Hepatocyte nuclear factor-1beta (HNF1β) was initially identified as a liver-specific transcription factor. It is a homeobox transcription factor that functions as a homodimer or heterodimer with HNF1α. HNF1β plays an important role in organogenesis during embryonic stage, especially of the liver, kidney, and pancreas. Mutations in the HNF1β gene cause maturity-onset diabetes of the young type 5 (MODY5), renal cysts, genital malformations, and pancreas atrophy. Recently, it has been shown that the expression of HNF1β is associated with cancer risk in several tumors, including hepatocellular carcinoma, pancreatic carcinoma, renal cancer, ovarian cancer, endometrial cancer, and prostate cancer. HNF1β also regulates the expression of genes associated with stem/progenitor cells, which indicates that HNF1β may play an important role in stem cell regulation. In this review, we discuss some of the current developments about HNF1β and tumor, the relationship between HNF1β and stem/progenitor cells, and the potential pathogenesis of HNF1β in various tumors.

BackgroundInflammatory cytokine is important in modulating injured diseases. Tumor necrosis factor-α (TNF-α), one of potent inflammatory cytokines, plays a dominant role in host defense reaction. However, the concrete effect of TNF-α on acute liver injury is totally unclear. Here we reported the concrete effect and possible mechanisms of TNF-α on acute liver injury induced by carbon tetrachloride (CCl4).MethodsSD male rats were equally divided into nine groups. CCl4 (1 ml/kg) was subcutaneously injected into the rats. Enbrel, a TNF-α inhibitor, were intraperitoneally injected at dose of 0, 0.25, 0.5, 1, 2, 4 or 8 mg/kg 15 min before the CCl4 injection. 24 h later, rats were sacrificed. Serum ALT and AST were measured with an autoanalyzer. Serum TNF-α were measured by ELISA. HE staining was used to observe the liver tissue morphology. Hepatocellular apoptosis were tested by immunochemistry and Tunnel kit. Inflammatory factors, involve IL-4, IL-6, IL-8, IL-β and IFN-γ were detected by RT-PCR. The NF-κB signal pathway and anti-apoptotic genes include Bcl-XL, FHC, XIAP and Bcl-2 were measured by western-blotting and RT-PCR.ResultsThe change of liver function presented an obvious “V” shape in the whole process of persistently increased Enbrel. As Enbrel was increased gradually from 0 to 1 mg/kg, serum TNF-α were blocked, ALT and AST were gradually decreased as TNF-α as well as the numbers of hepatocellular apoptosis, and were declined to the minimum at 1 mg/kg Enbrel. As Enbrel was increased gradually from 1 to 8 mg/kg, ALT, AST and hepatocellular apoptosis were increased instead, and reached to the maximum at 8 mg/kg Enbrel. HE showed that the seriousness of hepatocellular steatosis was the most at 8 mg/kg Enbrel, and second at 0 mg/kg, the weakest at 1 mg/kg in the acute liver injury. Western-blotting and RT-PCR showed NF-κB, p-IκBα and antiapoptotic genes include Bcl-XL, FHC, XIAP, Bcl-2 were decreased as TNF-α was blocked by increased Enbrel.ConclusionOur results suggested that TNF-α had a dual role in acute liver injury. It was regulated might via the corporate effect of NF-κB signal pawahway and anti-apoptosis. Meanwhile, our findings provide a reference for clinical treatment of acute liver injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0074-x) contains supplementary material, which is available to authorized users.

Hepatocyte nuclear factor-1beta (HNF-1B) is involved in the hepatobiliary specification of hepatoblasts to cholangiocytes during liver development, and is strongly expressed throughout adult biliary epithelium. The aim of this study was to examine the expression of HNF-1B in different pathologic subtypes of primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC), and the relationship between HNF-1B expression, clinicopathological features and prognosis. We retrospectively investigated 2 cohorts of patients, including 183 HCCs and 69 ICCs. The expression of HNF-1B was examined by immunohistochemistry. We found that HNF-1B expression was associated with pathological subtype of primary tumor, and HNF-1B expression in HCC tissue may be associated with the change of phenotype on recurrence. The HNF-1B expression was positively correlated with biliary/HPC (hepatic progenitor cell) markers expression. Further, multivariable analysis showed that HNF-1B expression was an independent prognostic factor for both overall survival and disease-free survival of HCC patients. However, no correlation between HNF-1B expression and survival was found in ICC patients. In summary, HCC with high HNF-1B expression displayed biliary phenotype and tended to show poorer prognosis. HNF-1B-positive malignant cells could be bipotential cells and give rise to both hepatocytic and cholangiocytic lineages during tumorigenesis.

CD45, the leukocyte common antigen, is expressed on almost all cells of the immunological and hematological systems. CD45 expression is related to a variety of diseases, including leukemia and lymphoma. In this study, we analyzed the expression level of CD45 across cancers and evaluated the relationship between its expression and patient prognosis. We further integrated methylation data to explore the differences in CD45 across cancers from a multi-omics perspective. We also analyzed the relationship between CD45 expression and levels of immune cell infiltrates and immune modifiers. Our results revealed the distinct expression characteristics and prognostic value of CD45 across multiple tumors. In addition, we screened drug targets based on the immune index defined by CD45 expression and identified that GPR84 affected the proliferation of tumor cells and was associated with the inflammation caused by immunotherapy. In summary, our findings provide a comprehensive understanding of the role of CD45 in oncogenesis and its prognostic significance across cancers.

The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.