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

• DOI: 10.1158/0008-5472.c.6507426
• Publication Date: 2024-03-12T22:53:47Z
• 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
• Keywords: Positive feedback; Feedback loop

<div>Abstract<p>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 let7 repressor LIN28B and its regulator IKBKB (IKKβ) sustain cell stemness by interacting with Wnt/TCF7L2 (TCF4) signaling pathway to promote progression. We found expression correlated clinical progression marker in breast patients. Functional studies demonstrated properties LIN28B-expressing human lung were enhanced IKKβ, whereas loss abolished these settings. These phenomena driven through interactions TCF7L2, which direct binding intron 1 gene, turn promoted TCF7L2 mRNA translation a positive feedback loop. Notably, RNAi-mediated silencing or pharmacologic inhibition IKKβ was sufficient suppress primary metastatic tumor growth <i>in vivo</i>. Together, our results establish LIN28B/TCF7L2 interaction loop as central mediator processes during metastasis, possibly offering new therapeutic target for generalized interventions advanced cancers. <i>Cancer Res; 75(8); 1725–35. ©2015 AACR</i>.</p></div>