ICAM3 mediates inflammatory signaling to promote cancer cell stemness.

Abstract

In this study, we present a medium throughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness. We identified several novel candidates that decrease OCT4 expression and reduce the ALDH + subpopulation both of which are characteristic of stemness. Furthermore, one of the novel candidates ICAM3 up-regulates in the ALDH + subpopulation, the side population and the developed spheres. ICAM3 knockdown reduces the side population, sphere formation and chemo-resistance in MDA-MB-231 human breast cancer cells and A549 lung cancer cells. In addition, mice bearing MDA-MB-231-shICAM3 cells develop smaller tumors and fewer lung metastases versus control. Interestingly, ICAM3 recruits and binds to Src by the YLPL motif in its intracellular domain which further activates the PI3K-AKT phosphorylation cascades. The activated p-AKT enhances SOX2 and OCT4 activity and thereby maintains cancer cell stemness. Meanwhile, the p-AKT facilitated p50 nuclear translocation/activation enhances p50 feedback and thereby promotes ICAM3 expression by binding to the ICAM3 promoter region. On this basis, Src and PI3K inhibitors suppress ICAM3-mediated signaling pathways and reduce chemo-resistance which results in tumor growth suppression in vitro and in vivo. In summary, we identify a potential CSC regulator and suggest a novel mechanism by which ICAM3 governs cancer cell stemness and inflammation.

• Authors: Wenzhi Shen, Junling Xie, Shuangtao Zhao, Renle Du, Xiaohe Luo, Huiwen He, Shan Jiang, Na Hao, Chong Chen, Chunlei Guo, Yanhua Liu, Yanan Chen, Peiqing Sun, Shengyong Yang, Na Luo, Rong Xiang, Yunping Luo
• Journal: Cancer letters (Cancer Lett) Vol. 422 Pg. 29-43 (05 28 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 29477378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Antigens, CD
• Biomarkers
• Cell Adhesion Molecules
• ICAM3 protein, human
• RNA, Small Interfering

Topics

• Animals
• Antigens, CD (genetics)
• Biomarkers
• Cell Adhesion Molecules (genetics)
• Cell Line, Tumor
• Computational Biology (methods)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Inflammation (genetics, metabolism, pathology)
• Mice
• Neoplasms (genetics, metabolism, pathology)
• Neoplastic Stem Cells (drug effects, metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction
• Transcriptome