Colorectal cancer (CRC) is one of the principal causes of cancer‑associated mortality worldwide. The high incidence of liver metastasis is the leading risk factor of mortality in patients with CRC, and the mechanisms of CRC liver metastasis are poorly understood. In the present study, 7 datasets, including 3 gene expression profile datasets and 4 microRNA (miRNA) expression profile datasets were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify potential key genes and miRNAs, which may be candidate biomarkers for CRC liver metastasis. Differentially expressed (DE) genes (DEGs) and DE miRNAs of primary CRC tumor tissues and liver metastatic CRC tumor tissues were selected using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery online database. Furthermore, Cytoscape with cytoHubba and the Molecular Complex Detection (MCODE) plug‑in were used to visualize a protein‑protein interaction (PPI) network for these DEGs, and to screen hub genes and gene modules in the PPI network. In addition, the online databases, TargetScan, miRanda, PITA, miRWalk and miRDB, were used to identify the target genes of the DE miRNAs. In the present study, 141 DEGs (97 upregulated and 44 downregulated) and 3 DE miRNAs (2 upregulated and 1 downregulated) were screened from the 3 gene expression microarray datasets and 4 miRNA expression microarray datasets, respectively. In total, 10 hub genes with a high degree of connectivity were selected from the PPI network, including albumin (ALB), coagulation factor II (F2), thrombin, apolipoprotein H (APOH), serpin family C member 1 (SERPINC1), apolipoprotein A1 (APOA1), α‑1‑microglobulin/bikunin precursor (AMBP), apolipoprotein C3 (APOC3), plasminogen (PLG), α‑2 HS glycoprotein (AHSG) and apolipoprotein B (APOB). The most important module was detected in the PPI network using the MCODE plug‑in. A total of 20 DEGs were identified to be potential target genes of these DE miRNAs, and novel miRNA‑DEGs regulatory axes were constructed. In vitro experiments were performed to demonstrate that miR‑885 promoted CRC cell migration by, at least partially, decreasing the expression of von Willebrand factor (vWF) and insulin‑like growth factor binding protein 5 (IGFBP5). In conclusion, by using integrated bioinformatics analysis and in vitro experiments, key candidate genes were identified and novel miRNA‑mRNA regulatory axes in CRC liver metastasis were constructed, which may improve understanding of the molecular mechanisms underlying CRC liver metastasis.

Lymph node (LN) metastasis is known as one of the most important prognostic factors for early gastric cancer (EGC) patients. Patients without LNM normally have better prognosis. However, there is no evaluation criteria to accurately assess the possibility of LN metastasis. Therefore, this study aims to establish an effective nomogram for prognosis prediction. In this study, 285 EGC patients from January 2010 to December 2015 were enrolled. Pearson’s Chi-Square (χ²) test (including continuity correction when appropriate) and logistics regression analyses was used to identify the risk factors for LN metastasis. The independent risk factors identified were then incorporated in a nomogram model. The predictive accuracy and discriminative ability of the nomogram were evaluated by receiver operating characteristic curve (ROC) and calibration curve. LN metastasis occurred in 59 (20.7%) EGC patients. And most of these patients were submucosal cancers (48/59). Chi-square test indicated lymphovascular emboli, carbohydrate antigen 19-9 (CA19-9), ulcer, tumor size, tumor infiltration and histological grade were the risk factors, and multivariate logistics analyses confirmed all these six factors were independent risk factors of LN metastasis, which were selected to construct the nomogram. The nomogram proved well calibrated and had good discriminative ability (C-index value: 0.842). The proposed nomogram could result in more-accurate risk prediction for EGC patients.

Previous studies showed Scutellaria barbata D. Don extract (SBE) is a potent inhibitor in hepatoma and could improve immune function of hepatoma H22-bearing mice. However, the immunomodulatory function of SBE on the tumor growth of hepatoma remains unclear. This study aimed to investigate the anti-tumor effects of SBE on hepatoma H22-bearing mice and explore the underlying immunomodulatory function. The hepatoma H22-bearing mice were treated by SBE for 30 days. The effect of SBE on the proliferation of HepG2 cells in vitro, the growth of transplanted tumor, the cytotoxicity of natural killer (NK) cells in spleen, the amount of CD4+CD25+Foxp3+ Treg cells and Th17 cells in tumor tissue, and the levels of IL-10, TGF-β, IL-17A, IL-2, and IFN-γ in serum of the hepatoma H22-bearing mice was observered. IL-17A was injected to the SBE treated mice from day 9 post H22 inoculation to examine its effect on tumor growth. SBE treatment inhibited the proliferation of HepG2 cells in vitro with a dose-dependent manner and significantly suppressed the tumor growth of hepatoma H22-bearing mice. Meanwhile, it increased NK cells’ cytotoxicity in spleen, down-regulated the amount of CD4+CD25+Foxp3+ Treg cells and Th17 cells in tumor tissue, and decreased IL-10, TGF-β, and IL-17A levels (P < 0.01) whereas increased IL-2 and IFN-γ levels (P < 0.01) in the serum of hepatoma H22-bearing mice. Moreover, administration of recombinant mouse IL-17A reversed the anti-tumor effects of SBE. SBE could inhibit the proliferation of HepG2 cells in vitro. Meanwhile, SBE also could inhibit the growth of H22 implanted tumor in hepatoma H22-bearing mice, and this function might be associated with immunomodulatory activity through down-regulating of Treg cells and manipulating Th1/Th17 immune response.

