KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling
Open Access
- 29 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (4), 1-14
- https://doi.org/10.1038/s41419-020-2479-z
Abstract
Tetraspanins CD9 and CD81 frequently serve as the surface markers of exosomes, which are involved in intercellular communication during tumor progression. KLF4 is a well-known tumor suppressor in various cancers. This study aims to investigate the relationship between KLF4 and CD9/CD81 in hepatocellular carcinoma (HCC). The results showed that CD9 and CD81 were transcriptionally activated by KLF4 in HCC cell lines. Decreased expressions of CD9 and CD81 were found in most HCC tumor tissues and predicted advanced stages. Furthermore, KLF4 expression was positively associated with CD9 and CD81 expression in HCC specimens. Functionally, overexpression of CD9 and CD81 inhibited HCC cell proliferation in vitro and in vivo and silencing CD9 and CD81 displayed opposite phenotypes. Mechanistically, we found that JNK signaling pathway may be involved in the growth suppression mediated by CD9 and CD81. In addition, increased expression of KLF4, CD9 or CD81 had no obvious impact on exosome secretion from HCC cells. Collectively, we identified CD9 and CD81 as new transcriptional targets of KLF4 and the dysregulated KLF4-CD9/CD81-JNK signaling contributes to HCC development. Our findings will provide new promising targets against this disease.Keywords
Funding Information
- National Natural Science Foundation of China (81772567, 81772568)
- the Outstanding Clinical Discipline Project of Shanghai Pudong
- Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai
This publication has 52 references indexed in Scilit:
- Krüppel-Like Factor 4 Acts as an Oncogene in Colon Cancer Stem Cell-Enriched Spheroid CellsPLOS ONE, 2013
- Comparative marker analysis of extracellular vesicles in different human cancer typesJournal of Extracellular Vesicles, 2013
- CD9 expression as a favorable prognostic marker for patients with malignant mesotheliomaOncology Reports, 2012
- Intercellular nanovesicle-mediated microRNA transfer: A mechanism of environmental modulation of hepatocellular cancer cell growthHepatology, 2011
- Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasionOncogene, 2011
- KLF4α Up-regulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients With Pancreatic CancerGastroenterology, 2010
- Exosomes: Extracellular organelles important in intercellular communicationJournal of Proteomics, 2010
- Hypoxic Tumor Cell Modulates Its Microenvironment to Enhance Angiogenic and Metastatic Potential by Secretion of Proteins and ExosomesMolecular & Cellular Proteomics, 2010
- Putative Tumor-Suppressive Function of Krüppel-Like Factor 4 in Primary Lung CarcinomaClinical Cancer Research, 2009
- High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma PatientsPLOS ONE, 2009