Considerable evidence suggests that pro-inflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here the study report that the let7 repressor LIN28B and its regulator IKKβ sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression.

The study 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 pharmacological inhibition of IKKβ was sufficient to suppress primary and metastatic tumor growth in vivo. Together, these results establish the LIN28B/TCF7L2 interaction loop as a central mediator of cancer stemness driven by pro-inflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers.

Reference:

Chong Chen, Fengqi Cao, et al. IKKβ enforces a LIN28B/TCF7L2 positive feedback loop that promotes cancer cell stemness and metastasis [J].Cancer Research, 2015. 10.1158/0008-5472.