Shifang Ren

Fudan University, Shanghai, Shanghai Shi, China

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Publications (5)10.94 Total impact

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    ABSTRACT: Klotho was originally characterized as an aging suppressor gene that predisposed Klotho-deficient mice to premature aging-like syndrome. Although Klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of Klotho in hepatocarcinogenesis remains poorly understood. In our present study, immunohistochemical Klotho staining levels in a clinical follow-up of 52 hepatoma patients were significantly associated with liver cirrhosis, tumor multiplicity and venous invasion. The overall survival rate of hepatoma patients with high Klotho expression was significantly lower than those patients with low Klotho expression. Moreover, Klotho overexpression increased cellular migration, anchorage-independent growth, and anoikis resistance in hepatoma cells. Klotho overexpression elevated p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Klotho-overexpressed hepatoma cells. More importantly, the pivotal significance of upregulated VEGFR2 protein levels mediated by Klotho expression was confirmed by VEGFR2 inhibitor Axitinib and blocking antibody treatment in hepatoma cells. Axitinib treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Klotho-overexpressed hepatoma cells. Conversely, knockdown of Klotho reduced VEGFR2/PAK1 dependent anoikis resistance, which could be reversed by PAK1 T423E. These results revealed a novel oncogenic function of Klotho in promoting anoikis resistance via activating VEGFR2/PAK1 signaling, thus facilitating tumor migration and invasion during hepatoma progression, which could provide a putative molecular mechanism for tumor metastasis.
    PLoS ONE 01/2013; 8(3):e58413. · 3.73 Impact Factor
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    ABSTRACT: The Escherichia coli homolog of GroEL, a 60 kDa heat shock protein (HSP), is a dominant protein produced not only in response to heat stress but also under in vitro growth condition. Beside its traditional cytoplasmic location, the surface exposures of GroEL have been observed in many pathogenic bacteria. To investigate the role of the surface-associated GroEL in the binding of E. coli to macrophages, we constructed a new strain of E. coli displaying GroEL on the outer membrane. We found that surface-associated GroEL increases the clearance ratio of E. coli by macrophages. It has been previously demonstrated that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the receptor for Hsp60 from different species. Our present results showed that GroEL on E. coli was recognized by LOX-1 on macrophages, leading to the phagocytosis of pathogen by macrophages. In addition, surface-associated GroEL made mice more susceptible to E. coli-induced peritonitis. These findings add to the research that clarifies the factors mediating bacterial adherence to host cells. Our results suggest that GroEL is a novel therapeutic target for modulating the immune response in infectious and inflammatory conditions.
    Microbes and Infection 10/2012; · 2.92 Impact Factor
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    ABSTRACT: CLEC-2 was first identified by sequence similarity to C-type lectin-like molecules with immune functions and has been reported as a receptor for the platelet-aggregating snake venom toxin rhodocytin and the endogenous sialoglycoprotein podoplanin. Recent researches indicate that CLEC-2-deficient mice were lethal at the embryonic stage associated with disorganized and blood-filled lymphatic vessels and severe edema. In view of a necessary role of CLEC-2 in the individual development, it is of interest to investigate its phylogenetic homology and highly conserved functional regions. In this work, we reported that CLEC-2 from different species holds with an extraordinary conservation by sequence alignment and phylogenetic tree analysis. The functional structures including N-linked oligosaccharide sites and ligand-binding domain implement a structural and functional conservation in a variety of species. The glycosylation sites (N120 and N134) are necessary for the surface expression CLEC-2. CLEC-2 from different species possesses the binding activity of mouse podoplanin. Nevertheless, the expression of CLEC-2 is regulated with a species-specific manner. The alternative splicing of pre-mRNA, a regulatory mechanism of gene expression, and the binding sites on promoter for several key transcription factors vary between different species. Therefore, CLEC-2 shares high sequence homology and functional identity. However the transcript expression might be tightly regulated by different mechanisms in evolution.
    Glycoconjugate Journal 06/2012; 29(5-6):335-45. · 1.88 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide, and novel therapeutic strategies are urgently required to improve clinical outcome. Interferon-alpha (IFN-α) and sorafenib are widely used as anti-tumor agents against various malignancies. In this study, we investigated the combined effects of IFN-α and sorafenib against HCC. We demonstrated that the combination therapy synergistically suppressed HCC cellular viability, arrested cell cycle propagation and induced apoptosis in HCC cells. Further research revealed that IFN-α and sorafenib collaboratively regulated the expression levels of cell cycle-related proteins Cyclin A and Cyclin B as well as the pro-survival Bcl-2 family proteins Mcl-1, Bcl-2 and Bcl-X(L). Moreover, sorafenib inhibited IFN-α induced oncogenic signaling of STAT3, AKT and ERK but not the activation of the tumor suppressor STAT1. Xenograft experiments also confirmed the combined effects of IFN-α and sorafenib on tumor growth inhibition and apoptosis induction in vivo. In conclusion, these results provide rationale for the clinical application of IFN-α and sorafenib combination therapy in HCC treatment.
    Biochemical and Biophysical Research Communications 05/2012; 422(4):687-92. · 2.41 Impact Factor
  • Li Zhu, Jing Zhang, Shifang Ren, Yinlong Guo
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    ABSTRACT: A novel strategy for facile, fast and highly effective enrichment of phosphopeptides by bentonite followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is presented. Bentonite is a Al(III)-containing, nontoxic and inexpensive natural nanomaterial with good biocompatibility. By employing bentonite into phosphopeptides enrichment, phosphopeptides binded on bentonite can be detected directly after simple wash, without nanomaterial preparation, desalting and elution process. The whole enrichment procedure can be easily completed within 10 min. Tryptic digest products from several standard proteins and nonfat milk are pretreated using bentonite to demonstrate the efficiency of this method, all the phosphorylation sites in a-casein and ß-casein can be detected unambiguously even at low fmol level. With all the advantages mentioned above, this method is of great potential for future studies of complex phosphoproteomes, and opens up new horizons for bentonite application.
    International Journal of Mass Spectrometry. s 343–344:23–27.