DIAGNOSTIC MARKERS AND DRUG TARGETS FOR TREATMENT OF CANCER

摘要

To disclose mechanisms of hepatocellular carcinogenesis and to identify novel diagnostic markers and/or drug targets for treatment of hepatocellular carcinomas (HCCs),we analyzed expression profiles of clinical HCCs using a genome-wide cDNA microarray.From among the transcripts that were commonly up-regulated in these tumors, we identified a novel human gene,at chromosoma l band 1 p36.13, termed DDEFL1 (development and differentiation enhancing fact or- like 1) encoding a product that shared structural features with centaurin- family proteins as well as VANGL1,LGN, and a novel gene termed ZNFN3A1 at chromosomal band 1 q44. The deduced 903-amino-acid sequence of DDFEL1 showed 46% homology to DDEF/ASAP1 (development and differentiation enhancing factor), and contained an Arf GTPase-activating protein (ArfGAP) domain and two ankyrin repeats. The predicted 428-amino-acid sequence of ZNFN3A1 contained a zf-MYND (MYND domain containing zinc finger protein ) domain and a SET (Su (var) 3-9, Enhancer-of-zeste, Trithorax) domain. VANGL1 (Van Gogh Like 1 ) is a gene homologous to strabismus (Van Gogh) that is involved in cell polarity and cell fate decisions in Drosophila.LGN protein interacts with alpha subunit of inhibitory heterotrimeric G proteinis (Ga12). Gene transfer of DDEFL 1,ZNFN3A1 or LGN promoted proliferation of cells that lacked endogeno us expression of either of these genes. Furthermore, reduction of DDEFL1, ZNFN3A1, VANGL1 or LGN expression by transfection of their specific anti-sen se S-oligonucleotides inhibited the growth of hepatocellular carcinoma cells.O ur results provide novel insight into hepatocarcinogenesis and may contribute t o development of new strategies for diagnosis and treatment of HCC.