Constitutive Activation of JAK3/STAT3 in Colon Carcinoma Tumors and Cell Lines

Division of Pathology and Laboratory Medicine, Box 72, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
American Journal Of Pathology (Impact Factor: 4.59). 11/2005; 167(4):969-80. DOI: 10.1016/S0002-9440(10)61187-X
Source: PubMed


Signal transducer and activator of transcription 3 (STAT3) has oncogenic potential. The biological effects of STAT3 have not been studied extensively in the pathogenesis of colon cancer, nor has the role of Janus kinase 3 (JAK3), the physiological activator of STAT3, been evaluated. Here, we demonstrate that activated STAT3 (pSTAT3) and activated JAK3 (pJAK3) are expressed constitutively in two colon cancer cell lines, SW480 and HT29. To evaluate the significance of JAK3/STAT3 signaling, we inhibited JAK3 with AG490 and STAT3 with a dominant-negative construct. Inhibition of JAK3 down-regulated pSTAT3. The blockade of JAK3/STAT3 signaling significantly decreased viability of colon cancer cells due to apoptosis and cell-cycle arrest through down-regulation of Bcl-2, Bcl-X(L), Mcl-1, and cyclin D2 and up-regulation of p21(waf1/cip1) and p27(kip1). We also examined histological sections from 22 tumors from patients with stage II or stage IV colon cancer and found STAT3, JAK3, and their activated forms to be frequently expressed. Furthermore, quantitative reverse transcriptase-polymerase chain reaction identified JAK3 mRNA in colon cancer cell lines and primary tumors. Our findings illustrate the biological importance of JAK3/STAT3 activation in the oncogenesis of colon cancer and provide novel evidence that JAK3 is expressed and contributes to STAT3 activation in this malignant neoplasm.

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Available from: Yasushi Fujio, Oct 08, 2015
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    • "Generally, STAT3-mediated transcription directs cells into cell survival and cell cycle progression. STAT3 is involved in cellular transformation and tumorigenesis (34). However, the molecular mechanisms leading to the aberrant STAT3 activation and STAT3-mediated transformation and tumorigenesis remain unclearly defined. "
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    ABSTRACT: Although interleukin-9 (IL-9) exhibits pleiotropic functions in the immune system, it remains a well-known cytokine in hematological malignancies. Previous cell culture and animal model studies have revealed that the Janus kinase-signal transducer and activator of transcription signaling pathway, which may be activated by a number of cytokines including IL-9, is critical in hematological malignancies. The current review summarizes the characterization of the biological activities of IL-9, highlights the clearly defined roles of the cytokine, and outlines questions with regard to the functions of IL-9 that require further exploration and their downstream signaling proteins, signal transducers and activators of transcription.
    Oncology letters 03/2014; 7(3):602-610. DOI:10.3892/ol.2013.1761 · 1.55 Impact Factor
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    • "JAK3 associates with the interleukin (IL)-2 family γ-chain receptors, transducing the signal from cytokines such as IL-2, IL-7, IL-9, IL-15, and IL-21 (Suzuki et al. 2000). Although JAK2 is often regarded as the primary partner of STAT3, constitutively active JAK3:STAT3 signaling has been reported as a poor prognosis indicator in anaplastic large-cell lymphoma and in colon cancer cell lines (Lin et al. 2005; Han et al. 2006). Our results suggest that STAT3 activates key regulators of cytokine signaling. "
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    ABSTRACT: STAT3 is a signal transducer that, when dysregulated, becomes a powerful oncogene found in many human cancers, including diffuse large B cell lymphoma. Diffuse large B cell lymphoma is the most common form of non-Hodgkin's lymphoma and has two major subtypes: germinal center B-cell-like and activated B-cell-like. When compared to the germinal center B-cell-like form, activated B-cell-like lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have integrated genome-wide studies of STAT3 DNA binding using ChIP-sequencing with whole-transcriptome profiling using RNA-sequencing. STAT3 binding sites are present near almost a third of all genes that differ in expression between the two subtypes, and examining the affected genes identifies previously undetected and clinically significant pathways downstream of STAT3 that drive oncogenesis. Novel treatments aimed at these pathways may increase the survivability of activated B-cell-like diffuse large B cell lymphoma.
    G3-Genes Genomes Genetics 10/2013; 3(12). DOI:10.1534/g3.113.007674 · 3.20 Impact Factor
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    • "Our results indicate that JAK/STAT signaling, another downstream target of the JNK pathway, supports survival of butyrate/propolis-treated CC cells. Our data are in agreement with observations that JAK/STAT3 signaling contributes to the viability of CC cells in vitro, a relevant finding since abnormal activation of this pathway is detected in primary colon cancers [43]. We observed that the addition of a JAK/STAT inhibitor (JAKi) to butyrate/CAPE- or butyrate/propolis-treated cells moderately augments apoptosis; however, exposure of CC cells to JAKi alone does not produce cell death (Figs. "
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