Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats

BACKGROUND AND AIMS: Hepatic regeneration is a heterogeneous phenomenon involving several cell populations. Oval cells are considered liver stem cells, a portion of which derive from bone marrow (BM). Recent studies have shown that granulocyte-colony stimulating factor (G-CSF) may be effective in facilitating liver repair. However, it remains unclear if G-CSF acts by mobilizing BM cells, or if it acts locally within the liver microenvironment to facilitate the endogenous restoration program. In the present study, we assessed the involvement of G-CSF during oval cell activation. METHODS: Dipeptidyl-peptidase-IV-deficient female rats received BM transplants from wild-type male donors. Four weeks later, rats were subjected to the 2-acetylaminofluorene/partial hepatectomy model of oval cell-mediated liver regeneration, followed by administration of either nonpegylated G-CSF or pegylated G-CSF. Control animals did not receive further treatments after surgery. The magnitude of oval cell reaction, the entity of BM contribution to liver repopulation, as well as the G-CSF/G-CSF-receptor expression levels were evaluated. In addition, in vitro proliferation and migration assays were performed on freshly isolated oval cells. RESULTS: Oval cells were found to express G-CSF receptor and G-CSF was produced within the regenerating liver. G-CSF administration significantly increased both the magnitude of the oval cell reaction, and the contribution of BM to liver repair. Finally, G-CSF acted as a chemoattractant and a mitogen for oval cells in vitro. CONCLUSIONS: We have shown that G-CSF facilitates hepatic regeneration by increasing the migration of BM-derived progenitors to the liver, as well as enhancing the endogenous oval cell reaction.     

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.     

PyMIF enhances the inflammatory response in a rodent model by stimulating CD11b+Ly6C+ cells accumulation in spleen

Macrophage migration inhibitory factor (PMIF) expressed by Plasmodium parasites has been proved to be similar to the mammalian MIF in both structure and biological activity and is a critical upstream regulator in antimalaria innate immunity. In this work, using a genetically modified (MIF‐KO) strain of highly lethal rodent Plasmodium yoelii 17XL (Py17XL), we found that PyMIF could increase the secretion of pro‐inflammatory factors by eliciting the CD11b⁺Ly6C⁺ cells accumulated in the spleen of infected mouse. In addition, the chemotactic effect of PyMIF was demonstrated to associate with cell receptors CXCR2, CXCR4 and the cell surface markers ICAM‐1, LFA‐4.     

Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants

Cell fusion is involved in many critical developmental processes, including zygote formation and organogenesis of placenta, bone, and skeletal muscle. In adult tissues, cell fusion has been shown to play an active role in tissue regeneration and repair, and its frequency of occurrence is significantly increased during chronic inflammation. Fusion between tumor cells and normal cells, or among tumor cells themselves, has also been speculated to contribute to tumor initiation, as well as phenotypic evolution during cancer progression and metastasis. Here, we show that dual metastasis organotropisms can be acquired in the same cell through in vitro or in vivo spontaneous fusion between bone- and lung-tropic sublines of the MDA-MB-231 human breast cancer cell line. The synkaryonic hybrids assimilate organ-specific metastasis gene signatures from both parental cells and are genetically and phenotypically stable. Our study suggests cell fusion as an efficient means of phenotypic evolution during tumor progression and additionally demonstrates the compatibility of different metastasis organotropisms.     

Up-regulation of PIK3CA promotes metastasis in gastric carcinoma

AIM:To explore expressions of PIK3CA in the progression of gastric cancer from primary to metastasis and its effects on activation of phosphatidylinositol 3-kinase(PI3K)/Akt pathway.METHODS:mRNA and protein levels of PIK3CA were assessed,respectively,by real-time quantitative polymerase chain reaction and immunohistochemistry in specimens of normal gastric mucosa,primary foci and lymph node and distant metastasis of gastric cancer.Akt and phosphorylated Akt protein were also examined by Western blotting in these tissues,in order to analyze the effect of PIK3CA expression level changes on the activation of PI3K/Akt signaling pathway.RESULTS:PIK3CA mRNA in lymph node metastasis were approximately 5 and 2 folds higher,respectively,than that in the corresponding normal gastric mucosa and primary gastric cancer tissues(P<0.05),while no statistical significance was found compared with distant metastasis.Immunohistochemically,PIK3CA protein expression was discovered in 7(35%)specimens of 20 primary foci vs 10(67%)of 15 of lymph node metastasis or 11(61%)of 18 of distant metastasis(35%vs 67%,P=0.015;35%vs 61%,P=0.044).With the increased level of PIK3CA expression,the total Akt protein expression remained almost unchanged,but p-Akt protein was upregulated markedly.CONCLUSION:Increased expression of PIK3CA is expected to be a promising indicator of metastasis in gastric cancer.Up-regulation of PIK3CA may promote the metastasis of gastric cancer through aberrant activation of PI3K/Akt signaling.     

