carcinoma.

Current advances of molecular-targeting therapies for hepatocellular carcinoma (HCC) have improved the overall survival significantly, whereas the results still remain unsatisfied. Recently, much attention has been focused on organelles, such as the mitochondria, to reveal novel strategies to control the cancers. The mitochondria are vital organelles which supply energy and maintain metabolism in most of the eukaryotic cells. They not only execute critical bioenergetic and biosynthetic functions but also regulate ROS homeostasis and apoptosis. Existing in a dynamic equilibrium state, mitochondria constantly undergo the fission and fusion processes in normal situation. Increasing evidences have showed that mitochondrial fission is highly related to the diseases and cancers. Distinctive works have proved the significant effects of mitochondrial fission on HCC behaviors and the crosstalks with other molecular pathways. Here, we provide an overview of the mitochondrial fission and the link with HCC, emphasizing on the underlying molecular pathways and several novel materials that modulate HCC behaviors.

siRNA-mediated silencing of PAI-1 gene acts as a promoter over the recanalization of endothelial progenitor cells in rats with venous thrombosis.

With the changing lifestyle, venous thrombosis (VT) is becoming increasingly prevalent and poses a burden on the health economy. Endothelial progenitor cells (EPCs) are recruited into resolving VT. We aimed to investigate the effect of plasminogen activator inhibitor 1 (PAI-1) silencing on the recanalization of VT in rat EPCs. EPCs and VT rat models were cultured and treated with negative control-siRNA vector and PAI-1-siRNA vector, respectively. 4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound-healing test, and Matrigel-induced tubular experiment were performed to detect the ability of cell proliferation, migration, and EPCs lumen formation. Immunohistochemistry was used to observe the recanalization of thrombus. The messenger RNA (mRNA) and protein expression of PAI-1 and vascular endothelial growth factor (VEGF) were determined by reverse transcription quantitative polymerase chain reaction and Western blot analysis. PAI-1-siRNA enhances the luminal formation ability of EPCs and significantly promotes EPCs homing. In response to PAI-1 gene silencing, tissues from inferior vena cava displayed reduced mRNA and protein expression of PAI-1, increased VEGF expression as well as promoted lumen-like structures. PAI-1 gene silencing can promote the recanalization of VT by enhancement of the luminal formation ability of rats' EPCs.

Circulating microRNAs for the diagnosis of hepatocellular carcinoma.

AIM: There are no existing biomarkers that demonstrate very reliable performance in the diagnosis of hepatocellular carcinoma (HCC), especially in the early stage. Studies have shown that numerous aberrantly expressed circulating microRNAs (miRNAs) can be used as a diagnostic tool for HCC; however, these studies have produced inconsistent results. METHODS: We performed a meta-analysis to summarize the diagnostic accuracy of circulating miRNAs, alpha-fetoprotein (AFP), and AFP combined with miRNAs in differentiating HCC patients from non-HCC controls, healthy controls and chronic liver disease controls. We also evaluated the diagnostic accuracy of circulating miRNAs for early-stage HCC. Furthermore, we systematically reviewed the diagnostic effectiveness of single miRNAs and individual miRNA panels. RESULTS: Circulating miRNAs showed good diagnostic performance. Compared with single miRNAs, the diagnostic accuracy of miRNA panels was clearly better. The combination of AFP and miRNAs improved the diagnostic accuracy compared with the use of miRNAs or AFP alone. For early-stage HCC patients, circulating miRNAs exhibited relatively satisfactory diagnostic accuracy. CONCLUSIONS: Circulating miRNAs can be used as an early diagnostic marker of HCC. The combination of miRNAs and AFP has great potential as a novel strategy for the diagnosis of HCC.

MiR-874 inhibits metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting SOX12.

MicroRNA-874 (miR-874), a novel cancer-associated microRNA (miRNA), has been reported to play a suppressive role in multiple malignancies. However, its function in cell migration and invasion in hepatocellular carcinoma (HCC) and the mechanisms responsible remain unclear. Here, we found miR-874 to be significantly downregulated in HCC tissues and cell lines. Moreover, this decreased expression strongly correlated with clinical stage and lymph node metastasis. Accordingly, ectopic expression of miR-874 in HCC cells markedly inhibited their migration, invasion, and epithelial-mesenchymal transition (EMT). Concerning the underlying mechanism, SRY (sex-determining region Y) -box 12 (SOX12) was identified as a direct target of miR-874, and its expression was found to be inversely correlated with that of this miRNA in HCC cells. Importantly, SOX12 knockdown had an inhibitory effect on HCC cells similar to that caused by miR-874 overexpression, whereas SOX12 overexpression in these cells negated the suppressive effects of miR-874 on migration, invasion, and EMT. Overall, these findings demonstrate that miR-874 inhibits metastasis and EMT in HCC by targeting SOX12, suggesting that this miRNA may constitute a promising therapeutic target for this disease.

Meta-analysis of CYP2E1 polymorphisms in liver carcinogenesis.

BACKGROUND: The CYP2E1 protein is a monooxygenase with certain polymorphisms linked to liver cancer. However, results from individual studies remain controversial. AIMS: To evaluate CYP2E1 polymorphisms in liver carcinogenesis through meta-analysis. METHODS: All studies about CYP2E1 polymorphisms and liver cancer were retrieved from seven major databases. Original data from each study were pooled and re-analyzed. RESULTS: Total of 16 articles with 4862 cases were selected, including 1820 cases of liver cancer and 3042 cases of controls. The c1 allelic frequency in the cases and controls was 83.3% and 85.3%, respectively. Five genetic variations were compared: dominant c1c2/c2c2 vs. c1/c1 (OR=0.987 (0.853, 1.141)), homozygous c2c2 vs. c1c1 (OR=0.767 (0.526, 1.119)), heterozygous c1c2 vs. c1c1 (OR=1.005 (0.854, 1.182)), recessive c2c2 vs. c1c2/c2c2 (OR=0.771 (0.530, 1.122)), and different alleles c2 vs. c1 (OR=0.947 (0.828, 1.082)). Pooled data were further analyzed based on ethnicity, control sources, and HWE (Hardy-Weinberg equilibrium). These results from stratified groups were similar to that of nonstratified groups. CONCLUSIONS: Our meta-analysis results suggest that there is no evidence for a major role of CYP2E1 polymorphism in liver carcinogenesis, but do not rule out the possibility in certain cases.

Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets.

Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal-from either an internal or external source-and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC.

Rare case of a solitary huge hepatic cystic lymphangioma.

A hepatic lymphangioma is a rare benign neoplasm and is usually associated with lymphangiomas of other viscera. A hepatic lymphangioma can be solitary, cystic or associated with multiple liver lesions and is characterized by cystic dilatation of lymphatic vessels in the hepatic parenchyma. A solitary lymphangioma is unusual. Here we report a rare case of a solitary huge primary hepatic cystic lymphangioma in a 42-year-old woman. It was discovered on routine physical examination and the patient had no obvious symptoms. Ultrasonography and computed tomography (CT) showed a giant "hepatic neoplasm" that occupied the right liver lobe. The lesion was approximately 20.0 cm × 15.0 cm × 10.0 cm in size and contained cystic and solid components. There were multiple septa inside the tumor, with some calcifications in the septa. Surgical resection was performed. Histological examination revealed multiple cystic structures lined with epithelial cells on the inner walls, accompanied by interstitial swelling and necrosis. The patient has now been followed up for nearly two years after surgery, with no recurrence to date.