Hepatic ischemia/reperfusion (I/R) injury is a major concern in liver surgery settings. Mitochondria are critical targets or the origin of tissue injury, particularly I/R injury. Mitophagy, a selective form of autophagy, is a fundamental process that removes damaged or unwanted mitochondria for mitochondrial quality control, but its role in hepatic I/R remains unclear. In the present study, we investigated the role of mitophagy in hepatic I/R by focusing on PTEN-induced putative kinase 1 (PINK1). Livers from 10-week-old mice and primary hepatocytes were subjected to in vivo hepatic I/R and in vitro hypoxia-reoxygenation (H/R), respectively. Analyses of oxidative stress, immunoblotting, and ATP generation showed that hepatic I/R leads to mitochondrial damage. Dysfunctional mitochondria promoted reactive oxygen species (ROS) production and apoptosis. Hepatic I/R led to decreases in the mitochondrial proteins COX4 and TOM20 and mitochondrial DNA and increases in the autophagy-related indicators LC3 and P62, which indicates that hepatic I/R promotes mitophagy. We found that I/R also leads to endoplasmic reticulum stress, which has frequent signal communication with mitochondria through the mitochondria-associated membranes (MAMs). We showed that the mitophagy-related proteins Parkin, Beclin, optineurin were enhanced in hepatic I/R. No significant change is in PINK1 but it translocated to MAMs region to initiate mitophagy. The silencing PINK1 by shRNA in cultured primary hepatocytes reduced the level of H/R-induced mitophagy, leading to the accumulation of dysfunctional mitochondria during H/R, increased production of ROS, mitochondria-induced apoptosis, and eventually hepatocyte death. Taken together, these findings indicate that PINK1-mediated mitophagy plays a key role in mitochondrial quality control and liver cell survival during I/R.

Liver ischemia/reperfusion (IR) injury is a severe complication of liver surgery. Moreover, nonalcoholic fatty liver disease (NAFLD) patients are particularly vulnerable to IR injury, with higher rates of postoperative morbidity and mortality after liver surgeries. Our previous study found that renalase (RNLS) was highly sensitive and responsive to oxidative stress, which may be a promising biomarker for the evaluation of the severity of liver IR injury. However, the role of RNLS in liver IR injury remains unclear. In the present study, we intensively explored the role and mechanism of RNLS in fatty liver IR injury in vivo and in vitro. C57BL/6 mice were divided into 2 groups feeding with high-fat diet (HFD) and control diet (CD), respectively. After 20 weeks’ feeding, they were suffered from portal triad blockage and reflow to induce liver IR injury. Additionally, oleic acid (OA) and tert-butyl hydroperoxide (t-BHP) were used in vitro to induce steatotic hepatocytes and to simulate ROS burst and mimic cellular oxidative stress following portal triad blockage and reflow, respectively. Our data showed that RNLS was downregulated in fatty livers, and RNLS administration effectively attenuated IR injury by reducing ROS production and improving mitochondrial function through activating SIRT1. Additionally, the downregulation of RNLS in the fatty liver was mediated by a decrease of signal transduction and activator of transcription 3 (STAT3) expression under HFD conditions. These findings make RNLS a promising therapeutic strategy for the attenuation of liver IR injury.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths due to tumor invasiveness, frequent intrahepatic dissemination and extrahepatic metastasis. However, the genes and signaling pathways that are involved remain incompletely understood. In this study, weighted gene coexpression network analysis (WGCNA) was performed to jointly analyze clinical information and gene expression data to identify key genes associated with clinical features. Through the bioinformatic analysis, the yellow module and microvascular invasion (MVI) were found to be highly associated (r=0.41) by Pearson's correlation analysis, and 20 hub genes were identified with both high gene significance (GS) and high module membership (MM) in the yellow module. Among these genes, FoxM1 and KIAA0101 were upregulated in HCC with MVI and were significantly positively correlated in HCC samples, indicating a novel regulatory network in HCC microvascular invasion. Moreover, in vitro experiments demonstrated that KIAA0101 is a direct target of FoxM1 and that KIAA0101 is required for the FoxM1-induced promotion of HCC cell invasion and migration. In addition, the FoxM1-KIAA0101 axis promotes HCC metastasis by inducing epithelial-mesenchymal transition (EMT). In summary, KIAA0101 is a novel target of FoxM1 and contributes to HCC metastasis by activating EMT. The FoxM1-KIAA0101 axis might be applied as a potential prognostic biomarker and therapeutic target for HCC.