Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 20, Issue 11, Pages 2020-2028Publisher
WILEY
DOI: 10.1111/jcmm.12890
Keywords
kidney cancer; tumour microenvironment; chemokine; patient prognosis
Categories
Funding
- Ministry of Science and Technology [MOST 103-2320-B-010-039-MY3, 103-2321-B-010-029]
- Ministry of Education (Aim for the Top University Plan)
- Tri-Service General Hospital
- National Defense Medical Center [TSGH-C98-13-S03, TSGH-C99-012-13-S03, TSGH-C100-129, TSGH-C103-062, TSGH-C104-507]
- Taipei City Hospital, Taiwan
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Within the tumour microenvironment, a complex network of chemokines and their receptors affects the initiation and progression of tumours. The higher levels of tumour necrosis factor-alpha (TNF-) are associated with tumour progression and an anti-TNF- monoclonal antibody has been used successfully to treat patients with renal cell carcinoma (RCC). However, the role of chemokines and their receptors in the TNF--promoted progression of RCC remains unclear. In this study, TNF- was found to enhance the migration, invasion and epithelial-mesenchymal transition (EMT) of RCC cells. To further investigate the molecular mechanism of TNF- on the progression of RCC, reverse transcription and quantitative PCR was used to screen chemokines and chemokine receptors that were associated with tumorigenesis. The results showed that TNF- significantly increased the expressions of CXCR2 and CXCR3 and their related ligands in RCC cells. Subsequently, we used a lentiviral shRNA system to knockdown the expression of CXCR2 and/or CXCR3 in RCC cells. CXCR2 and CXCR3 silencing inhibited the induction of Slug and ZEB-1 with TNF- treatment of RCC cells. In addition, the knockdown of both CXCR2 and CXCR3 resulted in a greater decrease in cell migration, invasion and clonogenic ability compared with either CXCR2 or CXCR3 knockdown alone. Moreover, CXCR2 and CXCR3 silencing significantly reduced the sphere-forming ability of RCC cells. High expression levels of CXCR2 and CXCR3 in cancer tissues correlated with tumour progression of renal cell carcinoma. These findings suggest that TNF- augments CXCR2 and CXCR3 to promote the progression of renal cell carcinoma leading to a poor prognosis.
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