1. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Dongguan 523808, China
2. Department of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, China.
3. Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia 19104, USA
4. Department of Pathology, Dongguan Hospital Affiliated to Jinan University, The Fifth People's Hospital of Dongguan, Dongguan 523905, China
5. Laboratory Animal Center, Guangdong Medical University, Zhanjiang, 524023 China
6. Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China
*These authors contributed equally to this study.
Previous studies have implicated the important role of mesenchymal stem/stromal cells (MSCs) within tumor microenvironment (TME) in the pathogenesis and progression of nasopharyngeal carcinoma (NPC), but the potential mechanisms are still unclear. Herein, we showed that an elevated IL-6 level was positively correlated with elevated expression of CD73 in TME of NPC. NPC specimens with an IL-6highCD73high phenotype showed higher expression levels of gp80, gp130, p-STAT3, MMP-9 and α-SMA, and clinically, a poorer prognosis than those with an IL-6lowCD73low phenotype. We found that stimulation with conditioned media derived from IL-6 gene knocked out MSC (MSCIL6KO-CM) down-regulated the expression of CD73, IL-6, gp80, p-STAT3, and proliferative cell nuclear antigen (PCNA) in CNE-2 NPC cells. Meanwhile, NPC cells co-cultured with MSCIL6KO-CM were more sensitive to cisplatin than those co-cultured with MSC-CM. Additionally, MSC-derived IL-6 transcriptionally upregulated CD73 expression via activating STAT3 signaling pathway in NPC cells. In summary, our findings suggest that MSCs promote NPC progression and chemoresistance by upregulation of CD73 expression via activating STAT3 signaling pathway.
Keywords: nasopharyngeal carcinoma, mesenchymal stem/stromal cells, tumor microenvironment, IL-6, CD73