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

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.

Chen C ，Cao F ，Bai L ，Liu Y ，Xie J ，Wang W ，Si Q ，Yang J ，Chang A ，Liu D ，Liu D ，Chuang TH ，Xiang R ，Luo Y ... -  《-》

Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis.

Chen C ，Bai L ，Cao F ，Wang S ，He H ，Song M ，Chen H ，Liu Y ，Guo J ，Si Q ，Pan Y ，Zhu R ，Chuang TH ，Xiang R ，Luo Y ... -  《-》

Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells.

Ren D ，Wang M ，Guo W ，Huang S ，Wang Z ，Zhao X ，Du H ，Song L ，Peng X ... -  《-》

IKKβ Kinase Promotes Stemness, Migration, and Invasion in KRAS-Driven Lung Adenocarcinoma Cells.

Rodrigues FS ，Miranda VS ，Carneiro-Lobo TC ，Scalabrini LC ，Kruspig B ，Levantini E ，Murphy DJ ，Bassères DS ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

The KRAS/Lin28B axis maintains stemness of pancreatic cancer cells via the let-7i/TET3 pathway.

Increasing evidence demonstrates that Lin28B plays critical roles in numerous biological processes including cell proliferation and stemness maintenance. However, the molecular mechanisms underlying Lin28B nuclear translocation remain poorly understood. Here, we found for the first time that KRAS promoted Lin28B nuclear translocation through PKCβ, which directly bound to and phosphorylated Lin28B at S243. Firstly, we observed that Lin28B was upregulated in pancreatic cancer, contributing to cellular migration and proliferation. Furthermore, nuclear Lin28B upregulated TET3 messenger RNA and protein levels by blocking the production of mature let-7i. Subsequently, increased TET3 expression could also promote the expression of Lin28B, thereby forming a Lin28B/let-7i/TET3 feedback loop. Our results suggest that the KRAS/Lin28B axis drives the let-7i/TET3 pathway to maintain the stemness of pancreatic cancer cells. These findings illuminate the distinct mechanism of Lin28B nuclear translocation and its important roles in KRAS-driven pancreatic cancer, and have important implications for development of novel therapeutic strategies for this cancer.

Liu Y ，Wang D ，Zhou M ，Chen H ，Wang H ，Min J ，Chen J ，Wu S ，Ni X ，Zhang Y ，Gong A ，Xu M ... -  《-》