HtrA3 Is Downregulated in Cancer Cell Lines and Significantly Reduced in Primary Serous and Granulosa Cell Ovarian Tumors

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.

Structural insights into the activation mechanisms of human HtrA serine proteases

“…[4]). Moreover, in ovarian and thyroid cancers the HtrA3L and HtrA3S variants were expressed differentially [22,76]. Thus, the HtrA3 expression depends on cancer type.…”

The HtrA3 protease promotes drug‐induced death of lung cancer cells by cleavage of the X‐linked inhibitor of apoptosis protein (XIAP)

“…Deregulation of the HtrA3 expression was correlated with oncogenesis. A decreased HtrA3 expression level was found in the primary tumors of ovary [14,16,21], endometrium [13] and lung [5,22]. In the ovarian [14,21] and endometrial [13] cancers the HtrA3 expression decreased as the degree of malignancy increased, and in approximately 30% of the ovarian malignant tumors the HtrA3 protein was undetectable [14].…”

Activins and activin antagonists in the human ovary and ovarian cancer

“…Messenger RNA for the HTRA-1, -2 and -3 genes is expressed in GCT and epithelial ovarian tumour cells with evidence that HTRA expression is down-regulated in these cancer cells when compared to normal ovarian tissue (Chien et al, 2004;Narkiewicz et al, 2008;Singh et al, 2013). Knock-down of HTRA1 in the epithelial tumour line SKOV3, resulted in an increase of anchorage-independent cell growth (Chien et al, 2004).…”