DTL is a Novel Downstream Gene of E2F1 that Promotes the Progression of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), one of the world's most prevalent malignancies, accounts for 90% of primary liver cancer cases. Recent studies have shown an increased expression of denticles E3 ubiquitin protein ligase homolog (DTL) in several different tumor types, but its function and regulatory mechanisms remain unclear. AIMS: This study aimed to investigate the expressions of the Cullin4 (CUL4) complex in HCC and elucidate the roles of DTL in HCC cells. METHODS: The relative expression of the CUL4 complex and its clinical significance were analyzed with The Cancer Genome Atlas (TCGA) data, and the level of DTL was confirmed by immunohistochemistry. The functions of DTL1 and upstream E2F1 were evaluated by a Western blot, MTT, transwell, and xenograft in HCC cell lines. RESULTS: The elevated mRNA expression of the CUL4 complex, including CUL4B, DDB1 (Damage Specific DNA Binding Protein 1), and DTL, was associated with the overall survival of HCC patients. We also found that the DTL protein was elevated in HCC tissues, and patients with highly expressed DTL and nucleus-located DTL had a poorer survival time. DTL knockdown significantly inhibited cancer proliferation, migration, and invasion. Further experiments showed that E2F1 was an upstream regulatory molecule of DTL, which was bound to the promoter of DTL, promoting the expression of DTL. CONCLUSION: The study results demonstrate that E2F1-DTL signaling promotes the growth, migration, and invasion of HCC cells, which provides new insights and a potential biological target for future HCC therapies.

Immune tolerance induced by RelB short-hairpin RNA interference dendritic cells in liver transplantation.

BACKGROUND: The induction of specific immune tolerance for alloantigen is the best method for solving transplant rejection. We have previously reported T-cell tolerance induced by RNA interference (RNAi) RelB dendritic cells (DCs), supporting the possibility of immunologic tolerance in liver transplantation. METHODS: A stable model of acute rejection was established in Lewis (RT11) rats that had received a liver graft from dark agouti-RT1a rats. To evaluate the immune tolerance of DCs of different maturity, the rats were randomly assigned to four groups (12 donor/recipient pairs): (1) control-DC group, recipient rats without preinjection; (2) RelB short hairpin (sh)RNAi-DC group, recipient rats with preinjection of tolerogenic DCs by way of RelB silencing; (3) imDC group, recipient rats with preinjection of immature DCs; and (4) lipopolysaccharide-DC group, recipient rats with preinjection of mature DCs. The immune tolerance of the grafts was evaluated by liver function tests (aspartate transaminase, total bilirubin), cytokines (interleukin [IL]-2, IL-4, IL-10 and interferon-γ), and histopathologic examination during the 2 wk after transplantation. The survival time of the rats was also observed. RESULTS: Compared with the other three groups, the graft survival time was significantly prolonged in the RelB shRNAi-DC group. In addition, RelB shRNAi-DCs resulted in the reduced secretion of IL-2 and interferon-γ and increased levels of IL-10 and IL-4. The symptoms of rejection were obviously alleviated in the RelB shRNAi-DC group, and the rejection activity index was still reduced after 2 wk. CONCLUSIONS: Injection of RelB-silenced DCs contributed to the reduced incidence of graft rejection and prolonged the graft survival time. The potential mechanisms involved the regulation and induction of immune-incompetent T cell by DCs.

Immunomodulatory effects of secondary metabolites from thermophilic Anoxybacillus kamchatkensis XA-1 on carp, Cyprinus carpio.

A bacterial strain with putative immunomodulatory properties was isolated from Xi'an hot springs in China. Comparison of 16S rRNA gene revealed a 97% similarity between the tested strain (designated XA-1) and Anoxybacillus kamchatkensis. Two compounds isolated from the secondary metabolites of XA-1 were identified by spectral data (infrared, nuclear magnetic resonance and mass spectrometry) as: (1) cyclo (Gly-L-Pro) and (2) cyclo (L-Ala-4-hydroxyl-L-Pro). Two cyclic dipeptides showed stimulatory properties towards a range of parameters when a dose of 20mg kg(-1) body weight was intraperitoneally injected in naive common carp, Cyprinus carpio. Innate immune parameters (serum SOD, lysozyme and bactericidal activity, and phagocytic activity by peripheral blood leucocytes) along with the expression of two immune-related genes (IL-1ß and iNOS) in blood were examined after 7, 14, 21, and 28 days of injection. In the absence of infection, immunomodulators should ideally not affect normal physiology and immunity of the host; possible negative outcomes of activated immune responses in the naive state are discussed. Protection by two bacterial dipeptides was assessed in an intraperitoneal injection challenge trial with live Aeromonas hydrophila. Both compounds reduced mortality, with the highest survival rate observed in the group that received compound 2 (80%) followed by the group that received compound 1 (65%) while control group scored the worse (15%). Elucidation of the involved protective mechanisms in carp requires future studies.