LDHA-mediated M2-type macrophage polarization via tumor-derived exosomal EPHA2 promotes renal cell carcinoma progression.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8811105 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2744 (Electronic) Linking ISSN: 08991987 NLM ISO Abbreviation: Mol Carcinog Subsets: MEDLINE

Publication: <2005- > : [Hoboken, N.J.] : Wiley-Liss
Original Publication: New York : Alan R. Liss, Inc., c1988-

Carcinoma, Renal Cell*/pathology ; Carcinoma, Renal Cell*/metabolism ; Carcinoma, Renal Cell*/genetics ; Receptor, EphA2*/metabolism ; Receptor, EphA2*/genetics ; Kidney Neoplasms*/pathology ; Kidney Neoplasms*/metabolism ; Kidney Neoplasms*/genetics ; Exosomes*/metabolism ; Disease Progression* ; Macrophages*/metabolism ; Macrophages*/pathology; Humans ; Animals ; Mice ; Cell Line, Tumor ; Cell Proliferation ; L-Lactate Dehydrogenase/metabolism ; L-Lactate Dehydrogenase/genetics ; Cell Movement ; Gene Expression Regulation, Neoplastic ; Male ; Tumor Microenvironment ; Prognosis ; TOR Serine-Threonine Kinases/metabolism ; Female ; Signal Transduction ; Mice, Nude ; Proto-Oncogene Proteins c-akt/metabolism

Lactate dehydrogenase A (LDHA) is known to promote the growth and invasion of various types of tumors, affects tumor resistance, and is associated with tumor immune escape. But how LDHA reshapes the tumor microenvironment and promotes the progression of renal cell carcinoma (RCC) remains unclear. In this study, we found that LDHA was highly expressed in clear cell RCC (ccRCC), and this high expression was associated with macrophage infiltration, while macrophages were highly infiltrated in ccRCC, affecting patient prognosis via M2-type polarization. Our in vivo and in vitro experiments demonstrated that LDHA and M2-type macrophages could enhance the proliferation, invasion, and migration abilities of ccRCC cells. Mechanistically, high expression of LDHA in ccRCC cells upregulated the expression of EPHA2 in exosomes derived from renal cancer. Exosomal EPHA2 promoted M2-type polarization of macrophages by promoting activation of the PI3K/AKT/mTOR pathway in macrophages, thereby promoting the progression of ccRCC. All these findings suggest that EPHA2 may prove to be a potential therapeutic target for advanced RCC.
(© 2024 Wiley Periodicals LLC.)

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82072812 National Natural Science Foundation of China; 82103599 National Natural Science Foundation of China; 23ZR1478500 Natural Science Foundation of Shanghai Municipality

Keywords: EPHA2; exosomes; lactate dehydrogenase A; macrophage; renal cell carcinoma

EC 2.7.10.1 (Receptor, EphA2)
0 (EPHA2 protein, human)
EC 1.1.1.27 (L-Lactate Dehydrogenase)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)

Date Created: 20240523 Date Completed: 20240709 Latest Revision: 20240805

20240805

10.1002/mc.23737

38780182