Jiajie Hou

IL-22 is related to development of human colon cancer by activation of STAT3

BackgroundIt has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC).MethodsThe expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model.ResultsOur results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22.ConclusionIn this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.

Estrogen‐sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3

Protein tyrosine phosphatase receptor type O (PTPRO), one of the receptor types of phosphotyrosine phosphatases (PTP), was recently described as a tumor suppressor in various kinds of cancers. We aimed to clarify the role of PTPRO in hepatocellular carcinoma (HCC). It was demonstrated in 180 pairs (120 male and 60 female) of clinical HCC specimens that the PTPRO level was significantly reduced, as compared with adjacent tissue, and the PTPRO level in male adjacent tissue was lower than in female. We further found that estrogen receptor alpha (ERα) could up‐regulate PTPRO expression as a transcription factor. Moreover, an in vitro study showed that cell proliferation was inhibited and apoptosis was promoted in PTPRO‐transduced HCC cell lines, whereas an in vivo study represented that tumor number and size was increased in ptpro−/− mice. As a result of its tumor‐suppressive position, PTPRO was proved to down‐regulate signal transducers and activators of transcription (STAT3) activity dependent on Janus kinase 2 (JAK2) and phosphoinositide 3‐kinase (PI3K) dephosphorylation. Conclusions: PTPRO expression results in pathological deficiency and gender bias in HCC, which could be attributed to ERα regulation. The suppressive role of PTPRO in HCC could be ascribed to STAT3 inactivation. (HEPATOLOGY 2013)

Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells.

Attenuated Listeria monocytogenes (LM) is a promising candidate vector for the delivery of cancer vaccines. After phagocytosis by antigen-presenting cells, this bacterium stimulates the major histocompatibility complex (MHC)-I and MHC-II pathways and induces the proliferation of antigen-specific T lymphocytes. A new strategy involving genetic modification of the replication-deficient LM strain ΔdalΔdat (Lmdd) to express and secrete human CD24 protein has been developed. CD24 is a hepatic cancer stem cell biomarker that is closely associated with apoptosis, metastasis and recurrence of hepatocellular carcinoma (HCC). After intravenous administration in mice, Lmdd-CD24 was distributed primarily in the spleen and liver and did not cause severe organ injury. Lmdd-CD24 effectively increased the number of interferon (IFN)-γ-producing CD8+ T cells and IFN-γ secretion. Lmdd-CD24 also enhanced the number of IL-4- and IL-10-producing T helper 2 cells. The efficacy of the Lmdd-CD24 vaccine was further investigated against Hepa1–6-CD24 tumors, which were inguinally inoculated into mice. Lmdd-CD24 significantly reduced the tumor size in mice and increased their survival. Notably, a reduction of T regulatory cell (Treg) numbers and an enhancement of specific CD8+ T-cell activity were observed in the tumor-infiltrating lymphocytes (TILs). These results suggest a potential application of the Lmdd-CD24 vaccine against HCC.

PTPRO plays a dual role in hepatic ischemia reperfusion injury through feedback activation of NF-κB

BACKGROUND & AIMS Nuclear factor-κB (NF-κB) activation in hepatocytes and macrophages appeared as a double-edged-sword in hepatic ischemia reperfusion (IR) injury. Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a potential activator of c-Src, which can in turn activate the NF-κB pathway. In this study, we aimed to determine the change and function of PTPRO in hepatocytes and macrophages during IR. METHODS Clinical patients with benign liver condition undergoing liver surgery were recruited in our study. Wild type (WT) and ptpro(-/-) C57BL/6 mice were processed to construct hepatic IR models. Isolated mouse hepatocytes and macrophages were treated with peroxide or TNFα in vitro. RESULTS In human and mouse IR models, PTPRO level was decreased in the early phase but reversed in the late phase. In vitro studies demonstrated that NF-κB up-regulated PTPRO transcription. Using ptpro(-/-) mice and primary cells, we found that PTPRO deficiency resulted in reduction of NF-κB activation in both hepatocytes and macrophages and was correlated to c-Src phosphorylation; PTPRO in hepatocytes alleviated, but PTPROt in macrophages exacerbated IR injury. CONCLUSIONS PTPRO activates NF-κB in a positive feedback manner, and plays a dual role in hepatic IR injury.

PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

Background/Aims: PTPRO (protein tyrosine phosphatase, receptor type O) is implicated in diverse physiological and pathological processes in cancer and hepatic ischemia/reperfusion injury, although little is known about its role in hepatic fibrosis. Methods: Here, by using genetically deficient mice, we reported that PTPRO knockout (PTPRO-/-) significantly attenuated liver injury, release of inflammatory factors, tissue remodeling, and liver fibrosis in two experimental mouse models of fibrogenesis induced by bile-duct ligation or carbon tetrachloride administration. Results: However, we proved that PTPRO expression was strongly downregulated in clinical and experimental liver fibrosis specimens. Further investigations revealed that stimulation of primary hepatic stellate cells (HSCs) and hepatocytes with specific activator platelet-derived growth factor (PDGF)-BB increased PTPRO transcription in HSCs but had the opposite effect in primary hepatocytes. More importantly, synthetic short hairpin RNA targeting PTPRO significantly neutralized PDGF-BB-induced HSC proliferation and myofibroblast marker expression through downregulated phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Conclusion: These observations confirm that PTPRO plays a critical role in liver fibrogenesis by affecting PDGF signaling in HSC activation and might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.

