Baldi A, De Luca A, Morini M et al.The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 21:6684-6688

Laboratory 'C', CRS, Regina Elena Cancer Institute, Rome, Italy.
Oncogene (Impact Factor: 8.46). 10/2002; 21(43):6684-8. DOI: 10.1038/sj.onc.1205911
Source: PubMed


Differential gene expression of cell lines derived from a malignant melanoma or its autologous lymph node metastasis using cDNA arrays indicated down-regulation of PRSS11, a gene encoding the serine protease HtrA1, a homolog of the Escherichia coli protease HtrA, in the metastatic line. Stable PRSS11 overexpression in the metastatic cell line strongly inhibited proliferation, chemoinvasion and Nm23-H1 protein expression in vitro, as well as cell growth in vivo in nu/nu mice. A polyclonal anti-HtrA1 serum demonstrated a significantly higher expression in primary melanomas when compared to unrelated metastatic lesions in a human melanoma tissue array, and down-modulation of HtrA1 expression in autologous lymph node melanoma metastases in seven out of 11 cases examined. These results suggest that down-regulation of PRSS11 and HtrA1 expression may represent an indicator of melanoma progression.

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    • "Although some different mechanisms were suggested to be responsible by different studies, a modulation of HtrA1 protein levels was widely observed to have a therapeutic value in cancer. In a study of Baldi et al., forced re-expression of the protein product in metastatic cells was shown to be able to partly revert the phenotype in terms of cell proliferation and migration [16]. In another study, an increase in the proteolytic activity of HtrAs was reported to be beneficial in cancer treatment by stimulation of "
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    ABSTRACT: HtrA1 is a serine protease which was shown to be down-regulated in a variety of human cancers. It is considered to be a tumor suppressor and suggested as a prognostic marker and a therapeutic candidate. In order to investigate any possible implication of HtrA1 in meningioma we studied 100 cases. We used immunohistochemistry to determine HtrA1 expression in tumor tissue. Expression levels were evaluated with respect to tumor grade and recurrence. Our data revealed a strong association between decrease in HtrA1 expression and increase in meningioma grade (p=0.005). Most importantly, patients with higher HtrA1 expression had a lower rate of recurrence (p<0.001). According to our results HtrA1 appeared as an immunohistochemical marker to predict behaviour of the meningioma, mainly the recurrence. Although the exact mechanisms of HtrA1 are still largely unknown, we think that further in vivo and in vitro studies explaining the molecular targets of HtrA1 would have a great importance with regard to its role as a therapeutic agent for meningioma. Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
    Full-text · Article · Jan 2015 · Advances in Medical Sciences
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    • "HtrA1 is downregulated in SV40 transformed fibroblasts 9, 10. Several reports have indicated a tumor suppressive role for HtrA1 in breast, lymph node melanoma, ovarian and gastric cancers 21, 25-27. "
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    ABSTRACT: Objective. The high temperature requirement factor A3 (HtrA3) is a serine protease homologous to bacterial HtrA. Four human HtrAs have been identified. HtrA1 and HtrA3 share a high degree of domain organization and are downregulated in a number of cancers, suggesting a widespread loss of these proteases in cancer. This study examined how extensively the HtrA (HtrA1-3) proteins are downregulated in commonly used cancer cell lines and primary ovarian tumors. Methods. RT-PCR was applied to various cancer cell lines (n=17) derived from the ovary, endometrium, testes, breast, prostate, and colon, and different subtypes of primary ovarian tumors [granulosa cell tumors (n=19), mucinous cystadenocarcinomas (n=6), serous cystadenocarcinomas (n=8)] and normal ovary (n = 9). HtrA3 protein was localized by immunohistochemistry. Results. HtrA3 was extensively downregulated in the cancer cell lines examined including the granulosa cell tumor-derived cell lines. In primary ovarian tumors, the HtrA3 was significantly lower in serous cystadenocarcinoma and granulosa cell tumors. In contrast, HtrA1 and HtrA2 were expressed in all samples with no significant differences between the control and tumors. In normal postmenopausal ovary, HtrA3 protein was localized to lutenizing stromal cells and corpus albicans. In serous cystadenocarcinoma, HtrA3 protein was absent in the papillae but detected in the mesenchymal cyst wall. Conclusion. HtrA3 is more extensively downregulated than HtrA1-2 in cancer cell lines. HtrA3, but not HtrA1 or HtrA2, was decreased in primary ovarian serous cystadenocarcinoma and granulosa cell tumors. This study provides evidence that HtrA3 may be the most relevant HtrA associated with ovarian malignancy.
    Full-text · Article · Feb 2013 · Journal of Cancer
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    • "Fourth, positive, statistically significant relationships have been found between HtrA1 expression level and survival in patients with gastric cancer [18] and mesothelioma [9]. Fifth, overexpression of HtrA1 in a metastasis-competent melanoma cell line strongly inhibited proliferation and invasive capability, and reduced HtrA1 expression was related to progression of melanomas in patient samples [10]. Despite these correlations, the tumor suppressor function(s) of HtrA1 has not yet been definitively tested or proven in animal models. "
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    ABSTRACT: Expression of the serine protease HtrA1 is decreased or abrogated in a variety of human primary cancers, and higher levels of HtrA1 expression are directly related to better response to chemotherapeutics. However, the precise mechanisms leading to HtrA1 down regulation during malignant transformation are unclear. To investigate HtrA1 gene regulation in breast cancer, we characterized expression in primary breast tissues and seven human breast epithelial cell lines, including two non-tumorigenic cell lines. In human breast tissues, HtrA1 expression was prominent in normal ductal glands. In DCIS and in invasive cancers, HtrA1 expression was greatly reduced or lost entirely. HtrA1 staining was also reduced in all of the human breast cancer cell lines, compared with the normal tissue and non-tumorigenic cell line controls. Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines. To mechanistically examine the functional consequences of HtrA1 loss, we stably reduced and/or overexpressed HtrA1 in the non-tumorigenic MCF10A cell line. Reduction of HtrA1 levels resulted in the epithelial-to-mesenchymal transition with acquisition of mesenchymal phenotypic characteristics, including increased growth rate, migration, and invasion, as well as expression of mesenchymal biomarkers. A concomitant decrease in expression of epithelial biomarkers and all microRNA 200 family members was also observed. Moreover, reduction of HtrA1 expression resulted in activation of the ATM and DNA damage response, whereas overexpression of HtrA1 prevented this activation. Collectively, these results suggest that HtrA1 may function as a tumor suppressor by controlling the epithelial-to-mesenchymal transition, and may function in chemotherapeutic responsiveness by mediating DNA damage response pathways.
    Full-text · Article · Jun 2012 · PLoS ONE
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