PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages
| Autor: | Mark T. Bedford, Michelle Van Scoyk, Vineet Gupta, Rama Kamesh Bikkavilli, Odile David, Robert A. Winn, Alessandra Di Lorenzo, Samia Q. Khan, Su Yanlin, Pei Ying Wu, Jianqiang Bao, Sreedevi Avasarala |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein-Arginine N-Methyltransferases Cancer Research Lung Neoplasms Methyltransferase Cell Culture Techniques Article Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Lung cancer Molecular Biology Cell Proliferation Chemistry Cell growth Macrophages Binding protein Nuclear Proteins respiratory system medicine.disease Survival Analysis In vitro Disease Models Animal 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Disease Progression Cancer research Macrophage migration inhibitory factor |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Increased expression of protein arginine methyl transferase 6 (PRMT6) correlates with worse prognosis in lung cancer cases. To interrogate the in vivo functions of PRMT6 in lung cancer, we developed a tamoxifen-inducible lung-targeted PRMT6 gain-of-function mouse model, which mimics PRMT6 amplification events in human lung tumors. Lung-targeted overexpression of PRMT6 accelerated cell proliferation de novo and potentiated chemical carcinogen (urethane)-induced lung tumor growth. To explore the molecular mechanism/s by which PRMT6 promotes lung tumor growth, we used proteomics-based approaches and identified interleukin-enhancer binding protein 2 (ILF2) as a novel PRMT6-associated protein. Furthermore, by using a series of in vitro gain-of-function and loss-of-function experiments, we defined a new role for the PRMT6–ILF2 signaling axis in alternate activation of tumor-associated macrophages (TAM). Interestingly, we have also identified macrophage migration inhibitory factor, which has recently been shown to regulate alternate activation of TAMs, as an important downstream target of PRMT6–ILF2 signaling. Collectively, our findings reveal a previously unidentified noncatalytic role for PRMT6 in potentiating lung tumor progression via the alternate activation of TAMs. Implications: This is the first study to demonstrate an in vivo role for PRMT6 in lung tumor progression via the alternate activation of TAMs. |
| Databáze: | OpenAIRE |
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