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ABSTRACT: Phenotypic switching of vascular smooth muscle cells (VSMCs) is known to play a key role in the development of atherosclerosis. However, the mechanisms that mediate VSMC phenotypic switching are unclear. We report here that TIPE2, the tumor necrosis factor (TNF) α-induced protein 8-like 2 (TNFAIP8L2), plays an atheroprotective role by regulating phenotypic switching of VSMCs in response to oxidized low-density lipoprotein (ox-LDL) stimuli. TIPE2-deficient VSMCs treated with ox-LDL expressed lower levels of contractile proteins such as SMA, SM-MHC and calponin, whereas the proliferation, migration and the synthetic capacity for growth factors and cytokines were increased remarkably. Furthermore, TIPE2 inhibited VSMCs proliferation by preventing G 1/S phase transition. Interestingly, these effects of TIPE2 on VSMCs were dependent on P38 and ERK1/2 kinase signals. As a result, neointima formation was accelerated in the carotid arteries of TIPE2-deficient mice. These results indicate that TIPE2 is a potential inhibitor of atherosclerosis.
Cell cycle (Georgetown, Tex.) 01/2013; 12(3). · 5.36 Impact Factor
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ABSTRACT: Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) family are recently identified proteins which are important for maintaining immune homeostasis. The mammalian TNFAIP8 family consists of four members: TNFAIP8, the first identified member of this family, TNFAIP8L1 (TNF-alpha-induced protein 8-like 1, TIPE1), TIPE2, and TIPE3, which share high degrees of sequence homology and involve in proliferation, inflammation, and cell death. Among the members, TNFAIP8 is considered to be associated with carcinogenesis, TIPE2 is an essential negative regulator of both innate and adaptive immunity and the depletion of TIPE2 would cause serve inflammatory disease. Whereas, little is known about TIPE1 and TIPE3.
Molecular Immunology 09/2011; 49(1-2):4-7. · 2.90 Impact Factor
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ABSTRACT: Members of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8 or TIPE) family play important roles in immune homeostasis and cancer. TIPE1 (TNFAIP8-like 1) is a new member of the TIPE family that may regulate cell death. However, due to the lack of a suitable antibody, the nature of cells and tissues that express TIPE1 protein has not been determined. In this study, we generated a highly specific antibody to TIPE1 and examined TIPE1 expression in various murine tissues and human cell lines by immunohistochemistry, reverse transcription real-time PCR, and Western blot. We found that TIPE1 protein was detected in a wide variety of tissues in C57BL/6 mice, such as neurons in brain, hepatocytes, germ cells of female and male reproductive organs, muscular tissues, and a variety of cells of the epithelial origin, particularly those with secretory functions. TIPE1 protein was not expressed in mature T or B lymphocytes, but detectable in human B lymphoblast cell line HMy2.CIR and murine T cell line EL4. Furthermore, high levels of TIPE1 mRNA were detected in most human carcinoma cell lines, especially in cells transformed with viral genomes. These results indicate that TIPE1 may perform functions in cell secretion and carcinogenesis, but not in immunity.
Molecular Immunology 07/2011; 48(12-13):1548-55. · 2.90 Impact Factor
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Wenjin Xi,
Yejia Hu,
Yugang Liu,
Jiao Zhang,
Lei Wang,
Yunwei Lou,
Zhonghua Qu,
Jian Cui,
Guizhong Zhang,
Xiaohong Liang,
Chunhong Ma,
Chengjiang Gao,
Youhai Chen, Suxia Liu
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ABSTRACT: Hepatitis B virus (HBV)-induced hepatic inflammation afflicts hundreds of millions of people worldwide and is a leading cause of hepatic cancer. While the deleterious effect of the chronic hepatitis is well recognized, the molecular mechanisms underlying the pathogenesis of HBV-induced hepatic inflammation are not well understood. We report here that the tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2 or TNFAIP8L2), a newly identified regulator of immune receptor signaling, plays an important role in controlling HBV-induced hepatitis. Patients with chronic hepatitis B had significantly reduced levels of TIPE2 expression in their peripheral blood mononuclear cells (PBMCs) as compared to healthy individuals. The TIPE2 expression negatively correlated with the blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (Tbil) as well as the HBV load of the patients. Importantly, using a murine model of HBV-induced hepatitis, we found that TIPE2-deficient mice developed significantly more severe hepatic inflammation than wild type mice. These results indicate that TIPE2 plays an important role in taming HBV-induced hepatic inflammation.
