Upregulation of RICTOR gene transcription by the proinflammatory cytokines through NF-κB pathway contributes to the metastasis of renal cell carcinoma
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Metastasis accounts for more than 50 % of deaths among renal cell carcinoma (RCC) patients, and therefore, it is important to study the biology of metastasis and identify metastasis-associated biomarkers for risk prognosis and stratification of patients for an individualized therapy of RCC. In cultured RCC cells, knockdown of Rictor by short hairpin RNA (shRNA) inhibited cell migration and invasion, probably due to impairments in activation of Akt. Pretreatment with tumor necrosis factor α (TNFα) or interleukin 6 (IL-6) enhanced the expression of Rictor and the migration of renal cancer cells. Mechanistic analysis showed that TNFα induced the activation of NF-κB in RCC cells. Luciferase reporter analysis revealed a NF-κB responding element (−301 to −51 bp) at the promoter region of Rictor. Chromatin immunoprecipitation (ChIP) analysis further confirmed that TNFα-induced binding of p65 with the promoter of Rictor. In a xenograft model, knockdown of Rictor-blocked RCC cells metastasis to the mouse lungs and livers. Taken together, our results suggest that the proinflammatory cytokine TNFα promotes the expression of Rictor through the NF-κB pathway.
KeywordsMetastasis NF-κB Rictor Renal cell carcinoma TNFα
This work was supported by the NFSC (81472683, 81072160, 81201646, and 81125019), 973 Program (2011CB933100), Program of Tianjin Higher School Innovation Team (TD12-5025), and Research Seed Foundation of Tianjin Medical University Cancer Hospital and Institute (1421). We thank Zhe Liu, Wei Du, and Litao Qin for their help in luciferase and ChIP assays, and Qiuping Dong for plasmid construction.
Compliance with ethical standards
The manuscript does not contain clinical studies or patient data. And all procedures performed in studies involving animals were in accordance with the ethical standards of the ethics committee in Cancer Institute and Hospital of Tianjin Medical University, which was draw up on the basis of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize suffering.
Conflicts of interest
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