Upregulation of RICTOR gene transcription by the proinflammatory cytokines through NF-κB pathway contributes to the metastasis of renal cell carcinoma.
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.
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China.
Bo
B
Sun
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China.
Liwei
L
Chen
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China.
Hui
H
Fu
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China.
Lin
L
Guo
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China. guohua_193@163.com.
Hua
H
Guo
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China. ningzhangtj@yahoo.com.|Research Center of Basic Medical Science, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, People's Republic of China. ningzhangtj@yahoo.com.
Ning
N
Zhang
D029742:Caenorhabditis elegans Proteins; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002633:Chemotaxis; D016207:Cytokines / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014158:Transcription, Genetic; D015854:Up-Regulation
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D016207:Cytokines; D016328:NF-kappa B; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C446241:nud-1 protein, C elegans
Metastasis; NF-κB; Renal cell carcinoma; Rictor; TNFα