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Published on: March 30, 2019
Cell cycle regulator ING4 is a suppressor of melanoma angiogenesis that is regulated by the metastasis suppressor
1Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract:
ING4 has been previously shown to play important roles in regulating apoptosis, cell cycle progress, cell migration, and invasion. In this study, we investigated the impact of ING4 on melanoma angiogenesis. ING4 overexpression strongly suppressed the growth of human umbilical vein endothelial cells (HUVEC) and their ability to form tubular structure in vitro. We also found that ING4 inhibits interleukin-6 (IL-6) at both mRNA and protein levels through suppressing NF-κB activity. Knockdown of endogenous ING4 resulted in enhanced HUVEC growth and IL-6 expression. Our in vivo studies using nude mice confirmed that ING4 inhibited blood vessel formation and the recruitment of CD31-positive cells in matrigel plugs. Furthermore, we found that expression of ING4 was induced by BRMS1, a metastasis suppressor that inhibits melanoma angiogenesis through inhibiting NF-κB activity and IL-6 level as well. Further experiments showed that ING4 knockdown abrogated the suppressive effect of BRMS1 on HUVEC growth, whereas ING4 overexpression inhibited BRMS1 knockdown-induced angiogenesis, indicating that ING4 is a downstream target of BRMS1 in regulating tumor angiogenesis. Collectively, our findings indicate that ING4 is induced by BRMS1 and that it inhibits melanoma angiogenesis by suppressing NF-κB activity and IL-6 expression. Restoration of ING4 function offers a potential new strategy for the treatment of human melanoma.
Insights
ING4 suppresses melanoma angiogenesis by inhibiting IL-6 and NF-κB activity. This metastasis suppressor is induced by BRMS1, offering a potential new treatment strategy for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Inhibitor of Growth family member 4 (ING4) is known to regulate apoptosis, cell cycle, migration, and invasion.
- Melanoma angiogenesis, the formation of new blood vessels that support tumor growth, is a critical process in melanoma progression.
Purpose of the Study:
- To investigate the role of ING4 in melanoma angiogenesis.
- To elucidate the molecular mechanisms by which ING4 affects angiogenesis.
- To explore the relationship between ING4 and BRMS1 in regulating melanoma angiogenesis.
Main Methods:
- In vitro studies using human umbilical vein endothelial cells (HUVECs) to assess cell growth and tube formation.
- Analysis of interleukin-6 (IL-6) and NF-κB activity.
- In vivo studies using matrigel plugs in nude mice to evaluate blood vessel formation.
- Investigation of ING4 expression induced by BRMS1 and its functional consequences.
Main Results:
- ING4 overexpression suppressed HUVEC growth and tube formation, inhibited IL-6 expression, and suppressed NF-κB activity.
- Knockdown of ING4 enhanced HUVEC growth and IL-6 expression.
- In vivo, ING4 inhibited blood vessel formation and CD31-positive cell recruitment.
- ING4 is induced by BRMS1 and acts as a downstream target, mediating BRMS1's anti-angiogenic effects.
Conclusions:
- ING4 inhibits melanoma angiogenesis by suppressing NF-κB activity and IL-6 expression.
- ING4 is a downstream mediator of BRMS1's anti-angiogenic function in melanoma.
- Restoring ING4 function presents a potential therapeutic strategy for human melanoma.
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