BRMS1在肺癌中的表达及其对肺癌细胞侵袭转移的影响

目的探讨乳腺癌转移抑制因子1(BRMS1)在肺癌中的表达及对肺癌细胞侵袭转移能力的影响。方法 Western blot及RT-PCR法检测肺癌及癌旁组织中BRMS1的表达,并将真核表达质粒p CMV-mycBRMS1及空白质粒转染到肺癌细胞A549。Transwell法检测细胞迁移和侵袭能力;Western blot检测核因子-κB(NF-κB)磷酸化水平及下游蛋白基质金属蛋白酶(MMP2),MMP9,骨桥蛋白(Osteopontin),E-钙粘蛋白(Ecadherin)的表达量。结果肺癌组织中BRMS1的蛋白及mRNA表达量都显著低于癌旁组织。与空白质粒组比较,真核表达质粒组中细胞迁移及侵袭能力降低,比值分别为[(0.98±0.10)及(0.17±0.03)],[(1.29±0.14)及(0.22±0.04)];NF-κB p65磷酸化水平降低,MMP2,MMP9,Osteopontin表达量下降,E-cadherin表达量上升(P0.01)。结论 BRMS1在肺癌组织中低表达,其过表达能显著抑制肺癌细胞A549侵袭转移,推测恢复肺癌组织BRMS1表达可能是转移性肺癌治疗方式之一。     

环氧化酶2、血管内皮生长因子C/血管内皮生长因子受体3与肺癌淋巴转移

淋巴转移是肺癌转移途径之一.在肺癌淋巴转移过程中,血管内皮生长因子及其受体家族发挥了重要的作用.尤其是淋巴内皮特异性受体血管内皮生长因子受体3及其配体血管内皮生长因子C对促进淋巴管生长具有关键的作用.同时近年研究表明环氧化酶2与肺癌淋巴转移呈正相关.环氧化酶2、血管内皮生长因子C/血管内皮生长因子受体3有望成为肺癌淋巴管转移靶向治疗的新靶点.     

Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.     

Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis

Based largely on studies in xenograft models, lipocalin-2 (Lcn2) has been implicated in the progression of multiple types of human tumors, including breast cancer. Here we examine the role of Lcn2 in mammary tumorigenesis and lung metastasis using an in vivo molecular genetics approach. We crossed a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with two independent gene-targeted Lcn2^−/− mouse strains of the 129/Ola or C57BL/6 genetic background. The onset and progression of mammary tumor development and lung metastasis in the female progeny of these crosses were monitored over a 20-week period. Female Lcn2^−/−MMTV-PyMT mice of the 129/Ola background (Lcn2^−/−PyMT¹²⁹) showed delayed onset of mammary tumors, and both Lcn2^−/−PyMT¹²⁹ mice and Lcn2^−/−MMTV-PyMT mice of the C57BL/6 background (Lcn2^−/−PyMT^B6) exhibited significant decreases in multiplicity and tumor burden (∼2- to 3-fold), as measured by total tumor weight and volume. At the molecular level, mammary tumors derived from Lcn2^−/−PyMT^B6 females showed reduced matrix metalloproteinase-9 (MMP-9) activity and a lack of high molecular weight MMP activity. However, although increased MMP-9 activity has been linked to tumor progression, neither Lcn2^−/−PyMT^B6 nor Lcn2^−/−PyMT¹²⁹ female mice showed a reduction in lung metastases compared to Lcn2^+/+PyMT controls. Our results demonstrate, using an in vivo animal model approach, that Lcn2 is a potent inducer of mammary tumor growth but not a significant promoter of lung metastasis.     

