IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis.

Abstract

Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKβ) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKβ, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAi-mediated silencing of LIN28B or pharmacologic inhibition of IKKβ was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers.

• Authors: Chong Chen, Fengqi Cao, Lipeng Bai, Yan Liu, Junling Xie, Wei Wang, Qin Si, Jian Yang, Antao Chang, Dong Liu, Dachuan Liu, Tsung-Hsien Chuang, Rong Xiang, Yunping Luo
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 8 Pg. 1725-35 (Apr 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25744721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• LIN28B protein, human
• RNA-Binding Proteins
• TCF7L2 protein, human
• Transcription Factor 7-Like 2 Protein
• I-kappa B Kinase

Topics

• Animals
• Cell Proliferation (genetics)
• Feedback, Physiological
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• I-kappa B Kinase (physiology)
• MCF-7 Cells
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Metastasis (genetics, pathology)
• Neoplastic Stem Cells (metabolism, pathology)
• RNA-Binding Proteins (genetics)
• Transcription Factor 7-Like 2 Protein (genetics)
• Tumor Cells, Cultured