Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment
| Autor: | Pei-pei Hou, Sheng-fu Wu, Dawang Zhou, Wenxiu Zhao, Jianming Liu, Qiao Wu, Hang-zi Chen, Xiaomin Wang, Li-juan Luo, Lu-ming Yao, Qinghua Chen, Xue-li Bian, Zhi-yuan Zhang, Jia-xin Zhou, Qi-tao Chen |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male STAT3 Transcription Factor Thyroid Hormones Carcinoma Hepatocellular CCL1 Biology PKM2 medicine.disease_cause Monocytes 03 medical and health sciences Chemokine CCL1 Mice 0302 clinical medicine Cell-Derived Microparticles Cell Line Tumor medicine Tumor Microenvironment Macrophage Animals Humans STAT3 neoplasms Molecular Biology Transcription factor 030304 developmental biology Aged Cell Proliferation Aged 80 and over 0303 health sciences Tumor microenvironment Macrophages Liver Neoplasms Membrane Proteins Cell Differentiation Cell Biology Extracellular vesicle Hep G2 Cells Middle Aged Prognosis digestive system diseases Mice Inbred C57BL Cancer research biology.protein Disease Progression Carcinogenesis Carrier Proteins 030217 neurology & neurosurgery |
| Zdroj: | Molecular cell. 78(6) |
| ISSN: | 1097-4164 |
| Popis: | Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC. |
| Databáze: | OpenAIRE |
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