Melatonin promotes differentiation of 3T3-L1 fibroblasts

Melatonin inhibits the genesis and growth of breast cancer by interfering at different levels in the estrogen-signaling pathways. Melatonin inhibits aromatase activity and expression in human breast cancer cells, thus behaving as a selective estrogen enzyme modulator. As the adipose tissue adjacent to the tumor seems to account for most aromatase expression and enzyme activity in breast tumors and also mediates the desmoplastic reaction or accumulation of undifferentiated fibroblasts around malignant epithelial cells, in this work, we studied the effects of melatonin on the conversion of preadipocytes (3T3-L1) into adipocytes and on the capability of these cells to synthesize estrogens by regulating the expression and enzyme activity of aromatase, one of the main enzymes that participates in the synthesis of estrogens in the peritumoral adipose tissue. Thus, in both differentiating and differentiated 3T3-L1 adipocytes, high concentrations of melatonin increased intracytoplasmic triglyceride accumulation, an indicator of adipogenic differentiation. Melatonin (1 mm) significantly increased the expression of both CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ, two main regulators of terminal adipogenesis, in 3T3-L1 cells. The presence of melatonin during differentiation also induced a parallel reduction in aromatase expression and activity and expression of the cells. The effects of melatonin were reversed by luzindole, a melatonin receptor antagonist, indicating that melatonin acts through known receptor-mediated mechanisms. These findings suggest that, in human breast tumors, melatonin could stimulate the differentiation of fibroblasts and reduce the aromatase activity and expression in both fibroblasts and adipocytes, thereby reducing the number of estrogen-producing cells proximal to malignant cells.     

Serum levels of matrix metalloproteinase 3 and macrophage colony‐stimulating factor 1 correlate with disease activity in ankylosing spondylitis

Objective

To assess the usefulness of measuring serum matrix metalloproteinase 3 (MMP‐3) and macrophage colony‐stimulating factor (M‐CSF) in patients with ankylosing spondylitis (AS).

Methods

Serum levels of MMP‐3 and M‐CSF were measured in AS patients who did and did not receive infliximab treatment. These were compared with those of 28 healthy subjects.

Results

In the group of AS patients not treated with biologics, both M‐CSF and MMP‐3 correlated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) values, but not with each other. Logistic regression analysis showed that MMP‐3 values were high in those with severely active disease. Infusions of infliximab in AS patients led to a significant decrease in the values of the BASDAI as well as the serum MMP‐3, but no change in the serum M‐CSF values.

Conclusion

MMP‐3 and M‐CSF are potentially useful markers of AS disease activity.

     

Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β

Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.