Molecular Immunology 04/2011; 48(9-10):1203-8. · 2.90 Impact Factor
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Guizhong Zhang,
Chunyan Hao,
Yunwei Lou,
Wenjin Xi,
Xuping Wang,
Yan Wang,
Zhonghua Qu,
Chun Guo,
Youhai Chen,
Yun Zhang, Suxia Liu
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ABSTRACT: Tumor necrosis factor-alpha-induced protein-8 like-2 (TNFAIP8L2, TIPE2) is a newly discovered negative regulator of innate immunity and cellular immunity. TIPE2 deficiency in mice causes fetal inflammatory diseases and TIPE2 downregulation in humans is associated with systemic autoimmunity. However, TIPE2 deficiency leads to a selective defect in humoral immunity. Due to the lack of a suitable antibody, the nature of cells and tissues that express TIPE2 protein has not been determined. In this study, we generated a highly specific antibody to TIPE2 and examined TIPE2 expression in various murine tissues by immunohistochemistry and RT-PCR. We found that TIPE2 was a cytoplasmic protein expressed preferentially in lymphoid tissues and a small group of non-lymphoid tissues. Within the lymphoid compartment, T cells appear to express high level of TIPE2 protein, while B cells and B cell zones of lymphoid organs were devoid of TIPE2. Within most of the non-lymphoid tissues, TIPE2 was not detected. However, several endocrine tissues and skeletal muscle expressed detectable TIPE2 protein and mRNA. Furthermore, high levels of TIPE2 were detected in monocyte/macrophage derived cell lines and ovarian adenocarcinoma cells, but not detectable or weakly expressed in most human carcinoma cell lines. These results indicate that TIPE2 may perform tissue-specific functions in both lymphoid and non-lymphoid compartments. They may also explain why TIPE2 deficiency enhanced cellular but not humoral immunity.
Molecular Immunology 09/2010; 47(15):2435-42. · 2.90 Impact Factor
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ABSTRACT: Hepatitis B virus (HBV) infection afflicts over 350 million people worldwide and is a leading cause of hepatitis, cirrhosis and hepatocellular carcinoma. HBV replicates noncytopathically in hepatocytes, and most of the hepatic injury is caused by the immune response to the virus. While most studies focused on the adaptive immune response, the role of the innate immune response, especially the complement activation, in HBV infection remains obscure. To identify proteins that are involved in the pathogenesis of HBV infection, we carried out gene microarray analysis to compare the gene expression profile of HBV transgenic BALB/c mice with that of control mice. CD59 mRNA, which encodes an important complement regulatory protein (CRP) expressed on cell surface, was found to be significantly downregulated in HBV transgenic liver, a result that was further confirmed by RT-PCR and real-time PCR. To explore the relationship between CD59 and HBV infection, we examined the effect of HBV on CD59 expression and complement-dependent cytolysis in two hepatocyte cell lines. We found that HBV could significantly downregulate CD59 expression and sensitize cells to complement-dependent lysis. Blocking CD59 function using a CD59-specific antibody greatly diminished the HBV effect. Similar CD59 downregulation was also observed in the livers of patients with chronic HBV infection. These results demonstrate that HBV can sensitize hepatocytes to complement-dependent cytotoxicity (CDC) through downregulating CD59, which may lead to the activation of complement system and cause liver inflammation.
