Crosstalk of renal cell carcinoma cells and tumor-associated macrophages aggravates tumor progression by modulating muscleblind-like protein 2/B-cell lymphoma 2/beclin 1-mediated autophagy |
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| Affiliation: | 1. Department of Urology, Xiangya Hospital, Central South University, Changsha, People''s Republic of China;2. Department of Urology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan China.;1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China;2. Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China;3. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China;1. School of Biological Sciences, The University of Auckland, Auckland, New Zealand;2. Department of Surgery, Faculty of Medicine and Health Sciences, The University of Auckland, Auckland, New Zealand;3. Counties Manukau District Health Board, Auckland, New Zealand;4. Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand;1. Pediatrics, University of California, San Francisco, San Francisco, California, USA;2. Crispr Therapeutics AG, Boston, Massachusetts, USA;3. ISCT Immune-Gene Therapy Committee, ISCT, Vancouver, California, USA;1. Gastroenterology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Policlinico G.B. Rossi and University of Verona, Verona, Italy;2. Division of Surgery and Cell Therapy Unit, Institute for Health Research, Jiménez Díaz Foundation University Hospital, Madrid, Spain;3. Laboratory of Advanced Cellular Therapies, Hematology Unit, Vicenza Hospital, Vicenza, Italy;1. Biotherapy Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;2. Cancer Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;3. Department of Thoracic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;4. School of Life Sciences, Zhengzhou University, Zhengzhou, China;5. State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China |
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| Abstract: | Background aimsM2-polarized tumor-associated macrophages contribute to the development of multiple human cancers, including renal cell carcinoma (RCC). However, the crosstalk mechanism between M2 macrophages and RCC remains unclear.MethodsThe authors constructed a co-culture system of M2 macrophages differentiated from THP-1 and RCC cells. Microscopic examination and quantitative real?time polymerase chain reaction (qRT-PCR) validated the morphology and types of macrophages. The proliferation, migration and invasion of RCC cells were assessed by Cell Counting Kit 8 (Dojindo Molecular Technologies, Inc, Santa Clara, CA, USA) and Transwell assay (Corning, Corning, NY, USA). Messenger RNA (mRNA) and protein expression of target molecules was detected by qRT?PCR and western blotting. Expression of Ki-67, E-cadherin and N-cadherin was measured by immunofluorescence staining or immunohistochemistry. Molecular interaction was evaluated by RNA pull-down, RNA immunoprecipitation and co-immunoprecipitation. A xenograft model was established to determine tumor growth in vivo.ResultsRCC cells triggered the activation of M2 macrophages. Functionally, M2-polarized macrophages facilitated the growth, migration, invasion and epithelial–mesenchymal transition of RCC cells by suppressing autophagy, whereas rapamycin, an activator of autophagy, significantly counteracted the tumor-promoting effects of M2 macrophages. Mechanistically, M2 macrophage-derived C-C motif chemokine 2 (CCL2) enhanced modulation of muscleblind-like protein 2 (MBNL2) expression. MBNL2 raised the stability of B-cell lymphoma 2 (Bcl-2) by directly binding to Bcl-2 mRNA, which endowed RCC cells with malignant properties via inhibition of beclin 1-dependent autophagy.ConclusionsRCC-induced M2-polarized macrophages secrete CCL2 to promote the growth and metastasis of RCC cells via inhibition of MBNL2/Bcl-2/beclin 1-mediated autophagy, which provide a novel perspective for the development of a therapeutic strategy for -RCC. |
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