title: IGF-1 promotes the growth and metastasis of hepatocellular carcinoma via the inhibition of proteasome-mediated cathepsin B degradation.
abstract: OBJECTIVE
  To investigate the molecular mechanisms of the high IGF-1 level linking diabetes and cancers, which is a risk factor.
  
  
  METHODS
  We used cell growth, wound healing and transwell assay to evaluate the proliferation and metastasis ability of the hepatocellular carcinoma (HCC) cells. Western blot and reverse transcription polymerase chain reaction were used to assess a previously identified lysosomal protease, cathepsin B (CTSB) expression in the HCC cell lines. C57 BL/6J and KK-Ay diabetic mice are used to detect the growth and metastasis of HCC cells that were depleted with or without CTSB shRNA in vivo. Statistical significance was determined by Student's t-test.
  
  
  RESULTS
  IGF-1 promoted the growth and metastasis of the HCC cell lines via its ability to enhance CTSB expression in both a time-dependent and concentration-dependent manner. HCC cells grew much faster in diabetic KK-Ay mice than in C57 BL/6J mice. Additionally, more metastatic nodules were found in the lungs of KK-Ay mice than the lungs of C57 BL/6J mice. CTSB depletion protects against the tumor-promoting actions of IGF-1 in HCC cells, as well tumor growth and metastasis both in vitro and in vivo. IGF-1 did not change the mRNA levels of CTSB but prolonged the half-life of cathepsin B in Hepa 1-6 and H22 cells. Our results showed that IGF-1 promotes the growth and metastasis of the HCC cells most likely by hindering CTSB degradation mediated by the ubiquitin-proteasome system (UPS), but not autophagy. Overexpression of proteasome activator 28, a family of activators of the 20S proteasome, could not only restore IGF-1-inhibited UPS activity but also decrease IGF-1-induced CTSB accumulation.
  
  
  CONCLUSIONS
  Our study demonstrates that IGF-1 promotes the growth and metastasis of hepatocellular carcinoma by inhibition of proteasome-mediated CTSB degradation.
authors.affiliation: Tian Lei, Department of Gastroenterology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou 121000, Liaoning Province, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Lei
authors.affiliation: Tian Lei, Department of Gastroenterology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou 121000, Liaoning Province, China.
authors.forename: Xie
authors.initials: X
authors.lastname: Ling
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000378:metabolism; D004795:Enzyme Stability; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D001324:Autoantigens; C099558:Ki antigen; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Cathepsin B; Diabetes; Hepatocellular carcinoma; IGF-1; Ubiquitin-proteasome system