Molecular Immunology 10/2009; 47(2-3):283-9. · 2.90 Impact Factor
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Lili Cao,
Lihui Han,
Zhiyong Zhang,
Jie Li,
Zhonghua Qu,
Juan Du,
Xiaohong Liang,
Yugang Liu,
Hua Liu,
Yongyu Shi, Suxia Liu,
Lifen Gao,
Wensheng Sun
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ABSTRACT: Acquisition of anoikis-resistance is a pre-requisite for cancer cell metastasis. We have demonstrated that hepatoma cells could resist anoikis by a synoikis-like survival style. In this study, we further suggest that acquisition of anoikis-resistance confer cancer cells more capacity for invasiveness, evading from cancer therapeutic agents and escaping from host immune attacks. We investigated the response of anoikis-resistant hepatoma cells to TNF-related apoptosis-inducing ligand (TRAIL), a typical immune surveillant molecule as well as a potential anticancer agent. Our data indicated that detached hepatoma cells not only resist TRAIL-induced apoptosis, but also domesticate TRAIL to exert a stealth "tumor counterattack" effect. These results reveal that acquisition of anoikis-resistance may act as a selective pressure to superimpose on hepatoma cells more metastatic potential for the development of cancer.
Experimental Cell Research 01/2009; 315(7):1148-56. · 3.58 Impact Factor
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Zhiyong Zhang,
Lili Cao,
Jie Li,
Xiaohong Liang,
Yugang Liu,
Hua Liu,
Juan Du,
Zhonghua Qu,
Min Cui, Suxia Liu,
Lifen Gao,
Chunhong Ma,
Lining Zhang,
Lihui Han,
Wensheng Sun
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ABSTRACT: Resistance to anoikis is a hallmark of human malignancies. Our results showed that hepatoma cells resisted anoikis by non-proliferation, non-apoptosis and cell cycle arrest which were termed synoikis-like. These synoikis-like cells are more resistant to extracellular stimuli and could spontaneously attach and proliferate again under suitable conditions, which indicate a reversible property of these cells. Microarray expression profile reveals the change of molecules involved in the synoikis-like hepatoma cells and our data indicated that ANGPTL4 contributed to anoikis resistance of hepatoma cells. These results demonstrated that hepatoma cells might resist anoikis through a synoikis-like survival style, which may facilitate tumor metastasis.
Cancer Letters 09/2008; 267(1):106-15. · 4.24 Impact Factor
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Xiaohong Liang,
Zhonghua Qu,
Zhiyong Zhang,
Juan Du,
Yugang Liu,
Min Cui,
Hua Liu,
Lifen Gao,
Lihui Han, Suxia Liu,
Lili Cao,
Peiqing Zhao,
Wensheng Sun
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ABSTRACT: The TNF-related apoptosis-inducing ligand (TRAIL) has recently been implicated in the death of hepatocytes under infectious but not normal conditions. Our previous studies showed that both the whole HBV genome and its HBx protein enhanced TRAIL-induced hepatocyte apoptosis. We report here that preS2-containing viral proteins are also potent regulators of TRAIL-induced apoptosis. HBV-transfected hepatoma cell line, HepG2.2.15, pretreated with antisense oligonucleotide against preS2 gene, showed a lower sensitivity towards TRAIL-induced apoptosis. However, this effect might not be related with the expression level of TRAIL receptors. These results establish that besides HBx, preS2 viral proteins are also involved in enhancing TRAIL-induced hepatocyte apoptosis. The novel role of preS2 would be useful to further unravel the mechanisms of imbalanced apoptosis during HBV infection and provides a potential therapeutic target for HBV-related diseases.
