Interleukin-6/Soluble Interleukin-6 Receptor Signaling Attenuates Proliferation and Invasion, and Induces Morphological Changes of a Newly Established Pleomorphic Malignant Fibrous Histiocytoma Cell Line

Nakanishi, Hirofumi; Yoshioka, Kiyoko; Joyama, Susumu; Araki, Nobuhito; Myoui, Akira; Ishiguro, Shingo; Ueda, Takafumi; Yoshikawa, Hideki; Itoh, Kazuyuki

doi:10.1016/s0002-9440(10)63312-3

Cited by 26 publications

(26 citation statements)

References 42 publications

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“…There was no significant change in the white blood cell count or the CRP levels prior to and after naproxen treatment. There are several possible mechanisms for the production of inflammatory markers, such as CRP and IL-6 (24)(25)(26). Tumor growth may cause tissue inflammation (24).…”

Section: Discussionmentioning

confidence: 99%

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Neoplastic fever in patients with bone and soft tissue sarcoma

Nakamura

Matsumine

Matsubara

et al. 2016

Molecular and Clinical Oncology

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Abstract. The development of fever is a common complication in the clinical course of cancer. If all other potential causes of fever are excluded, the possibility of neoplastic fever should be considered. The aim of the present study was to determine the incidence of neoplastic fever in patients with bone and soft tissue sarcomas. Between January 2009 and December 2014, 195 patients with bone and soft tissue sarcoma (111 men and 84 women; mean age, 55 years) were admitted to

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Section: Discussionmentioning

confidence: 99%

“…Tumor-associated mononuclear cells may produce IL-6 as an immune cytokine response to tumor growth (25). Cancer cells may increase the production of inflammatory proteins (26). Tumor growth cannot be reduced by naproxen; therefore, radical tumor treatment is required to improve these hematological abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Neoplastic fever in patients with bone and soft tissue sarcoma

Nakamura

Matsumine

Matsubara

et al. 2016

Molecular and Clinical Oncology

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“…22 In addition, it was recently shown that IL6 plays a pivotal role for proliferation and invasion of malignant fibrous histocytoma (MFH). 23 It is possible that IL6 may have similar functions in MLS/RCLS. The oncogenic potential of IL6 makes it important to determine if this factor is a downstream target of FUS-DDIT3 in MLS.…”

Section: Discussionmentioning

confidence: 99%

Myxoid liposarcoma FUS‐DDIT3 fusion oncogene induces C/EBP β‐mediated interleukin 6 expression

Göransson

Elias

Ståhlberg

et al. 2005

Intl Journal of Cancer

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The myxoid/round cell liposarcoma oncogene FUS-DDIT3 is the result of a translocation derived gene fusion between the splicing factor FUS and DDIT3. In order to investigate the downstream targets of DDIT3, and the transforming effects of the FUS-DDIT3 fusion protein, we have introduced DDIT3-GFP and FUS-DDIT3-GFP constructs into a human fibrosarcoma cell line. The gene expression profiles of stable transfectants were compared to the original fibrosarcoma cell line by microarray analysis. We here report that the NFkB and C/EBP b controlled gene IL6 is upregulated in DDIT3-and FUS-DDIT3-expressing fibrosarcoma cell lines and in myxoid liposarcoma cell lines. Strong expression of the tumor associated multifunctional cytokine interleukin 6 was confirmed both at mRNA and protein level. Knockdown experiments using siRNA against CEBPB transcripts showed that the effect of FUS-DDIT3 on IL6 expression is C/EBP b dependent. Chromatin immunoprecipitation revealed direct interaction between the IL6 promoter and the C/EBP b protein. In addition, the effect of DDIT3 and FUS-DDIT3 on the expression of other acute phase genes was examined using real-time PCR. We demonstrate for the first time that DDIT3 and FUS-DDIT3 show opposite transcriptional regulation of IL8 and suggest that FUS-DDIT3 may affect the synergistic activation of promoters regulated by C/EBP b and NFkB. 2,3 DDIT3 is a bZIP transcription factor known to form heterodimers with C/EBP-family members 4 and other bZIP subfamilies such as the AP-1 and ATF3 families. 5,6 Thus, DDIT3 and its oncogenic variant FUS-DDIT3 may act by binding to bZIP proteins and modulate their activity and/or specificity. DDIT3 was initially reported to act as a dominant negative modulator in the C/EBP system. 4 However, as DDIT3 harbors a basic DNA binding domain and binds DNA in a sequence specific manner, it was later proposed to act as a more broad transcriptional regulator. 7 Previous studies indicate that expression of the FUS-DDIT3 fusion protein is required for the development of MLS/RCLS and sufficient for initiation of tumors resembling MLS/RCLS in transgenic mice. 8 In order to understand the transformation process leading to this tumor type, it is crucial to identify downstream target genes of the FUS-DDIT3 fusion protein. We have introduced DDIT3-GFP and FUS-DDIT3-GFP fusion constructs into a human fibrosarcoma cell line and compared the gene expression profiles in stable transfectants with the original fibrosarcoma cell line by microarray analysis. The IL6 gene was found to be upregulated both at mRNA and protein level by the forced expression of DDIT3 or FUS-DDIT3. We show that upregulation at the IL6 promoter by DDIT3 and FUS-DDIT3 is C/EBP b dependent using siRNA knockdown and Chromatin Immuno Precipitation (ChIP) analysis. Further, DDIT3 and FUS-DDIT3 are found to have opposite effect on the expression of the inflammatory cytokine IL8. Material and methods Plasmid constructionThe full length coding regions of DDIT3 and FUS-DDIT3 cDNA type II 9 were cloned into the pEGFP-N...

