الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Apoptosis is a genetically controlled process by which unnecessary or damaged single cells undergo self-destruction when apoptosis genes are activated. Apoptosis is necessary for normal development and homeostasis of multicellular organisms. Tissue homeostasis mainly depends on the balance between cell proliferation and cell death. Apoptosis is an intrinsic death program that occurs in various physiological and pathological situations which is highly conserved throughout evolution. Cellular disruption in apoptosis results from activation of a family of cysteine proteases known as caspases. Caspases are synthesized as inactive proenzymes, which upon activation cleave various substrates in the cytoplasm or nucleus leading to morphological and biochemical changes in cell death.
STAT3 proteins have distinct domains which are NH2 terminal, coiled-coil, DNA binding, linker, SH2 and COOH terminal transactivation domains, each of them have certain functions. STAT3 can induce several gene expressions encoding molecules that play a role in a variety of biological functions such as cell growth, anti- and pro-apoptosis, cell motility, negative feedback loop (suppression of cytokine productions), regulatory cytokine production and anti-bacterial activity depending on cell types. STAT3 also participates in regulation of hematopoiesis and immune response. The finding that STAT3 is involved in all these distinct functions has suggested that STAT3 is a major signal transducer downstream of glycoprotein (gp)130-like receptors. Thus, STAT3, a single transcription factor can be involved in contradictory cell responses due to induction of distinct sets of target genes by STAT3 in different cells. As a consequence of these diverse functions, STAT3 plays a crucial role in inflammatory, autoimmune and certain neoplastic diseases. STAT3 can be detected by X-ray crystallography, FLAP, MSD, microarray technology, IHC and genome scans. Tumorigenesis is a process by which normal cells are transformed into cancer cells. It is characterized by a progression of changes on cellular and genetic level that ultimately reprogram the cell to undergo uncontrolled cell division, thus forming a malignant mass. STAT3 is an oncogenic transcription factor. It plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic STAT3 is persistently activated in several human cancers and transformed cell lines as breast cancer, multiple myeloma, head and neck tumors, ovarian and prostate cancer. Frequent STAT3 activation in tumor cells is largely due to the fact that STAT3 is a point of convergence for numerous tyrosine kinases. STAT3 is activated by tyrosine phosphorylation, which is normally a transient and tightly regulated process. In tumor cells, constitutive activation of STAT3 is linked to persistent activity of tyrosine kinases. STAT3 appears to regulate processes involved in the hallmarks of cancer: growth, evasion of apoptosis, angiogenesis, metastasis, tissue invasion and cell immortalization. STAT3 contributes to tumor cells survival and proliferation through up-regulation of genes encoding apoptosis inhibitors and cell-cycle regulators such as Bcl-XL, Mcl-1, cyclins D1/D2 and c-Myc. This interrupting of STAT3 signaling can be achieved by small molecule chemical inhibitors of STAT3, dominant-negative variants of STAT3, antisense STAT3 oligonucleutides, inhibition of signal mediators acting upstream of STAT3 such as inhibitors of protein tyrosine kinases and other alternative strategies. All of these act as methods of new therapies for treatment of cancers. Conclusion: Modulating expression of key components of apoptosis machinery to tip the balance between pro- and anti-apoptotic signals in tumor cells is a rational approach to cancer therapy. Therefore, STAT3 is qualified as a valid target for development of novel anticancer therapeutic modalities. Direct inhibition of STAT3 activity by small molecule chemical inhibitors, use of dominant-negative variants of STAT3, antisense STAT3 oligonucleutides and inhibitors of protein tyrosine kinases, all of these can reduce proliferation or enhance apoptosis in various types of cancer.