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

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

Cancer research (2015-03-07)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Paclitaxel, from semisynthetic, ≥98%
Sigma-Aldrich
Tantalum(V) ethoxide, 99.98% trace metals basis
Sigma-Aldrich
MISSION® esiRNA, targeting human LIN28B
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Tcf7l2
Sigma-Aldrich
Paclitaxel, from Taxus yannanensis, powder
Sigma-Aldrich
Paclitaxel, from Taxus brevifolia, ≥95% (HPLC), powder
Paclitaxel natural for peak identification, European Pharmacopoeia (EP) Reference Standard
Paclitaxel, European Pharmacopoeia (EP) Reference Standard
Paclitaxel semi-synthetic for system suitability, European Pharmacopoeia (EP) Reference Standard
Tantalum(V) ethoxide, packaged for use in deposition systems
Sigma-Aldrich
MISSION® esiRNA, targeting human TCF7L2
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Lin28b
Paclitaxel semi-synthetic for peak identification, European Pharmacopoeia (EP) Reference Standard