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author:("Ma, wanfang")
1.  Anti-IGF-1R monoclonal antibody inhibits the carcinogenicity activity of acquired trastuzumab-resistant SKOV3 
Background
Antibody resistance, not only de novo but also acquired cases, usually exists and is related with lower survival rate and high risk of recurrence. Reversing the resistance often results in better clinical therapeutic effect. Previously, we established a trastuzumab-resistant ovarian cancer cell line, named as SKOV3-T, with lower HER2 and induced higher IGF-1R expression level to keep cell survival.
Methods
IGF-1R was identified important for SKOV3-T growth. Then, a novel anti-IGF-1R monoclonal antibody, named as LMAb1, was used to inhibit SKOV3-T in cell growth/proliferation, migration, clone formation and in vivo carcinogenicity.
Results
In both in vitro and in vivo assays, LMAb1 showed effective anti-tumor function, especially when being used in combination with trastuzumab, which was beneficial to longer survival time of mice as well as smaller tumor. It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.
Conclusion
We achieved satisfactory anti-tumor activity using trastuzumab plus LMAb1 in trastuzumab-resistant ovarian cancer model. In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.
doi:10.1186/s13048-014-0103-5
PMCID: PMC4260252  PMID: 25424625
IGF-1R; Monoclonal antibody; Acquired resistant; Trastuzumab; Ovarian cancer
2.  The C-Type Lectin OCILRP2 Costimulates EL4 T Cell Activation via the DAP12-Raf-MAP Kinase Pathway 
PLoS ONE  2014;9(11):e113218.
OCILRP2 is a typical Type-II transmembrane protein that is selectively expressed in activated T lymphocytes, dendritic cells, and B cells and functions as a novel co-stimulator of T cell activation. However, the signaling pathways underlying OCILRP2 in T cell activation are still not completely understood. In this study, we found that the knockdown of OCILRP2 expression with shRNA or the blockage of its activity by an anti-OCILRP2 antagonist antibody reduced CD3/CD28-costimulated EL4 T cell viability and IL-2 production, inhibit Raf1, MAPK3, and MAPK8 activation, and impair NFAT and NF-κB transcriptional activities. Furthermore, immunoprecipitation results indicated that OCILRP2 could interact with the DAP12 protein, an adaptor containing an intracellular ITAM motif that can transduce signals to induce MAP kinase activation for T cell activation. Our data reveal that after binding with DAP12, OCILRP2 activates the Raf-MAP kinase pathways, resulting in T cell activation.
doi:10.1371/journal.pone.0113218
PMCID: PMC4239057  PMID: 25411776
3.  Upregulation of heat shock factor 1 transcription activity is associated with hepatocellular carcinoma progression 
Molecular Medicine Reports  2014;10(5):2313-2321.
Heat shock factor 1 (HSF1) is associated with tissue-specific tumorigenesis in a number of mouse models, and has been used a as prognostic marker of cancer types, including breast and prostatic cancer. However, its role in human hepatocellular carcinoma (HCC) is not well understood. Using immunoblotting and immunohistochemical staining, it was identified that HSF1 and its serine (S) 326 phosphorylation, a biomarker of HSF1 activation, are significantly upregulated in human HCC tissues and HCC cell lines compared with their normal counterparts. Cohort analyses indicated that upregulation of the expression of HSF1 and its phospho-S326 is significantly correlated with HCC progression, invasion and patient survival prognosis (P<0.001); however, not in the presence of a hepatitis B virus infection and the expression of alpha-fetoprotein and carcinoembryonic antigen. Knockdown of HSF1 with shRNA induced the protein expression of tumor suppressor retinoblastoma protein, resulting in attenuated plc/prf5 cell growth and colony formation in vitro. Taken together, these data markedly support that HSF1 is a potential prognostic marker and therapeutic target for the treatment of HCC.
doi:10.3892/mmr.2014.2547
PMCID: PMC4214332  PMID: 25199534
heat shock factor 1; retinoblastoma protein; hepatocellular carcinoma; phosphorylation
4.  Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism 
The Scientific World Journal  2014;2014:908121.
Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE) combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS). Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated. The downregulated proteins included enzymes related to glycolysis and TCA cycle, suggesting that glucose is not properly utilized in S. epidermidis when saeRS was deleted. The study will be helpful for treatment of S. epidermidis infection from the viewpoint of metabolic modulation dependent on two-component signal transduction system SaeRS.
doi:10.1155/2014/908121
PMCID: PMC3921950  PMID: 24592198
5.  TIPE2 Controls Innate Immunity to RNA by Targeting the PI3K–Rac Pathway 
RNA receptors such as TLR3 and RIG-I/MDA5 play essential roles in innate immunity to RNA viruses. However, how innate immunity to RNAs is controlled at the molecular level is not well understood. We describe here a new regulatory pathway of anti-RNA immunity that comprises PI3K (phosphoinositide kinase-3), its target GTPase Rac, and the newly described immune regulator TIPE2 (TNF-α-induced protein 8 like-2, or TNFAIP8L2). Poly (I:C), a double-stranded RNA receptor ligand, activates Rac via its guanine nucleotide exchange factor Tiam; this leads to the activation of cytokine genes, and paradoxically down-regulation of Tipe2 gene. TIPE2 is a negative regulator of immunity; its deficiency leads to hyper-activation of the PI3K–Rac pathway as exemplified by enhanced AKT, Rac, PAK, and IRF3 activities. As a consequence, TIPE2 knockout myeloid cells are hyper-reactive to Poly (I:C) stimulation, and TIPE2 knockout mice are hypersensitive to Poly (I:C)-induced lethality. These results indicate that TIPE2 controls innate immunity to RNA by targeting the PI3K–Rac pathway. Therefore, manipulating TIPE2 or Rac functions can be effective for controlling RNA viral infections.
doi:10.4049/jimmunol.1103477
PMCID: PMC3436961  PMID: 22904303
TNFAIP8; RNA; Innate Immunity; Rac; TLR; PI3K
6.  Tagged and untagged TRAIL show different activity against tumor cells 
Oncology Letters  2012;4(6):1301-1304.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a novel cytotoxic ligand belonging to the TNF superfamily which is currently being developed as a cancer therapeutic drug. Here, we observed the different functions of recombinant TRAIL protein with a foreign protein label and non-labeled TRAIL. We used a prokaryotic expression system to prepare two different versions of the extracellular TRAIL 114–281aa protein: TRAIL-HS, a protein modified with 6xHis-Tag and S-Tag; and TRAIL-FT, which had no foreign protein. The proteins were purified using Ni-NTA chromatography (TRAIL-HS) and cation ion-exchange column chromatography (TRAIL-FT) and identified by SDS-PAGE and western blot analysis. We compared the abilities of the proteins to bind to death receptor 5 (DR5) by ELISA and to induce apoptosis in a normal liver cell line (Chang liver) and a human T-lymphocyte leukemia cell line (Jurkat) by MTT assay, GR staining and FACS. The results indicate that the biological functions of TRAIL-FT were superior to those of TRAIL-HS in binding and the induction of apoptosis, and may be useful to further the development and applications of TRAIL.
doi:10.3892/ol.2012.908
PMCID: PMC3506756  PMID: 23205127
recombinant TRAIL; prokaryotic expression; apoptosis
7.  Structural basis of LaDR5, a novel agonistic anti-death receptor 5 (DR5) monoclonal antibody, to inhibit DR5/TRAIL complex formation 
BMC Immunology  2012;13:40.
Background
As a member of the TNF superfamily, TRAIL could induce human tumor cell apoptosis through its cognate death receptors DR4 or DR5, which can induce formation of the death inducing signaling complex (DISC) and activation of the membrane proximal caspases (caspase-8 or caspase-10) and mitochondrial pathway. Some monoclonal antibodies against DR4 or DR5 have been reported to have anti-tumor activity.
Results
In this study, we reported a novel mouse anti-human DR5 monoclonal antibody, named as LaDR5, which could compete with TRAIL to bind DR5 and induce the apoptosis of Jurkat cells in the absence of second cross-linking in vitro. Using computer-guided molecular modeling method, the 3-D structure of LaDR5 Fv fragment was constructed. According to the crystal structure of DR5, the 3-D complex structure of DR5 and LaDR5 was modeled using molecular docking method. Based on distance geometry method and intermolecular hydrogen bonding analysis, the key functional domain in DR5 was predicted and the DR5 mutants were designed. And then, three mutants of DR5 was expressed in prokaryotic system and purified by affinity chromatograph to determine the epitope of DR5 identified by LaDR5, which was consistent with the theoretical results of computer-aided analysis.
Conclusions
Our results demonstrated the specific epitope located in DR5 that plays a crucial role in antibody binding and even antineoplastic bioactivity. Meanwhile, revealed structural features of DR5 may be important to design or screen novel drugs agonist DR5.
doi:10.1186/1471-2172-13-40
PMCID: PMC3436762  PMID: 22788777
TRAIL; Death receptor 5; Monoclonal antibody; Apoptosis; Breast cancer

Results 1-7 (7)