Biochemical and Biophysical Research Communications 06/2008; 369(2):456-63. · 2.48 Impact Factor
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Zhiyong Zhang,
Lihui Han,
Lili Cao,
Xiaohong Liang,
Yugang Liu,
Hua Liu,
Juan Du,
Zhonghua Qu,
Changjun Zhu, Suxia Liu,
Hui Li,
Wensheng Sun
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ABSTRACT: Anoikis resistance is the prerequisite of cancer cells metastasis. Elucidation of the mechanism of anoikis resistance remains a significant challenge. We reported here a model to mimic anoikis resistant process of hepatoma cells in vitro. Experimental results indicated cell to cell aggregation could mediate anoikis resistance of BEL7402 hepatoma cells. Further investigation of these aggregations indicated the biological properties changed greatly after the hepatoma cells lost their anchorage. Aggregation forming process could be separated into three distinct phases according to their biological characteristics, comprising of premature phase, mature phase and postmature phase. Mature phase aggregations have the premium state of cell viability and may mimic the metastatic cells in the circulating system. Biological properties of these three phases aggregations were studied in details including morphological alteration, cell viability and microarray expression profiles. It indicated there was a great upregulation of adhesion molecules during the process of aggregation formation and the cell to cell contact in the aggregation may be mediated independent of calcium involved adhesion pathway. This model might shed light on the anoikis resistance mechanism of hepatoma cells and help to develop new therapies that may target the anoikis resistant hepatoma cells in the metastasis process.
Folia Histochemica et Cytobiologica 02/2008; 46(3):331-6. · 0.81 Impact Factor
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ABSTRACT: The preS2 domain is the minimal functional unit of transcription activators that is encoded by the Hepatitis B virus (HBV) surface (S) gene. It is present in more than one-third of the HBV-integrates in HBV induced hepatocarcinoma (HCC). To further understand the functional role of PreS2 in hepatocytes, a PreS2 expression plasmid, pcS2, was constructed and stably transfected into HepG2 cells. We conducted growth curve and colony-forming assays to study the impact of PreS2 expression on cell proliferation. Cells transfected with PreS2 proliferated more rapidly and formed colonies in soft agar. PreS2 expressing cells also induced upregulation of human telomerase reverse transcriptase (hTERT) and telomerase activation by RT-PCR and the modified TRAP assay. Blocking expression of hTERT with antisense oligonuleotide reversed the growth rate in cells stably transfected with PreS2. Our data suggest that PreS2 may increase the malignant transformation of human HCC cell line HepG2 by upregulating hTERT and inducing telomerase activation.
Biochemical and Biophysical Research Communications 05/2007; 355(2):379-84. · 2.48 Impact Factor
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ABSTRACT: To construct a hepatoma directed gene delivery system which could transfer preS2 antisense RNA to liver cancer cells specifically, and to explore a new therapeutic strategy for hepatocellular carcinoma by blocking hepatitis B virus (HBV) with antisense RNA targeting hepatocellular carcinoma.
GE7 and HA20 were synthesized and mixed with pEBAF-as-preS2, a hepatocarcinoma specific HBV antisense expression vector, to construct a novel HBV antisense RNA delivery system named AFP-enhancing 4-element complex. Nude mice bearing hepatocelluar carcinoma cells HepG2.2.15 were injected with AFP-enhancing 4-element complex via a tail vein. Total RNA from tissues was extracted, and reversal transcription-ploymerase chain reaction (RT-PCR) was used to detect the expression of preS2. Different doses of AFP-enhancing 4-element complex was injected into nude mice at different time points, and tumor diameter was measured.
AFP-enhancing 4-element complex was constructed successfully. RT-PCR showed preS2 antisense RNA delivered by AFP-enhancing 4-element complex only expressed in liver tumor HepG2.2.15 cells of the mice. After the treatment of AFP-enhancing 4-element complex with dose of 0.2 micro g per mouse (once a week for 4 weeks), the mean tumor diameter of nude mice was significantly shorter than that of the control groups (0.995 +/- 0.35 cm vs 2.125 +/- 0.25 cm, P < 0.01).
An HBV antisense RNA gene delivery system targeting hepatocellular carcinoma, AFP-enhancing 4-element complex, was constructed successfully. PreS2 antisense RNA expressed specifically in hepatocelluar carcinoma cells significantly inhibits tumor growth of mice bearing hepatocarcinoma HepG2.2.15 and may have therapeutic potential in HBV related hepatocarcinoma.
Chinese medical journal 05/2003; 116(5):717-20. · 0.86 Impact Factor
