LAGE3 promotes angiogenesis on hepatocellular carcinoma by stabilizing VEGFA mRNA.

RNA modification plays important roles in various physiological and pathological process. LAGE3 is a component of EKC/KEOPS complex, which is probably involved in the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs, but its exact role in HCC is less studied. Our study reveals that LAGE3 exhibits upregulated expression in HCC compared with normal hepatocellular tissue. High expression of LAGE3 promotes hepatocellular cell proliferation and migration. Further investigations suggest that the increased expression of LAGE3 cloud lead to upregulated VEGFA secretion and angiogenesis in HCC. The mechanistic study reveals LAGE3 is required for the VEGFA mRNA stability. This research may open new avenues for diagnosis and targeted therapy in HCC.

High expression of aurora kinase B predicts poor prognosis in hepatocellular carcinoma after curative surgery and its effects on the tumor microenvironment.

Background: Currently, the only broadly used biomarker for hepatocellular carcinoma (HCC), alpha fetoprotein (AFP), has multiple limitations and the need for novel biomarkers is urgent. Aurora kinase B (AURKB) is a key mitotic protein kinase which performs a critical function in cell cycle progression. Nonetheless, neither the function nor the mechanism of AURKB in HCC following curative surgery is fully grasped at this time. This study sought to evaluate the impact of AURKB on prognosis and the tumor immune microenvironment (TIME) in HCC. Methods: We evaluated both the expression profile of AURKB in HCC and its clinical value using online databases and clinical specimens. The prognostic value of AURKB was studied by Kaplan-Meier survival analysis, and the link between AURKB and tumor-infiltrating immune cells (TIICs) were analyzed. Results: We found the mRNA expression patterns of AURKB were remarkably upregulated in HCC in contrast with adjoining normal tissues (P<0.001). Upregulation of the AURKB protein in HCC was additionally verified by clinical samples. The expression of AURKB was substantially associated with Child-Pugh, microvascular invasion (MVI), Edmondson-Steiner grade, and tumor recurrence. Furthermore, patients diagnosed with HCC who had a low AURKB expression had a better. Our data suggested age [hazard ratio (HR): 1.34], alanine aminotransferase (ALT) (HR: 1.65), tumor size (HR: 1.99), mor number (HR: 1.60), MVI (HR: 1.93), grade (HR: 5.58), and AURKB expression (HR: 3.63) independently functioned as prognostic risk indicators for HCC (P<0.05). Importantly, we also found AURKB expression was inversely linked to resting natural killer (NK) cells, M2 macrophages, activated mast cells, and naive B cells, and positively linked to M0 macrophages, T follicular helper cells (Tfh), regulatory T cells (Treg), and resting myeloid dendritic cells. In addition, AURKB expression was also positively linked to the immune checkpoints of PDCD1, CD274, CTLA4, and LAG3. Finally, 1,696 DEGs were discovered, and were predominantly implicated in chromosome segregation, cell cycle, xenobiotic metabolic process, calcium signaling pathway, bile secretion, tyrosine metabolism, and DNA replication. Conclusions: AURKB may be a potential prognostic biomarker for HCC after curative surgery, which correlates with MVI and the TIME in HCC.

The SNP of rs6854845 suppresses transcription via the DNA looping structure alteration of super-enhancer in colon cells.

Single-nucleotide polymorphisms (SNPs) identified by Genome-Wide Association Studies (GWASs) have been determined to closely connect with multiple diseases. Previous studies revealed one underlying mechanism that SNPs located within the regulatory elements could affect the encoding gene expression through long-range regulation. SNP rs6854845 was suggested to be a risk of colon cancer in human population. Nevertheless, the underlying molecular mechanism for colon carcinogenesis remains largely unknown. In present study, rs6854845 with G > T mutation in situ in FHC, HCT-116 and SW-480 cells were generated by Crispr/Cas9. The nearby chromatin organization was investigated by chromatin conformation capture (3C). And the expression of coding gene regulated by super-enhancer (SE) was detected by real-time PCR. We observed a significantly different pattern of the genome organization upon rs6854845 generation in colon epithelial cells but not in colon cancer cells. Moreover, we observed the shifted enrichment of H3K4me1 and H3K27ac at the SE (chr4:75.7M-76.0 M) where rs6854845 located. Furthermore, we observed that the transcription of the gene clusters regulated by SE were affected by rs6854845 in colon cells. Overall, our results demonstrated that SNP rs6854845 located in SE could destroy the long-range chromosomal interaction between SE and target gene clusters thereby affecting the transcription of these genes.

miR-194 inhibits liver cancer stem cell expansion by regulating RAC1 pathway.

Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver CSCs remains unclear. Herein, we observed low expression of miR-194 in chemoresistant HCC cells. A remarkable decrease of miR-194 was detected in EpCAM or CD133-positive liver CSCs and CSC-enriched hepatoma spheres. Interference miR-194 facilitated liver CSCs expansion by enhancing the self-renewal of liver CSCs. While up-regulating miR-194 inhibited liver CSCs expansion by suppressing the self-renewal of liver CSCs. Furthermore, hepatoma cells with miR-194 overexpression performed more sensitivity to sorafenib treatment. Mechanistically, functional studies found that Ras-related C3 botulinum toxin substrate 1 (RAC1) was a direct target of miR-194. Overexpression of miR-194 inhibited the expression of RAC1 in liver CSCs. Special RAC1 siRNA diminished the discrepancy in liver CSC proportion and the self-renewal capacity between miR-194 overexpression hepatoma cells and control cells, which further confirmed that RAC1 was required in miR-194-inhibited liver CSCs expansion. More importantly, downregulated expression of miR-194 was a predictor of poor prognosis of HCC patients.

Thrombin-activatable fibrinolysis inhibitor is activated in an instant blood-mediated inflammatory reaction after intraportal islet transplant.

OBJECTIVES: Activated thrombin-activatable fibrinolysis inhibitor is a coagulation factor in some thrombotic diseases. However, available data on whether thrombin-activatable fibrinolysis inhibitor is activated in islet transplant are limited. In this study, changes of plasma-activated thrombin-activatable fibrinolysis inhibitor levels in instant blood-mediated inflammatory reaction after islet transplant were assessed. MATERIALS AND METHODS: Plasma concentrations of thrombin-antithrombin complex, D-dimer, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor were assessed at 0 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours after an intraportal islet transplant using rats via an enzyme-linked immunosorbent assay, or solid-phase, 2-site chemiluminescent immunometric assay. We recovered the liver at 1 hour after the transplant for histologic examination. RESULTS: Thrombin-antithrombin complex, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor levels increased immediately after we stopped islet infusion, and their peak levels occurred at 1 hour after islet infusion. D-dimer levels increased continually after islet infusion was stopped, and peaked 24 hours after infusion. Histologic examination of the liver 1 hour after islet infusion revealed frequent portal venous thrombi, with entrapped islets. The entrapped islets showed a disrupted morphology. CONCLUSIONS: Activated thrombin-activatable fibrinolysis inhibitor was generated and peaked 1 hour after islet transplant according with activating coagulation, indicating that thrombin-activatable fibrinolysis inhibitor is activated and accumulated at levels in instant blood-mediated inflammatory reaction was sufficient to affect fibrinolysis.