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.
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Chong
C
Chen
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Fengqi
F
Cao
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Lipeng
L
Bai
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Yan
Y
Liu
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Junling
J
Xie
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Wei
W
Wang
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Qin
Q
Si
Department of Immunology, Nankai University, Tianjin, China.
Jian
J
Yang
Department of Immunology, Nankai University, Tianjin, China.
Antao
A
Chang
Xuanwu Hospital, Capital Medical University, Beijing, China.
Dong
D
Liu
Xuanwu Hospital, Capital Medical University, Beijing, China.
Dachuan
D
Liu
Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Tsung-Hsien
TH
Chuang
Department of Immunology, Nankai University, Tianjin, China.
Rong
R
Xiang
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Collaborative Innovation Center for Biotherapy, School of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. yunpingluo@hotmail.com.
Yunping
Y
Luo
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D014407:Tumor Cells, Cultured
C516326:LIN28B protein, human; D016601:RNA-Binding Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051550:I-kappa B Kinase