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“…Serumfree conditioned medium served as a chemoattractant and was added to the lower chamber. After 16 hours, the migrating cells on the lower side of the filter were fixed with 70% methanol following the protocol previously described (27,28). The chemoinvasion assay was carried out as previously described (29).…”

Section: In Vitro Chemotaxis and Chemoinvasion Assaysmentioning

confidence: 99%

“…Cell proliferation analysis was done as previously described (28). Briefly, Walker 256 cells (5 Â 10 3 cells) were plated into 24-well plates and cultured in DMEM with 10% FCS for 24 hours.…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

Intrathecal Administration of Y-27632, a Specific Rho-Associated Kinase Inhibitor, for Rat Neoplastic Meningitis

Nakagawa¹,

Yoshioka

Miyahara³

et al. 2005

Molecular Cancer Research

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The small GTP-binding protein Rho and its target Rho-associated kinase trigger an intracellular signaling cascade that controls actin cytoskeleton and plays an essential role in cell motility and adhesion. A specific Rho-associated kinase inhibitor, Y-27632, has been reported to inhibit cancer invasion. Clinically, disseminated tumor cells in the cerebrospinal fluid invade the intraparenchymal region, damaging the brain and nerves, resulting in fatal brain stem dysfunction, despite intrathecal chemotherapy. To expand therapeutic options for this devastating neoplastic meningitis, we evaluated the potential use of intrathecal Y-27632 administration by employing Walker 256 cells, a rat mammary cancer cell line. Y-27632 dose-dependently inhibited chemotactic and invasive activity of Walker 256 cells. Y-27632 also inhibited the phosphorylation level of regulatory myosin light chain in vitro, but the effect was temporary and was considerably diminished within 16 hours. Y-27632 induced striking morphologic changes in Walker 256 cells, as evidenced by decreased cell-matrix adhesion in culture dishes and three-dimensional collagen I gels, and slightly inhibited colony formation in soft agar. Nevertheless, this drug treatment did not affect Walker 256 cell growth rate. We were able to administer continuous delivery of this inhibitor using an osmotic pump and maintaining drug concentration of 10 Mmol/L within the brain. Importantly, this concentration of Y-27632 showed minimal neurotoxicity both in vitro and in vivo. We found that an intrathecal therapy, combining 5-fluoro-2V -deoxyuridine with Y-27632, significantly increased the survival time of rats bearing meningeal carcinomatosis in comparison with animals treated with 5-fluoro-2V -deoxyuridine alone.Taken together, our findings indicate that continuous intrathecal administration of Y-27632 could be a promising therapeutic method when combined with chemotherapy for treating human neoplastic meningitis. (Mol Cancer Res 2005;3(8):425 -33)

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Interleukin-6/Soluble Interleukin-6 Receptor Signaling Attenuates Proliferation and Invasion, and Induces Morphological Changes of a Newly Established Pleomorphic Malignant Fibrous Histiocytoma Cell Line

Cited by 26 publications

References 42 publications

Neoplastic fever in patients with bone and soft tissue sarcoma

Neoplastic fever in patients with bone and soft tissue sarcoma

Myxoid liposarcoma FUS‐DDIT3 fusion oncogene induces C/EBP β‐mediated interleukin 6 expression

Intrathecal Administration of Y-27632, a Specific Rho-Associated Kinase Inhibitor, for Rat Neoplastic Meningitis

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