Interaction of PTPRO and TLR4 signaling in hepatocellular carcinoma

Protein tyrosine phosphatase receptor type O (PTPRO) has been identified as a tumor suppressor in a number of cancers including hepatocellular carcinoma (HCC). Toll-like receptor 4 (TLR4) plays diverse roles in HCC tumorigenesis and progression. The association between PTPRO and TLR4 signaling in HCC remains largely unknown. We aimed to clarify the interaction between PTPRO and TLR4 in HCC. Surprisingly, we found reduced and positive-related expression of TLR4 and PTPRO in 84 human HCC specimens. Increased TLR4 expression and activity was found in PTPRO-overexpressed HCC cells stimulated with lipopolysaccharide (LPS). The feedback regulation of PTPRO and TLR4 was dependent on nuclear factor-κB (NF-κB) activation, as suggested by NF-κB inhibition and luciferase reporter assay. Our study suggests that the effect of PTPRO on TLR4 signaling is dependent on NF-κB pathway, suggesting an interesting PTPRO/TLR4/NF-κB signaling feedback loop in HCC carcinogenesis and progression.

Aggravated Liver Injury but Attenuated Inflammation in PTPRO-Deficient Mice Following LPS/D-GaIN Induced Fulminant Hepatitis

Background/Aims: Critical roles of PTPRO and TLR4 have been implicated in hepatocellular carcinoma. However, little is known about their modifying effects on inflammation-related diseases in liver, particularly fulminant hepatitis (FH). We aim to investigate the potential role of PTPRO and its interaction with TLR4 in LPS/D-GaIN induced FH. Methods: A LPS/D-GaIN induced mouse FH model was used. RAW264.7 cells were transfected with PTPRO over-expressed lentiviral plasmids for further investigation. Results: The mortality of PTPRO KO mice is higher than WT mice after LPS/D-GaIN administration. Aggravated liver injury was demonstrated by increased level of serous ALT and AST and numerous hepatic cells death in PTPRO KO mice following LPS/D-GaIN administration. Interestingly, inflammation was attenuated in PTPRO-deficient mice following LPS/D-GaIN administration, which was suggested by decreased inflammatory cytokines (TNF-a, IFN-γ, IL-1ß, IL-6, IL-17A and IL-12) and cells infiltrating into spleen (CD3+IFN-γ+ cells, CD3+TNF-a+ cells, F4/80+/TLR4+ cells). A feedback regulation between PTPRO and TLR4 dependent on NF-γB signaling pathway was demonstrated in vivo and in vitro. Conclusion: PTPRO plays an important role in FH by interacting with TLR4. The crosstalk between PTPRO and TLR4 is a novel bridge linking innate immune and adaptive immune in acute liver injury.

Survival and Inflammation Promotion Effect of PTPRO in Fulminant Hepatitis Is Associated with NF-κB Activation

Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A–induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α–induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3β/β-catenin cascade. Increased β-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced β-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3β/β-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.

Clinicopathological features and prognostic factors of young patients with surgically treated liver cancer.

AbstractThis article compares the clinical characteristics and prognosis of young patients in different age groups with liver cancer (LC).In this retrospective study, we searched the Surveillance, Epidemiology, and End Results population-based database and identified 2641 patients who had been diagnosed with LC between 1988 and 2005. These patients were categorized into 2 different age ranges: Group 1 (⩽35 years) and Group 2 (36–45 years). Five-year cancer-specific survival (CSS) data were obtained. Kaplan–Meier methods and multivariable Cox regression models were used to analyze the long-term survival outcomes and risk factors.There were significant differences between the age groups for stage and tumor size (P < 0.001). The 5-year liver CSS rate was 20.4% and 14.5%, respectively (P < 0.001). Univariate and multivariate analysis also confirmed the difference (P < 0.001). Further analysis showed that this significant difference existed in localized, regional, and distant-stage patients.Young patients with LC of age 18 to 45 years are inherently heterogeneous. Patients aged ⩽35 years have better CSS than those aged 36 to 45 years, despite exhibiting unfavorable clinicopathological characteristics.

A bystander cell-based GM-CSF secreting vaccine synergized with a low dose of cyclophosphamide presents therapeutic immune responses against murine hepatocellular carcinoma.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting cellular tumor vaccines contribute to the induction of potent antitumor immune responses in murine models and patients suffering from cancers. Hepatocellular carcinoma (HCC) is one of the most frequent and malignant cancers in China. We describe, for the first time, a GM-CSF releasing vaccine strategy that represents a step toward combating this type of cancer. In this study, a bystander cell-based GM-CSF secreting vaccine against murine HCC, Hepa1–6/B78H1-GM-CSF, was co-administered with a low dose of cyclophosphamide (CY). After challenging with tumor and vaccination, immunological assays demonstrated that the cellular antitumor immune responses were efficiently activated and that tumor development was significantly retarded, which was dependent on synergy with CY. The promising outcome of the anti-HCC vaccine in the murine model demonstrates the feasibility of a future clinical application for this treatment in HCC patients.