Expression and Functional Significance of HtrA1 Loss in Endometrial Cancer

Abstract

Purpose: The purpose of this study was to determine if loss of serine protease HtrA1 in endometrial cancer will promote the invasive potential of EC cell lines.Experimental design: Western blot analysis and immunohistochemistry methods were used to determine HtrA1 expression in EC cell lines and primary tumors, respectively. Migration, invasion assays and in vivo xenograft experiment were performed to compare the extent of metastasis between HtrA1 expressing and HtrA1 knocked down clones.Results: Western blot analysis of HtrA1 in 13 EC cell lines revealed complete loss of HtrA1 expression in all seven papillary serous EC cell lines. Downregulation of HtrA1 in Hec1A and Hec1B cell lines resulted in a three-to fourfold increase in the invasive potential. Exogenous expression of HtrA1 in Ark1 and Ark2 cells resulted in three-to fourfold decrease in both invasive and migration potential of these cells. There was an increased rate of metastasis to the lungs associated with HtrA1 downregulation in Hec1B cells compared to control cells with endogenous HtrA1 expression. Enhanced expression of HtrA1 in Ark2 cells resulted in significantly less tumor nodules metastasizing to the lungs compared to parental or protease deficient (SA mutant) Ark2 cells. Immunohistochemical analysis showed 57% (105/184) of primary EC tumors had low HtrA1 expression. The association of low HtrA1 expression with high-grade endometrioid tumors was statistically significant (P ¼ 0.016).Conclusions: Collectively, these data indicate loss of HtrA1 may contribute to the aggressiveness and metastatic ability of endometrial tumors.

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis

“…The decrease in expression of these proteins in breast cancer has been previously described as conferring a selective advantage to cancer cells resulting in a more aggressive phenotype. [33][34][35] The reduced expression of fibulin-1 and Sushi domain-containing protein 2 (SUSD2) in bone metastatic cells was consistent with the previously reported role of these proteins in the reduction of cancer cell migration and invasion. 36,37 We were particularly interested in the differential expression of SUSD2 because its gene has been isolated only recently 37 and its expression in breast cancer has never been reported.…”

Decrease in serine protease HtrA1 expression correlates with grade and recurrence in meningiomas

“…Wang et al reported a significant reduction in HtrA1 expression in breast cancer cell lines compared with their non-tumorigenic counterparts [8]. Downregulation of HtrA1 was also demonstrated by immunohistochemical (IHC) studies in endometrial, esophageal, lung, breast and hepatocellular carcinomas [7,[9][10][11][12][13]. In mesothelioma HtrA1 was suggested as an IHC marker influencing the overall survival [14].…”

Survival benefits in colorectal adenocarcinoma with the use of metformin among a black diabetic inner city population

“…One study has shown that combinatorial treatment of metformin and the chemotherapeutic doxorubicin leads to death of both CSCs and nonstem cancer cells in culture and prolonged relapse rate in a mouse xenograft model of breast cancer cells [23]. Similar promising findings have been seen with other chemotherapeutic agents such as paclitaxel and cisplatin [24,25]. Moreover, CSCs in CRC are CD133 high/CD44 high expressing and exhibit radiation resistance, further investigation is needed to examine the effect of metformin use in patients treated with neoadjuvant or adjuvant chemotherapy on both mortality and relapse rate [26].…”