Changes in expression of human serine protease HtrA1, HtrA2 and HtrA3 genes in benign and malignant thyroid tumors

Abstract

Human HtrA proteins are serine proteases involved in essential physiological processes. HtrA1 and HtrA3 function as tumor suppressors and inhibitors of the TGF-β signaling pathway. HtrA2 regulates mitochondrial homeostasis and plays a pivotal role in the induction of apoptosis. The aim of the study was to determine whether the HtrA proteins are involved in thyroid carcinogenesis. We used the immunoblotting technique to estimate protein levels of HtrA1, HtrA2, long and short variants of HtrA3 (HtrA3-L and HtrA3-S) and TGF-β1 in tissues of benign and malignant thyroid lesions, and control groups. We found that the levels of HtrA2 and HtrA3-S were higher in thyroid malignant tumors compared to normal tissues and benign tumors. The HtrA3-L level was increased in malignant tumor tissues compared to benign tumor tissues and control tissues from patients with benign lesions, and elevated in normal tissues from patients with thyroid carcinoma compared to normal tissues from patients with benign lesions. We also compared levels of HtrA proteins in follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) and found that these types of carcinoma differed in the expression of HtrA3-S and HtrA1. These results indicate the implication of HtrA proteins in thyroid carcinogenesis suggest that HtrA3 variants may play different roles in cancer development, and that the increased HtrA3-L levels in thyroid tissue could be correlated with the development of malignant lesions. The TGF-β1 levels in tumor tissues were not significantly altered compared to control tissues.

HtrA1: Its future potential as a novel biomarker for cancer

“…Zurawa-Janicka et al ( 49 ) assessed HtrA1 in tissue extracts from 40 subjects; 20 with normal thyroid and 20 with follicular (n=12) or papillary (n=8) tumors using WB. Protein band intensities assessed by densitometry yielded relative values.…”

Structural insights into the activation mechanisms of human HtrA serine proteases

“…These results indicate that the PDZ domain is not required for proteolysis and in this respect HtrA3 resembles HtrA1 [109]. Interestingly, proteolysis of a peptide substrate by purified HtrA3 showed typical Michaelis-Menten kinetics [133], suggesting a lack of the intersubunit cooperation typical for allosteric enzymes, including human HtrA2 [76]. However, existence of an unknown so far allosteric regulator of HtrA3 can not be excluded.…”

“…[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.…”

Molecular structure and the role of high‐temperature requirement protein 1 in skeletal disorders and cancers

“…Subsequent studies have also reported that HTRA1 expression is decreased in different types of cancers, including metastatic cancers. [47][48][49][50][51][52] An early study on ovarian cancer has suggested a high frequency of loss of heterozygosity near HTRA1 may be associated with its decreased 54 Inhibitory effects of HTRA1 on Wnt signalling is protease-independent and may be associated with TGF-β signalling. 54 Down-regulation of HTRA1 in endometrial cancer has shown increased invasive and metastatic ability in tumour cells.…”