Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction

Hiwatashi, Kiyokazu; Tamiya, Taiga; Hasegawa, Eiichi; Fukaya, Takao; Hashimoto, Masayuki; Kakoi, Kyosuke; Kashiwagi, Ikko; Kimura, Akihiro; Inoue, N.; Morita, Rimpei; Yasukawa, Hideo; Yoshimura, Akihiko

doi:10.1016/j.canlet.2011.04.024

Cited by 65 publications

(59 citation statements)

References 39 publications

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“…Inactivating SOCS1 mutation has also been reported in B-cell lymphoma [81]. In contrast, inactivation of SOCS3 specifically in macrophages promotes the expression of the MCP2/CCL8 chemokine and is linked to the reduction of tumor metastases in mice [84].…”

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 96%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs sometimes can bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 96%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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“…Overall, this work points toward a central role for ERK-regulated transcription factors in regulating the induction of the SOCS-3 gene in response to elevations in intracellular cAMP. These findings may have consequences for a broad range of signaling scenarios in which understanding of the molecular basis controlling SOCS-3 gene induction may have therapeutic benefit; these range from stimulating ERK-dependent SOCS-3 induction in vascular endothelial cells to combat chronic inflammation (Parnell et al, 2011), to suppression of SOCS-3 in macrophages to combat the progression of cancer (Hiwatashi et al, 2011).…”

Section: Regulation Of Socs-3 Gene Expression By Erk 665mentioning

confidence: 99%

“…Indeed, SOCS-3 has been reported to be a tumor suppressor in breast cancer cells (Barclay et al, 2009), and methylation of CpG islands within the SOCS-3 promoter regions occurs frequently in a variety of cancers, including melanoma (Tokita et al, 2007), glioblastoma (Martini et al, 2008), head and neck squamous cell carcinoma (Weber et al, 2005), and cancers of the lung (He et al, 2003b) and gut (Tischoff et al, 2007), thereby preventing SOCS-3 induction and limiting its damping actions on cell growth. Despite this, inhibition of SOCS-3 induction in macrophages may actually be therapeutic for the suppression of tumor metastasis, because hyperactivation of STAT3 in these cells simultaneously exerts anti-inflammatory as well as antitumor effects through the concomitant suppression of IL-6 and TNF␣ production and increased production of monocyte chemotactic protein 2 (Hiwatashi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase-Dependent SOCS-3 Gene Induction Requires c-Jun, Signal Transducer and Activator of Transcription 3, and Specificity Protein 3 Transcription Factors

Wiejak¹,

Dunlop²,

Gao³

et al. 2012

Mol Pharmacol

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SOCS-3 gene induction by cAMP-elevating agents or the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), in primary HUVECs was found to require PKC-and PKC-dependent extracellular signal-regulated kinase (ERK) activation. The minimal, ERK-responsive element of the SOCS-3 promoter was localized to a region spanning nucleotides Ϫ107 to the transcription start site and contains conserved binding sites for AP-1 and SP1/SP3 transcription factors, as well as proximal and distal signal transducer and activator of transcription (pSTAT and dSTAT) binding elements. All three classes of transcription factor were activated in response to ERK activation. Moreover, representative protein components of each of these transcription factor binding sites, namely c-Jun, STAT3, and SP3, were found to undergo ERKdependent phosphorylation within their respective transactivation domains. Mutational analysis demonstrated an absolute requirement for the SP1/SP3 binding element in controlling basal transcriptional activity of the minimal SOCS-3 promoter. In addition AP-1, pSTAT, and SP1/SP3 binding sites were required for ERK-dependent, PMA-stimulated SOCS-3 gene activation. The dSTAT site seems to be important for supporting activity of the AP-1 site, because combined deletion of both sites completely blocks transcriptional activation of SOCS-3 by PMA. Together these results describe novel, ERK-dependent regulation of transcriptional activity that requires codependent activation of multiple transcription factors within the same region of the SOCS-3 gene promoter.

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“…To further characterize the effect of T-MPs on M2 macrophages, we compared the effect on M2 polarization between T-MPs and tumor lysates or lactic acid, two known factors inducing M2 macrophage polarization. 12,18 Notably, although the addition of lysates from H22 (liver), LLC (lung), CT26 (colon) and B16 (melanoma) tumor cells or lactic acid resulted in the upregulation of arginase 1 expression in M0 macrophages, the corresponding TMPs caused even higher expression of arginase 1 (Fig. 1H).…”

Section: T-mps Induce the Differentiation Of Macrophages Toward M2 Phmentioning

confidence: 99%

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression

Chen

et al. 2016

OncoImmunology

105

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Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

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Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction

Cited by 65 publications

References 39 publications

SOCS proteins in regulation of receptor tyrosine kinase signaling

SOCS proteins in regulation of receptor tyrosine kinase signaling

Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase-Dependent SOCS-3 Gene Induction Requires c-Jun, Signal Transducer and Activator of Transcription 3, and Specificity Protein 3 Transcription Factors

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression

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