Identification of brain-derived neurotrophic factor as a novel functional protein in hepatocellular carcinoma.
This study aims to identify a novel molecule that may contribute to hepatocarcinogenesis in a rat orthotopic hepatocellular carcinoma model. The hepatocellular carcinoma model was generated by injection of tumor cells into the left lobe of the liver. Proteomic approaches, including ProteinChip and two-dimensional electrophoresis, were used to identify proteins from serially collected rat serum samples. By both ProteinChip and two-dimensional electrophoresis techniques, the level of a 27-kDa protein was found to be augmented in serum samples during tumor development, decreased after left lobectomy, and reincreased at the time of tumor recurrence. The protein was identified to be brain-derived neurotrophic factor (BDNF). By using specific primers and monoclonal antibody, the expression pattern of BDNF was confirmed in tumor tissue but not in the adjacent nontumorous liver tissue. In addition, the truncated isoform of BDNF receptor-tyrosine protein kinase receptor B was only found in tumor tissue. An in vitro study showed that exogenous BDNF could induce tumor cell proliferation predominantly in relatively small numbers of inoculated cells. Administration of BDNF to tumor cell lines induced significantly increased expression of heat shock protein 90 (Hsp90) and cyclin D1, and blocking the activity of Hsp90 could reverse the up-regulation of cyclin D1 induced by BDNF. The present study revealed that BDNF and its receptor were uniquely expressed in tumor tissue and cell lines of hepatocellular carcimona but not in nontumorous liver tissue and normal cell line. BDNF could stimulate tumor cell proliferation in a Hsp90-dependent manner.
Yang
Zhen Fan
ZF
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
Ho
David W
DW
Lam
Chi Tat
CT
Luk
John M
JM
Lum
Ching Tung
CT
Yu
Wan Ching
WC
Poon
Ronnie T
RT
Fan
Sheung Tat
ST
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D008297:Male; D040081:Protein Array Analysis; D051381:Rats; D011915:Rats, Inbred BUF; D020813:Receptor, trkB / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019208:Brain-Derived Neurotrophic Factor; D018841:HSP90 Heat-Shock Proteins; D019938:Cyclin D1; D020813:Receptor, trkB