Stat3 regulates genes common to both wound healing and cancer

Dauer, Daniel J.; Ferraro, Bernadette; Song, Lanxi; Yu, Bin; Mora, Linda; Buettner, Ralf; Enkemann, Steve; Jove, Richard; Haura, Eric B.

doi:10.1038/sj.onc.1208469

Cited by 349 publications

(313 citation statements)

References 57 publications

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“…Recently, overexpression of Stat3C in A549 carcinoma cells followed by microarray analyses revealed that Stat3 regulated genes are common to both wound healing and cancer, including cell invasion/ migration, angiogenesis and remodeling of ECM, based on the concept that tumors are 'wounds that do not heal' (Dauer et al, 2005). This supports our observation that hyperactive Stat3 plays a role in wound healing gone awry, as seen in keloids.…”

Section: Discussionsupporting

confidence: 82%

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

et al. 2006

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Keloids, partially considered as benign tumors, represent the most extreme example of cutaneous scarring that uniquely afflicts humans as a pathological response to wound healing. It is characterized by excessive deposition of collagen and other extracellular matrix components by dermal fibroblasts. Upon cutaneous injury, cocktails of chemokines, cytokines and growth factors are secreted temporally and spatially to direct appropriate responses from neutrophils, macrophages, keratinocytes and fibroblasts to facilitate normal wound healing. Signal transducer and activator of transcription 3 (Stat3) is an oncogene and a latent transcription factor activated by various cytokines and growth factors. We investigated the possible role of Stat3 in keloid scar pathogenesis by examining skin tissue and cultured fibroblasts from keloid-scarred patients. We observed enhanced expression and phosphorylation of Stat3 in keloid scar tissue, and in cultured keloid fibroblasts (KFs) in vitro. Increased activation of Janus kinase (Jak)2, but not Jak1, was detected in KFs, and suppression of Jak2 by its inhibitor repressed Stat3 Y705 phosphorylation. Inhibition of Stat3 expression and phosphorylation by short interfering RNA or Cucurbitacin I resulted in the loss of collagen production, impaired proliferation and delayed cell migration in KFs. We show, for the first time, a role of Stat3 in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars.

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Section: Discussionsupporting

confidence: 82%

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

et al. 2006

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“…Inhibition of the JAK/STAT pathway appears to be a viable option for the following reasons. The JAK/STAT pathway regulates the expression of a number of proinflammatory cytokines (24,43). We found that phosphorylated JAK1 and -2 levels are increased in aged adipose tissue (Fig.…”

Section: Discussionmentioning

confidence: 74%

“…4E). STAT3 is a STAT family member that induces and maintains an inflammatory microenvironment by regulating a range of inflammatory cytokines and mediators, including the SASP components IL-6, IL-8, PAI-1, MCP-1, and GM-CSF (24,43). We observed that phosphorylated STAT3 (Tyr705) was elevated in senescent preadipocytes and was substantially decreased upon treatment with JAK inhibitor 1 (Fig.…”

Section: Significancementioning

confidence: 79%

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Tchkonia

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

638

519

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Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.JAK/STAT pathway | cellular senescence | ruxolitinib | interleukin-6 | frailty

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“…2) [24][25][26][27][28]. Interestingly, while these genes were overexpressed in JAK2 V617F patients relative to healthy controls, this was not the case in non-V617F patients.…”

Section: Resultsmentioning

confidence: 99%

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

Schwemmers

Will

Waller

et al. 2007

Experimental Hematology

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Objective-Presence of the JAK2 V617F mutation in only 40-60% of patients with Essential Thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, Polycythemia vera (PV) and Idiopathic Myelofibrosis (IMF). Analogous to JAK2 V617F , these mutations cause constitutive JAK2 and STAT activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/ STAT signal transduction pathway, underlie a subset of JAK2 V617F -negative ET.Methods-cDNA microarrays and qRT-PCR were used to compare gene expression in 40 ET patients with and without the JAK2 V617F mutation.Results-Unsupervised clustering of gene expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2 V617F mutation. Patients lacking the JAK2 V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and SOCS2. In addition, JAK2 V617F -negative patients showed lower levels of STAT3 phosphorylation.Conclusions-These data demonstrate that a large proportion of JAK2 V617F -negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ETinducing changes will facilitate both a molecular classification of ET and the development of rationally designed therapies.

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Stat3 regulates genes common to both wound healing and cancer

Cited by 349 publications

References 57 publications

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

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