RECK gene expression in hepatocellular carcinoma: Correlation with invasion-related clinicopathological factors and its clinical significance

Abstract

The RECK (reversion-inducing-cysteine-rich protein with Kazal motifs) gene was initially isolated as a transformation suppressor gene. It encodes a membrane-anchored glycoprotein with multiple serine protease inhibitor-like domains. The RECK gene is expressed widely in normal organs but is undetectable in many tumor-derived cell lines. When artificially expressed in such cell lines, RECK suppresses their invasive and metastatic activities. Clinical implications of these findings, however, remained undefined because of the lack of studies using fresh human tumor samples. In the present study, we have addressed this issue by analyzing the levels of RECK gene expression in hepatocellular carcinoma (HCC). RECK mRNA was detectable by RNA blot hybridization in all the tumorous and contiguous nontumorous tissues obtained from 64 patients with HCC. In 26 cases, the RECK expression in tumorous tissues was higher than that in nontumorous tissues. The expression of RECK protein in these tissues could also be demonstrated by immunohistochemistry. Patients with high RECK mRNA expression in tumorous tissues tended to show better survival (P ‫؍‬ .02), and such tumors had a tendency to be less invasive. Univariate and multivariate analysis revealed that the RECK mRNA expression is a novel and independent variable affecting overall survival (P ‫؍‬ .01). These findings support the hypothesis that RECK has negative effects on the invasiveness of HCC cells and suggest the feasibility of RECK mRNA as a promising prognostic molecular marker for HCC. (HEPATOLOGY 2001;33:189-195.)The RECK (reversion-inducing-cysteine-rich protein with Kazal motifs) gene was isolated by cDNA expression cloning as a gene that induces flat morphology when expressed in a v-Ki-ras-transformed NIH 3T3 cell line. 1 The RECK gene encodes a membrane-anchored glycoprotein of about 110 kDa with multiple epidermal growth factor-like repeats and serine protease inhibitor-like domains. The RECK gene was ubiquitously expressed in various normal tissues and non-neoplastic cell lines, whereas in several tumor-derived cell lines and oncogene-transformed fibroblasts, its expression was strongly suppressed. Restored expression of the RECK gene inhibited the invasive or metastatic activities of some of these tumorderived cell lines with concomitant suppression of the secretion of matrix metalloproteinase (MMP)-9 from these cells.Many efforts have been devoted to understand the molecular mechanisms of invasion and metastasis in human cancers. 2 A number of molecules, including adhesion molecules, 3,4 metalloproteinases, 5 and angiogenic factors, 6 have been implicated as key players in invasion and metastasis. Hepatocellular carcinoma (HCC) is a very common malignancy and a major cause of cancer deaths in Asian countries. Although several molecules have also been involved in the metastatic process of HCC, 7-10 none of them has shown to be of great impact on the prognosis of this disease. It is, therefore, a matter of urgency to identify novel and effective prognostic indica...

Overexpression of miR-21 Promotes an In vitro Metastatic Phenotype by Targeting the Tumor Suppressor RHOB

“…This is consistent with earlier work that identified RECK as a tumor suppressor gene (27). In HCC, loss of RECK expression has been associated with poor prognostics (28). FIGURE 6.…”

Membrane type-matrix metalloproteinases and tumor progression

“…RECK is expressed in a variety of human tissues, but its expression is downregulated in many cancer cell lines and cancer tissues such as hepatocellular carcinoma [176] and pancreatic cancer [177]. RECK-/-mouse have disrupted vascular development, neural tube and mesenchymal tissues integrity and die at embryonic day 10.5 [178].…”

Matrix metalloproteinase inhibitor reversion‐inducing cysteine‐rich protein with Kazal motifs

“…6 -8 In support of this hypothesis, increased transcriptional expression of RECK in tumor cells compared with concomitant normal tissue cells was correlated with prolonged survival in patients with hepatocellular carcinoma (HCC). 9 Remarkably, an adverse prognosis of patients with breast carcinoma whose tumors expressed high levels of the secreted MMP inhibitors TIMP-1 10 -13 or TIMP-2 11,14 has been reported. The expression pattern and functional role of RECK in breast carcinoma currently is unknown.…”