title: let-7b and let-7c are determinants of intrinsic chemoresistance in renal cell carcinoma.
abstract: BACKGROUND
  Renal cell carcinoma (RCC) is characterized by inherent resistance to chemotherapy. Earlier studies demonstrated that microRNAs (miRNAs) might be involved in the chemosensitivity of cancers. MicroRNA let-7, a putative tumor suppressor, is dysregulated in many cancers. Our study aims to investigate the exact role of let-7 in chemotherapy sensitivity of 5-fluorouracil (5-FU) in RCC.
  
  
  METHODS
  The clinical significance of let-7b and let-7c expression in surgically resected specimens was assessed by qRT-PCR. Cell proliferation assay and colony formation assay were used to assess the survival of 786-O cells treated with let-7b or let-7c combined with 5-FU. Western blot was used to detect the expression of Akt2 and caspase-7. Luciferase assay was used to detect the direct binding of let-7b and let-7c to the 3'-untranslated region (UTR) of Akt2.
  
  
  RESULTS
  Expression of let-7b and let-7c was significantly decreased in 32 paired clear cell renal cell carcinoma tissue specimens and the dysregulation of let-7b was associated with pathological grade. Transfection of let-7b or let-7c combined with 5-FU inhibited proliferation and potentiated the antitumor efficacies of 5-FU at tolerated concentration. let-7b and let-7c suppressed the luciferase activity of reporter plasmid containing the 3'-UTR of Akt2. Overexpression of let-7b and let-7c reduced Akt2 expression, and Akt2 inhibition enhanced the sensitivity to 5-FU by affecting apoptotic pathway.
  
  
  CONCLUSIONS
  Expression of let-7b and let-7c was frequently decreased in clear cell renal cell carcinoma tissues. The dysregulation of let-7b and let-7c may be involved in chemoresistance of RCC cells to 5-FU by down-regulating Akt2.
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, People's Republic of China. jingtao_peng@163.com.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, People's Republic of China. moren325@163.com.|Department of Urology, Inner Mongolia Autonomous Region Peoples Hospital, 20 Zhaowuda Road, Hohhot, Inner Mongolia, 010017, People's Republic of China. moren325@163.com.
authors.forename: Ren
authors.initials: R
authors.lastname: Mo
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, People's Republic of China. fyzy0856@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, People's Republic of China. jief67@sina.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil