Abstract
We have previously identified several novel genes, which are differentially expressed among human normal liver and hepatocellular carcinomas (HCCs). The full-length liver fibrinogen-related gene-1 (LFIRE-1) cDNA was cloned from the human normal liver cDNA library. LFIRE-1 is highly homologous to HFREP-1 with discrepancy at 5' untranslated region (UTR) and encodes the same fibrinogen-related protein, which suggest that these two sequences might be alternative splicing forms of the same gene, LFIRE-1/HFREP-1, located at human chromosome 8p22. The LFIRE-1 and HFREP-1 are specifically expressed in normal human liver tissue, but reduced or undetectable in most of HCC specimens at both RNA and protein level. Furthermore, the reduction or nonexpression of LFIRE-1/HFREP-1 is significantly associated with the degree of tumor differentiation. Loss of heterozygosity (LOH) analysis revealed allelic loss of LFIRE-1/HFREP-1 on chromosome 8p22 in 57.1% (24/42) of HCC specimens. We detected three inactivation mutations among 45 cases of HCC specimens examined, two of which lost the remaining allele and the third had a replacement of conserved cysteine residue with glycine residue. Notably, the downregulation of LFIRE-1/HFREP-1 expression is frequently associated with allelic loss. The reduction of LFIRE-1/HFREP-1 expression by antisense approach enhances cancer cell proliferation and colony formation in soft agar. Moreover, restoration of exogenous wild-type LFIRE-1/HFREP-1 expression but not LFIRE-1/HFREP-1 missense mutations in human HCC cells inhibited their anchorage-dependent or -independent growth in vitro, and suppressed their tumorigenicity in nude mice. In conclusion, our data demonstrated that liver-specific gene LFIRE-1/HFREP-1 was frequently downregulated and might possess growth suppressor activity in HCC.
Highlights
Human primary hepatocellular carcinoma (HCC) ranks fifth in frequency of cancer worldwide (Haydon and Hayes, 1995; Sherman, 1995; Chen et al, 1997)
The deregulation of liver fibrinogen-related gene-1 (LFIRE-1)/HFREP-1 was related to cell growth and tumorigenicity in vitro and in vivo. These results suggested that the downregulation of LFIRE-1/ HFREP-1 in HCC cells may contribute to hepatocarcinogenesis
We reported that the human LFIRE-1/HFREP1 was a liver-specific gene and frequently downregulated or lost in HCCs at both mRNA and protein
Summary
Human primary hepatocellular carcinoma (HCC) ranks fifth in frequency of cancer worldwide (Haydon and Hayes, 1995; Sherman, 1995; Chen et al, 1997). In subSaharan Africa, Southeast Asia and the coastal part of mainland China, the incidence of HCC reaches more than 100/100 000 cases per year (Nagai and Buendia, 1998). The development of HCC is a multistep process, during which multiple genetic alterations are accumulated to facilitate cell transformation (Bishop, 1987; Fearon and Vogelstein, 1990; Knudson, 1993; Buendia, 2000; Hanahan and Weinberg, 2000). Many of them are deregulated or mutated; and as a result, affect the cell proliferation or survival. These findings are, in most cases, observed in many other types of cancer. More critical molecules specific for HCC, which will be more informative, remain to be elucidated
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