The gut microbiota consists of a dynamic multispecies community of bacteria, fungi, archaea, and protozoans, playing a fundamental role in the induction, training, and function of the host immune system. The liver is anatomically and physiologically linked to the gut microbiota via enterohepatic circulation, specifically receiving intestine-derived blood through the portal vein. The gut microbiota is crucial for maintaining immune homeostasis of the gut-liver axis. A shift in gut microbiota composition can result in activation of the mucosal immune response causing homeostasis imbalance. This imbalance results in translocation of bacteria and migration of immune cells to the liver, which is related to inflammation-mediated liver injury and tumor progression. In this review, we outline the role of the gut microbiota in modulating host immunity and summarize novel findings and recent advances in immune-based therapeutics associated with the gut-liver axis. Moving forward, a deep understanding of the microbiome-immune-liver axis will provide insight into the basic mechanisms of gut microbiota dysbiosis affecting liver diseases.
BackgroundArsenic trioxide (ATO) is commonly used in the treatment of acute promyelocytic leukemia (APL), but does not benefit patients with solid tumors. When combined with other agents or radiation, ATO showed treatment benefits with manageable toxicity. Previously, we reported that metformin amplified the inhibitory effect of ATO on intrahepatic cholangiocarcinoma (ICC) cells more significantly than other agents. Here, we investigated the chemotherapeutic sensitization effect of metformin in ATO-based treatment in ICC in vitro and in vivo and explored the underlying mechanisms.MethodsICC cell lines (CCLP-1, RBE, and HCCC-9810) were treated with metformin and/or ATO; the anti-proliferation effect was evaluated by cell viability, cell apoptosis, cell cycle, and intracellular-reactive oxygen species (ROS) assays. The in vivo efficacy was determined in nude mice with CCLP-1 xenografts. The active status of AMPK/p38 MAPK and mTORC1 pathways was detected by western blot. In addition, an antibody array was used screening more than 200 molecules clustered in 12 cancer-related pathways in CCLP-1 cells treated with metformin and/or ATO. Methods of genetic modulation and pharmacology were further used to demonstrate the relationship of the molecule. Seventy-three tumor samples from ICC patients were used to detect the expression of ERK3 by immunohistochemistry. The correlation between ERK3 and the clinical information of ICC patients were further analyzed.ResultsMetformin and ATO synergistically inhibited proliferation of ICC cells by promoting cell apoptosis, inducing G0/G1 cell cycle arrest, and increasing intracellular ROS. Combined treatment with metformin and ATO efficiently reduced ICC growth in an ICC xenograft model. Mechanistically, the antibody array revealed that ERK3 exhibited the highest variation in CCLP-1 cells after treatment with metformin and ATO. Results of western blot confirm that metformin and ATO cooperated to inhibit mTORC1, activate AMP-activated protein kinase (AMPK), and upregulate ERK3. Metformin abrogated the activation of p38 MAPK induced by ATO, and this activity was partially dependent on AMPK activation. Inactivation of p38 MAPK by SB203580 or specific short interfering RNA (siRNA) promoted the inactivation of mTORC1 in ICC cells treated with metformin and ATO. Activation of p38 MAPK may be responsible for resistance to ATO in ICC. The relationship between p38 MAPK and ERK3 was not defined by our findings. Finally, AMPK is a newfound positive regulator of ERK3. Overexpression of EKR3 in ICC cells inhibited cell proliferation through inactivation of mTORC1. ERK3 expression is associated with a better prognosis in ICC patients.ConclusionsMetformin sensitizes arsenic trioxide to suppress intrahepatic cholangiocarcinoma via the regulation of AMPK/p38 MAPK-ERK3/mTORC1 pathways. ERK3 is a newfound potential prognostic predictor and a tumor suppressor in ICC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0424-0) contains supplementary material, which ...
The heterogeneity of hepatocellular carcinoma (HCC) commonly leads to therapeutic failure of HCC. Cytokeratin 19 (CK19) is well acknowledged as a biliary/progenitor cell marker and a marker of tumor stem cell. CK19-positive HCCs demonstrate aggressive behaviors and poor outcomes which including worse overall survival and early tumor recurrence after hepatectomy and liver transplantation. CK19-positive HCCs are resistant to chemotherapies as well as local treatment. This subset of HCC is thought to derive from liver progenitor cells and can be induced by extracellular stimulation such as hypoxia. Besides being a stemness marker, CK19 plays an important role in promoting malignant property of HCC. The regulatory network associated with CK19 expression has been summarized that extracellular stimulations which transmit into cytoplasm through signal transduction pathways (TGF-β, MAKP/JNK and MEK-ERK1/2), further induce important nuclear transcriptional factors (SALL4, AP1, SP1) to activate CK19 promoter. Novel noncoding RNAs are also involved in the regulation of CK19 expression. TGFβR1 becomes a therapeutic target for CK19-positive HCC. In conclusion, CK19 can be a potential biomarker for predicting poor prognosis after surgical and adjuvant therapies. CK19-pisitive HCCs exhibit distinctive molecular profiling, should be diagnosed and treated as a separate subtype of HCCs.
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