Overexpression of Insulin-Like Growth Factor-1 (IGF-I) Receptor and the Invasiveness of Cultured Keloid Fibroblasts

Yoshimoto, Hiroshi; Ishiguro, Hiroshi; Ohtsuru, Akira; Akino, Kozo; Murakami, Ritsuko; Kuroda, Hiroaki; Namba, Hiroyuki; Ito, Masahiro; Fujii, Tohru; Yamashita, Shunichi

doi:10.1016/s0002-9440(10)65335-7

Cited by 72 publications

(71 citation statements)

References 28 publications

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“…Current findings (44,45) have demonstrated that the invasive activity of some cancer cells is largely dependent on IGF-IR. Because IGF-IR is thought to play a major role in growth and development of RCC, we here tested whether RCC can show IGF-IR dependent invasive activity.…”

Section: Inhibition Of Igf-i Signaling By Vhl Gene Product 20703mentioning

confidence: 97%

Inhibition of Insulin-like Growth Factor-I-mediated Cell Signaling by the von Hippel-Lindau Gene Product in Renal Cancer

Datta¹,

Nambudripad²,

Pal³

et al. 2000

Journal of Biological Chemistry

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Section: Inhibition Of Igf-i Signaling By Vhl Gene Product 20703mentioning

confidence: 97%

Inhibition of Insulin-like Growth Factor-I-mediated Cell Signaling by the von Hippel-Lindau Gene Product in Renal Cancer

Datta¹,

Nambudripad²,

Pal³

et al. 2000

Journal of Biological Chemistry

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“…Platelet-derived growth factor (PDGF)a receptor expression was shown to be enhanced in KFs, which corresponded to increased mitotic response upon exposure to all three PDGF isoforms (Haisa et al, 1994). Overexpression of insulinlike growth factor-I receptor detected in KFs appeared to enhance their invasiveness, but not fibroproliferation (Yoshimoto et al, 1999). Elevated interleukin (IL)-6 (Xue et al, 2000) and vascular endothelial growth factor (Wu et al, 2004) expression have also been observed in KFs.…”

Section: Introductionmentioning

confidence: 95%

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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“…Previous studies showed that cultured fibroblasts often exhibit characteristics typical of their in vivo phenotypes (Calderon et al, 1996;Tuan and Nichter, 1998;Yoshimoto et al, 1999;Younai et al, 1994). Although we described higher levels of caspase-2 and -3 expression in hypertrophic scars and keloid, Wassermann et al (1998) reported that the immunostaining levels of ICE and Fas were decreased in hypertrophic scar-derived fibroblasts.…”

Section: Akasaka Et Almentioning

confidence: 99%

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

Akasaka

Ishikawa

Ono

et al. 2000

Laboratory Investigation

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SUMMARY:Recent studies have suggested that the regulation of apoptosis during wound healing is important in scar establishment and development of pathological scarring. To examine the phenomenon of apoptosis and its involvement in the process of pathological scarring, we immunohistochemically quantified differential levels of expression of caspase-3 and -2, which are activated during apoptosis in vitro, in surgical resected scar tissues. We divided 33 cases of normally healed flat scars and 18 cases of pathological scars (15 cases of hypertrophic scars and 3 cases of keloid) into three groups (S1 ϭ Ͻ10 months' duration; S2 ϭ 10 to 40 months' duration; and S3 ϭ Ͼ40 months' duration) according to the duration of scar. In all three groups examined, the semiquantitative scores for caspase-3 staining were significantly higher for the combination of hypertrophic scars and keloid as a group compared with normally healed flat scars, suggesting reduced cell survival and increased apoptotic cell death in hypertrophic scars and keloid. Apoptosis and caspase proteolytic activities were examined in vitro using two flat scar-derived fibroblast lines (FSFB-1 and -2) and two keloid-derived fibroblast lines (KFB-1 and -2). After 24 hours of serum deprivation, apoptotic cells were significantly increased in both KFB lines, whereas serum deprivation of FSFB-1 cells did not result in a significant increase in apoptotic cell number. After serum deprivation, significant increases in caspase-3 proteolytic activities were detected in both KFB lines compared with both FSFB lines. In contrast, no significant differences with caspase-8 activity were observed between similarly treated KFB and FSFB lines. Furthermore, serum deprivation-induced apoptosis of KFB-2 cells was significantly inhibited by the caspase-3 inhibitor Ac-Asp-Glu-Val-Asp-fluoromethyl ketone (DEVD-FMK), indicating that caspase-3 is important for serum deprivation-induced apoptosis in KFB-2 cells. Considering the role of caspase-3 as a key effector molecule in the execution of apoptotic stimuli, our results suggested that enhanced expression of caspase-3 in hypertrophic scars and keloid induces apoptosis of fibroblasts, which may play a role in the process of pathological scarring. (Lab Invest 2000, 80:345-357).

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Overexpression of Insulin-Like Growth Factor-1 (IGF-I) Receptor and the Invasiveness of Cultured Keloid Fibroblasts

Cited by 72 publications

References 28 publications

Inhibition of Insulin-like Growth Factor-I-mediated Cell Signaling by the von Hippel-Lindau Gene Product in Renal Cancer

Inhibition of Insulin-like Growth Factor-I-mediated Cell Signaling by the von Hippel-Lindau Gene Product in Renal Cancer

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

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

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