Breast cancer remains the second leading cause of death among women in the United States (1). Prognosis for early-stage disease is favorable, whereas late-stage disease with tumor cell spread beyond the primary site (i.e., metastasis) frequently heralds poorer outcomes (1). Therapy of metastatic disease usually involves systemic chemotherapy combined with radiation, providing mostly palliative options to reduce metastatic outgrowth (2). Multiple unique and distinct biological steps and an interplay between transformed and nontransformed cells highlight complexities of the metastatic process, which habitually thwarts clinical intervention. In principle, targeting these processes independently or collectively could culminate in effective antimetastatic therapies.Melanoma differentiation-associated gene-9 (mda-9), also known as Syntenin-1 or syndecan binding protein (SDCBP), was cloned in our laboratory using subtraction hybridization from terminal differentiating metastasis-derived human melanoma cells treated with interferon (IFN)-β and the protein kinase C activator, mezerein (3, 4) (designated as mda-9/Syntenin). Preferential elevated expression of mda-9/Syntenin is evident in histologically distinct tumors and contributes to several steps in the metastatic process (5). These include tumor cell invasion and migration (6, 7), induction of angiogenesis through secretion of proangiogenic factors (8–10), enhancement of epithelial–mesenchymal transition (EMT) (11, 12), regulation of the expression of integrins affecting cell-adhesion processes (13), exosome biogenesis and exosome-mediated signaling in cell–cell communication (14), and recently immune-modulation suppressing host-immune surveillance (15). Cancer cell-independent functions of MDA-9/Syntenin also contribute to metastatic progression by regulating immunosuppressive cell infiltration in the metastatic niche (16). Based on its relevance to the invasive and metastatic phenotype of cancers, MDA-9/Syntenin represents a prospective target for rational design of antimetastatic drugs.Differential expression of MDA-9/Syntenin in cancer versus adjacent normal tissue is often a predictor of poor clinical outcomes (8). A relationship exists between MDA-9/Syntenin (SDCBP) and breast cancer in rat mammary tumors (genomic localization) (17) and in metastasis and clinical situations in human triple negative and other human breast cancers (11, 15, 18). MDA-9/Syntenin plays a pivotal role in EMT induction that includes initiation of Smad-dependent EMT through interaction with TGF-βR1, disrupting receptor internalization (11). Physical interaction between MDA-9/Syntenin and TGF-β activates small GTPases, Rho A, and CDC 42 (12). In addition, MDA-9/Syntenin enhances primary tumor growth and lung metastasis through immune evasion by up-regulating PD-L1 (program death ligand 1) through STAT3 activation, causing T cell apoptosis (15). In breast cancer, MDA-9/Syntenin affects tumor cell proliferation in estrogen receptor-negative breast cancer, causing cells to bypass the G1/S checkpoint promoting S-phase entry (19). MDA-9/Syntenin is also considered a potential antigen in breast cancer (20). These observations endorse MDA-9/Syntenin as a prospective target for the therapy of breast cancer metastasis.Disturbing MDA-9/Syntenin protein:protein interactions is viewed as a viable strategy to disrupt key downstream signaling pathways regulating cancer cell invasion and metastasis (reviewed in ref. 5). Fragment-based drug discovery guided by NMR identified a first in-class interaction inhibitor of the PDZ1 domain of MDA-9/Syntenin, PDZ1i (21), displaying efficacy against glioblastoma multiforme, neuroblastoma, and prostate cancer (5, 13, 22, 23). PDZ1i suppresses cancer cell-autonomous and nonautonomous functions of MDA-9/Syntenin, culminating in strong antiinvasive and antimetastatic properties in vitro and in vivo, without inducing overt cytostatic or toxic effects in normal or most cancer cells. Informed by the crystal structure of MDA-9/Syntenin, peptide-based inhibitory molecules have been developed and validated in cell-based assays (24). Additionally, a genetic approach using adenovirus-mediated delivery of shmda-9 has shown efficacy in xenografted human melanoma (8) and prostate cancer (25) in nude mice. These investigations confirm MDA-9/Syntenin as a viable target for suppressing both primary and metastatic tumor growth and support further evaluation of PDZ1i on breast cancer metastasis.Evidence from both experimental models and clinical studies show a relationship between abundance of tumor-infiltrating immune cells and metastasis (26). To create a permissive environment in a secondary site, disseminated tumor cells employ multiple strategies, including reducing host immune surveillance (27). In several mouse tumor models, myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells with immunosuppressive properties, are expanded in the blood, lymph nodes, and spleen (28). They help shape the microenvironment and metastatic niches by regulating both innate and adaptive immunity (29). In breast cancer mouse models, MDSCs accumulate in the lungs prior to metastatic spread (30) and promote immune suppression by producing reactive oxygen species and arginase (Arg-1) (31). Not surprisingly, various chemotherapeutic agents, such as gemcitabine (32), 5-flurouracil (33), and docetaxel (34) decrease MDSC accumulation in the tumors’ stroma, thereby enhancing antitumor immune responses (29). Similar soluble factors are operational in primary tumors and metastases, including granulocyte-macrophage colony-stimulating factor, interleukins (e.g., IL-6, IL-1β), and vascular endothelial growth factor (VEGF), causing MDSC infiltration. Tumor cells in the metastatic niche that produce various cytokines or growth factors also regulate this process.We have now explored a potential role of MDA-9/Syntenin in breast cancer progression with specific emphasis on a relevant interleukin, IL-1β, representing an important inflammatory cytokine mediating cancer pathogenesis and tumor progression (35). Inflammation regulates fundamental pathways that are causative of the cancer phenotype, including proliferation, survival, and migration (36). IL-1β regulates tumor initiation/progression, angiogenesis, Th17 cell differentiation, and expansion of MDSCs (35). Additionally, IL-1β controls macrophage recruitment and invasion, and metastasis of cancer cells (35). Based on these seminal roles in orchestrating the neoplastic process, IL-1β represents a potential therapeutic target and its regulation deserves further analysis. We now confirm that MDA-9/Syntenin, which can be obstructed by the small-molecule inhibitor PDZ1i, regulates IL-1β, thereby directly controlling breast cancer pathogenesis.     

