Correlation Of STAT3 And VEGF Expression With The Development Of Human Meningioma And Glioma

BackgroundThe Janus protein tyrosine kinase/Signal transducer and activator of transcription signal pathway is one of the main effectors in transducing signals from the cell surface to the nucleus. The correlation between JAKs and STATs families was found during studies on interferon (IFN) gamma-dependent gene expression. The selectively activation of the proteins signal transducers and activators of transcription (STATs) (STAT1-4, STAT5a, STAT5b, and STAT6) by Janus kinases (JAKs) (JAK1, JAK2, JAK3 and TYK2) is involved in the oncogenesis by regulating cell survival, growth and differentiation in many cancerous cell lines and human tumors. Of the seven STAT proteins, constitutive activated STAT3 has been implicated in multiple myeloma, lymphomas, leukemias, and several solid tumors. IL-6 inducible STAT3 pathway was found in head and neck squamous cell carcinoma cells. Evidences show that curcumin inhibition of IL-6 induced STAT3 phosphorylation and consequent STAT3 nuclear translocation. Colon cancer cells showed inhibited angiogenesis and metastasis with blocked STAT3 and VEGF expression. So STAT3 may be a target gene for cancer therapy.Evidences show that The JAK and STAT families of proteins are important effectors in brain tumors. The function of JAK/STAT signal pathway is best explained in SCID mice models. JAK1-/- and STAT3-/- mice die during embryogenesis because of impaired neurological and lymphoid development. The JAK1/STAT3 signal pathway is important in cell transformation and carcinogenesis, and their expression is associated with glioma differentiation.STAT3 is a key signal transduction protein that mediates signaling by cytokines and contributes to oncogenesis. Interleukin-6 induces VEGF expression in glioblastoma cell lines via STAT3. Activated STAT3 may be increased in malignant glioma patients and is associated with poor patient survival. Evidence indicates that STAT3 is necessary for tumor cell proliferation and transformation. STAT3 regulates target genes such as cyclin Dl and VEGF that are involved in cell survival and angiogenesis.For most solid tumors, tumor angiogenesis is required for tumor growth and development stimulated by angiogenic inducers, and regulated by many angiogenic inducers, including fibroblast growth factor (FGF), VEGF, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-β(TGF-β). As a key angiogenic factor, vascular endothelial growth factor (VEGF, also called VEGFa) originally isolated from tumor cells, is involved in tumor cell proliferation, angiogenesis and metastasis. The expression of the oncogene VEGF is an important factor in tumor angiogenesis for solid tumor growth and leads to tumor proliferation and metastasis. VEGF expresses in most of solid tumors and tumor cell lines including fleshy tumor, lymphadenoma, meningioma, glioma, gastric cancer, colon carcinoma, ovarian cancer, liver cancer. Animal experiments indicate that inhibition of VEGF expression reduces tumor angiogenesis and inhibits tumor growth. Angiogenesis is a crucial characteristic of brain biology, and detailed knowledge about angiogenesis of tumors of the central nervous system is important to improve therapy of brain tumors. VEGF is considered a major regulator of angiogenesis in various brain tumors.Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Angiogenesis, the recruitment of new blood vessels, is an essential component of tumor progression. Meningioma and glioma are common primary brain tumors, and classifiedⅠ-Ⅲgrade andⅠ-Ⅳgrade according to the 2000 World Health Organization classification of human brain tumors. Surgical resection is curative when complete removal of benign cancers is possible, incompletely resected tumors and high-grade lesions are frequently treated with fractionated radiotherapy or stereotactic radiosurgery. Malignant brain tumors are highly vascularized and their growth is angiogenesis-dependent. As such, inhibition of the sprouting of new capillaries from pre-existing blood vessels is one of the most promising therapeutic approaches. Although several molecular mechanisms contribute to angiogenesis in tumors, VEGF pathway appears particularly important and has been a prominent therapeutic target in cancer treatment.ObjectiveVEGF, originally isolated from tumor cells, induces tumor angiogenesis and promotes tumor cell proliferation, angiogenesis and metastasis. As a solid tumor, meningioma and glioma depend on neovascularization by angiogenesis for expansion. The oncogenic potential of STAT3 is critical in tumor occurrence and development of human cancers. Here, we studied whether VEGF expression regulated by a Janus kinase 1 (JAK1)/STAT3 signal pathway might be involved in the pathogenesis of human meningioma and glioma.Materials and MethodsWe obtained 40 meningioma specimens (26 from males; donor mean age 49.0±13.0 years),63 glioma specimens (from 25 males, donor mean age 47.9±14.9 years) and 6 normal brain tissues. All patients had not undergone preoperative treatments such as chemotherapy or radiotherapy. All tumors were histologically classified as malignant according to the 2000 World Health Organization classification of human brain tumors.Using RT-PCR, western blot analysis and immunohistochemistry, we measured JAK1, STAT3 and VEGF expression in brain tissue from patients with meningioma and glioma.Results1. Normal brain tissue did not expressed JAK1, p-JAK1, STAT3, p-STAT3 and VEGF, but highly expressed in tumor tissues; Relative expression of JAK1, STAT3 were strongly correlated with VEGF expression in meningioma by RT-PCR (P< 0.05); Correlation analysis of JAK1 versus STAT3, STAT3 versus VEGF, p-JAK1 versus p-STAT3, p-JAK1 versus VEGF and p-STAT3 versus VEGF in showed strong correlation at protein level in meningioma by western blot analysis, expression level was associated with tumor differentiation (P< 0.05); Results of frequency of positivity seen on immunohistochemistry were in agreement with those seen on western blot analysis; p-STAT3 expressed in cell nuclear, all meningioma tumors positive for p-STAT3 also showed VEGF expression VEGF expression, and correlated with meningioma differentiation (P< 0.05).2. Normal brain tissue did not show elevated expression of JAK1, STAT3 and VEGF at mRNA and protein level. The relative expression of JAK1 was strongly correlated with that of STAT3, and the expression of JAK1 and STAT3 was highly correlated with that of VEGF in glioma tissues (P< 0.05); The frequency and intensity of the expression was increased in grade I and grade II glioma tissues at mRNA and protein level, with the highest levels in grade III tissues (P< 0.05); Tyrosine phosphorylation is considered a switching signal to activate STATs, in glioma tissues, we did not study the tyrosine phosphorylation status of JAK1 and STAT3, but the expression of JAK.1 was stably associated with that of STAT3 in tumor tissues, and significantly correlated with differentiated status of human glioma (P< 0.05). So upregulation of JAK1 and STAT3 may be a pathological event.ConclusionsVEGF is regulated by a JAK1/STAT3 signal pathway and is associated with meningioma and glioma histological differentiation. STAT3 represents a point of convergence for angiogenic events in the signal pathway and may play a central role during occurrence, development of human meningioma and glioma.