Prostate CancerDecreased RECK Expression Indicating Proteolytic Imbalance in Prostate Cancer is Associated with Higher Tumor Aggressiveness and Risk of Prostate-Specific Antigen Relapse after Radical Prostatectomy
Introduction
Despite current improvements in diagnosis and therapy of prostate cancer (pCA), there are problems of overtreatment based on the absence of indicators to accurately predict the aggressiveness of pCA. The conventional prognostic markers like tumor stage, tumor grade, and preoperative prostate-specific antigen (PSA) show limited accuracy to predict the clinical outcome [1], [2]. Thus, the search for novel biomarkers that are capable of discriminating between pCA with low and high aggressiveness and recurrence potential is a compelling task to provide the opportunity of custom-made therapy. Tissue invasion and metastasis are essential alterations that occur in malignancy [3]. A dysbalance of matrix metalloproteinases (MMPs), promoting tumor invasion and metastasis, to their inhibitors is characteristic for pCA [4], [5], [6] and opens the possibility of counteracting MMPs with synthetic inhibitors [7], [8]. Consequently, we directed our efforts to the new endogenous MMP inhibitor RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), an inhibitor of MMP-2, MMP-9, and MT1-MMP.
RECK was originally found to suppress transformation in v-Ki-ras-transformed NIH3T3 fibroblasts. The glycoprotein RECK has serine protease inhibitor-like domains and a C-terminal tail of glycophosphatidylinositol anchoring the protein extracellularly to the cell membrane where it inhibits MMPs [9]. RECK −/− mouse embryos die with severe vascular disorders [10]. This finding agrees with the suppressive function of RECK on tumor angiogenesis and metastasis [9], [10]. RECK messenger RNA (mRNA) is expressed in different human organs and normal cell lines, but was not detected in several tumor cell lines [9]. Recent studies imply a predictive role for RECK in tumorigenesis. Its transcriptional level in human hepatocellular carcinomas correlated positively with the survival time of the patients and negatively with tumor invasion [11]. Similar results were shown in pancreatic adenocarcinomas [12]. Mammary carcinomas revealed decreased expression of RECK mRNA in comparison with normal breast tissue [13]. Patients with higher RECK expression showed a prolonged recurrence-free survival time. Likewise, immunohistochemical experiments on lung cancer and colorectal carcinomas suggested a prognostic role for RECK, because enhanced RECK expression correlated with less tumor angiogenesis and a better postoperative prognosis [14], [15], [16]. In colorectal cancer, RECK mRNA expression was negatively correlated to MMP-2 and positively associated with overall survival [17].
In view of these results and the rare data for RECK expression in pCA [18], we evaluated the significance of RECK in pCA. Our aim was to determine the expression of RECK at the transcriptional and translational levels, and to clarify the relationship of RECK expression with clinicopatholologic parameters of pCA to evaluate the validity of RECK as a diagnostic or prognostic marker.
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Patients
Two hundred forty-seven patients with pCA treated with radical prostatectomy at the Department of Urology, University Hospital Charité, between 1989 and 2001 were included in this study approved by the local ethics committee. Tumor stage was determined according to Union Internationale Contre le Cancer [19] and tumor grading according to Gleason [20]. Clinicopathologic characteristics are given in Table 1. The follow-up time was defined as the interval from the date of surgery to the latest
RECK mRNA expression
Matched samples of tumor and adjacent normal tissue were examined by quantitative RT-PCR from 15 patients (median age: 61, range: 47–70 years; mean preoperative PSA level: 11.5 μg/l, range 4.4–20.6 μg/l). The RNA quality did not differ different between the matched samples. The mean absorbance ratio at 260 to 280 nm was 2.00 (range: 1.88–2.06), and the mean RNA integrity number 7.89 (range: 7.0–8.8). Clinicopatholologic parameters were as follows: (all pM0; pN0) 9× pT2, 6× pT3; 10× R0, 5× R1; Gleason
Discussion
Consistent with the known function of RECK as a tumor suppressor [9], [26] we found a reduced expression of RECK in pCA, compared with matching normal prostate tissues, on mRNA as well as on protein level. The 24% decrease of RECK mRNA in our study corresponds to the decrease of about 40% and 56% in colorectal and breast cancer samples [13], [17]. After we had finished our experiments, downregulation of RECK transcripts was reported even for prostate carcinomas [18] but related to BPH only. We
Conclusion
Decreased RECK expression correlated with the aggressiveness of pCA and the PSA relapse-free time could become an adjunct biomarker in pCA patients of higher risk. That way RECK could contribute to improve the follow-up and treatment decision for these patients. Further studies are recommended to validate the RECK functionality in prostate tissue to use that molecule as basis for new potential preventive or therapeutic interventions in pCA.
Acknowledgements
This study was partly supported by the SONNENFELD-Stiftung.
We thank Britta Beyer for excellent technical assistance.
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2014, Modern PathologyReversion-inducing cysteine-rich protein with Kazal motif (RECK) expression: An independent prognostic marker of survival in colorectal cancer
2012, Human PathologyCitation Excerpt :These studies showed, for example, a down-regulation of RECK expression in pancreatic cancer, breast cancer, carcinoma of the bladder, prostate cancer, and non–small cell lung cancer [22-27]. Furthermore, RECK expression positively correlated with longer survival of patients with cancer in several publications: increased levels indicated a better prognosis, decreased levels a poorer prognosis [21-28]. In CRC, decreased expression and lower messenger RNA (mRNA) levels of RECK have been observed previously [29,30].
RECK Variants are Associated with Clinicopathological Features and Decreased Susceptibility in Mexican Patients with Colorectal Cancer
2022, Tohoku Journal of Experimental Medicine
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G.K. and K.J. shared senior authorship.