A Novel Liver–Specific Zona Pellucida Domain Containing Protein That Is Expressed Rarely in Hepatocellular Carcinoma

Abstract

We currently identified a liver-specific gene that encodes a novel zona pellucida (ZP) domaincontaining protein named liver-specific ZP domain-containing protein (LZP). The full-length complementary DNA (cDNA) of human LZP has 2,255 bp with a complete open reading frame (ORF) of 1,635 bp. The gene is localized on chromosome 10q21.3 and spans 40 kb with 9 encoding exons and 8 introns. The deduced protein sequence has 545 amino acid residues, with an N-terminal signal peptide followed by 3 epidermal growth factor (EGF)-like domains and a ZP domain in C-terminal section. Interestingly, human LZP is expressed specifically in liver out of 23 tissues examined, and its mouse counterpart was detected at very early stage during embryo development. Moreover, LZP can be secreted into blood, albeit the protein was localized mainly on the nuclear envelop of hepatocytes. Most importantly, LZP is down-regulated in hepatocellular carcinoma (HCC) and HCC cell lines; meanwhile, the decreased level of hLZP messenger RNA (mRNA) could, at least in some HCC samples, be related to the methylation status of the putative LZP promoter. However, overexpression of hLZP in HCC cell line SMMC-7721 and human liver cell line L02 by stable cell transfection did not inhibit cell growth, implying that the down-regulation of hLZP in HCC might be a consequence of the dedifferentiation involved in hepatocarcinogenesis. In conclusion, these data suggest that LZP is a liver-specific protein involved possibly in hepatocellular function and development, and the protein could be used as potential negative biomarker for HCC pathologic diagnosis. ( H epatocellular carcinoma (HCC) is the major malignancy associated with liver and is one of the most common malignant tumors in the world, especially in Asia, Africa, and southern Europe. Of the ϳ350,000 new HCC cases per year, two thirds occur in Asia, in which China accounts for 50%. 1 Risk factors for hepatocarcinogenesis include infection with hepatitis B virus (HBV), hepatitis C virus, alcohol-induced cirrhosis, exposure to chemical carcinogens, and other factors associated with chronic inflammatory and hepatic regenerative changes. 1,2 Oncogenes such as c-myc and cyclin D1 and tumor suppressor genes such as p53, Rb, and p16 INK4a have been found to be involved in pathogenesis of HCC. [3][4][5][6][7] Mutations in ␤-catenin and AXIN1 gene have been detected and appear to play an important role in hepatocellular carcinogenesis. 8,9 A putative tumor suppressor gene LPTS localized at chromosome 8p23, which has a high-frequency loss of heterozygosity region in HCC, was considered a candidate involved in hepatocarcinogenesis. 10 However, the molecular mechanisms involved in malignant transformation of hepatocytes are still largely unknown.Recently, many transcriptome approaches, such as expressed sequence tag (EST) sequencing, complementary DNA (cDNA) microarray, and oligonucleotide chip, were used for studying the molecular mechanism of HCC. [11][12][13] In our previous work, comprehensive characteristics of HBV...

Identification and characterization of D8C, a novel domain present in liver‐specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy

“…LZP is a recently identified liver-specific protein, possibly involved in hepatocellular function and development [1]. Interestingly, while comparing the domain architectures of LZP and UMOD, we found that these two proteins have similar domain composition, but that the location of the three EGF repeats varies.…”

“…Expression of LZP is down-regulated in hepatocellular carcinoma (HCC) and HCC cell lines; meanwhile, which might be caused, at least in part, by the decreased level of LZP mRNA. LZP might be implicated in hepatocellular function and development [1].…”

A duplicated motif controls assembly of zona pellucida domain proteins

“…Moreover, different ZP domain proteins with short propeptides ending with an EHP, such as DMBT1 and LZP (Fig. 5), are also secreted (21,38). However, the EHP cannot simply be a secretion signal: even if the EHP ultimately dissociates from the mature protein, its presence at the plasma membrane is required for assembly of secreted, full-length ZP3 constructs (Fig.…”

Association of Autophagy Defect with a Malignant Phenotype and Poor Prognosis of Hepatocellular Carcinoma

“…Human HCC cell lines, including HepG2, Hep3B, SMMC-7721, MHCC97-L (17-19), MHCC97-H (19), HCCLM3 (17,20), HCCLM6 (21), and a human normal hepatic cell line, L-02 (22,23), were routinely maintained in high-glucose DMEM or RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum, 100 units/mL penicillin, and 100 mg/mL streptomycin. All cell lines were cultured at 37jC in a humidified incubator in an atmosphere of 5% CO 2 .…”