survivin 基因-31G/C 位点多态性和肺癌关联研究

目的：探讨 survivin 基因启动区-31G/C 位点多态性是否与肺癌发生相关,同时评估小细胞肺癌和非小细胞肺癌这一病理分型与多态性的关系,揭示吸烟因素是否参与了这一基因位点的多态性产生。方法临床收集血液标本。病例组为病理诊断明确的肺癌患者,对照组为我院体检中心体检健康的匹配者。采用 PCR-限制性片段长度多态性分析方法,对133例肺癌患者与150名对照者外周血基因-31G/C 位点多态性定性分析。将含有-31G/C 位点目的基因片段进行 PCR 扩增,扩增产物应用限制性内切酶酶切,酶切产物进行凝胶电泳并置于凝胶显像系统成像。随机抽取酶切样本进行基因测序检测,并按照吸烟程度、肺癌的病理分型进一步深入分析。结果基因型频率-31GG、-31GC、-31CC在肺癌组和对照组分别是21.05%、51.13%、27.82%与22.67%、54.67%、22.67%,而在小细胞肺癌组则分别是25.86%、34.48%、39.66%,只在小细胞肺癌组和对照组间差异有统计学意义(χ2=8.06,P =0.018)。在不同吸烟情况下肺癌组和对照组基因表达差异无统计学意义(P >0.05)。结论小细胞肺癌发生和-31G/C 位点多态性具有一定相关性,吸烟这一因素与-31G/C 位点多态性无明显关联性。     

Granulocyte colony-stimulating factor (G-CSF) mediated mobilization of leukemic cells in Philadelphia chromosome positive acute lymphoblastic leukemia expressing myeloid antigens (my+Ph+ALL)

The therapeutic benefit of G-CSF in the treatment of acute lymphoblastic leukemia has been well established. G-CSF has been used to shorten neutropenia induced by conventional dose cytotoxic chemotherapy and allogeneic bone marrow transplantation. Recently autologous peripheral blood progenitor cell transplantation has been explored to treat high-risk ALL. Several in vitro studies suggest that subpopulations of lymphoblasts express G-CSF receptors. Furthermore, enhanced growth of Ph⁺ ALL cells expressing myeloid antigens stimulated by G-CSF has been demonstrated in vitro. However, the clinical relevance of these findings has been questioned. We report a patient with my⁺Ph⁺ALL in whom the administration of G-CSF after high-dose Cytarabin and Mitoxantrone led to a significant mobilization of leukemic cells and contamination of the stem cell harvest during cytologic marrow remission. Am. J. Hematol. 58:330–333, 1998. © 1998 Wiley-Liss, Inc.     

P115 promotes growth of gastric cancer through interaction with macrophage migration inhibitory factor

AIM:To investigate the role of P115 in the proliferation of gastric cancer cells and the mechanism involved.METHODS:The RNA and protein level of P115 and macrophage migration inhibitory factor(MIF)in gastric cancer and normal gastric tissue/cells were measured and the effect of P115 on cell proliferation was assessed.The role of P115 in cell cycle checkpoints was investigated and the related proteins and signaling pathways,such as cyclin D1,Mcm2,p53,PCNA as well as the MAPK signaling pathway were determined.The interaction between P115 and MIF and the effect of P115 on MIF secretion were examined.The data were analyzed via one-way ANOVA comparisons between groups and P<0.05 was considered significant.RESULTS:P115 and MIF were both specifically expressed in gastric cancer tissues compared with normal gastric mucosa(both P<0.01).The mRNA and protein levels of P115 and MIF in gastric cancer cell lines MKN-28 and BGC-823 were higher than in the human gastric epithelial cell line GES-1(both P<0.01).In MKN-28 and BGC-823 cell lines,P115 promoted cell proliferation and G0-G1to S phase transition.In addition,several cell cycle-related regulators,including cyclin D1,Mcm2,PCNA,pERK1/2 and p53 were up-regulated by P115.Furthermore,the interaction between P115 and MIF was confirmed by co-immunoprecipitation assay.ELISA showed that P115 stimulated the secretion of MIF into the culture supernatant(P<0.01)and the compensative expression of MIF in cells was observed by Western blotting.CONCLUSION:P115 promotes proliferation of gastric cancer cells through an interaction with MIF.