期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 16, 页码 -出版社
MDPI
DOI: 10.3390/ijms21165806
关键词
KRAS; lung cancer; IKK beta kinase; stemness; cancer stem cells; NF-kappa B signalling; migration; invasion
资金
- Fundacao de Apoio a Pesquisa do Estado de Sao Paulo (FAPESP) [2016/19757-2]
- FAPESP [2012/13774-1, 2016/22520-4, 2016/10404-0]
- FAPESP Research Internships Abroad (BEPE) fellowship [2017/22125-0]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [155381/2016-4]
- graduate program in Biochemistry and Molecular Biology of the University of Sao Paulo - Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [PROEX 1888/2016]
KRAS oncogenic mutations are widespread in lung cancer and, because direct targeting of KRAS has proven to be challenging, KRAS-driven cancers lack effective therapies. One alternative strategy for developing KRAS targeted therapies is to identify downstream targets involved in promoting important malignant features, such as the acquisition of a cancer stem-like and metastatic phenotype. Based on previous studies showing that KRAS activates nuclear factor kappa-B (NF-kappa B) through inhibitor of nuclear factor kappa-B kinase beta (IKK beta) to promote lung tumourigenesis, we hypothesized that inhibition of IKK beta would reduce stemness, migration and invasion of KRAS-mutant human lung cancer cells. We show that KRAS-driven lung tumoursphere-derived cells exhibit stemness features and increased IKK beta kinase activity. IKK beta targeting by different approaches reduces the expression of stemness-associated genes, tumoursphere formation, and self-renewal, and preferentially impairs the proliferation of KRAS-driven lung tumoursphere-derived cells. Moreover, we show that IKK beta targeting reduces tumour cell migration and invasion, potentially by regulating both expression and activity of matrix metalloproteinase 2 (MMP2). In conclusion, our results indicate that IKK beta is an important mediator of KRAS-induced stemness and invasive features in lung cancer, and, therefore, might constitute a promising strategy to lower recurrence rates, reduce metastatic dissemination, and improve survival of lung cancer patients with KRAS-driven disease.
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