Enhanced expression of a 35 kDa fragment of inter-alpha-trypsin inhibitor H4 in sera of healthy pregnant women and patients with hydatidiform mole

Abstract

BackgroundAccumulated data from previous studies appear to suggest a link between the overexpression of a 35 kDa fragment of serum inter-alpha-trypsin inhibitor H4 (ITIH4) with cancers that are associated with up-regulated levels of oestrogens. The truncated fragment was postulated to be a product of oestrogen-induced action of kallikrein on native ITIH4. The present lectin-based proteomic analyses were performed to assess the specificity of the 35 kDa fragment of ITIH4 as a potential cancer biomarker and determine whether it was also overexpressed in the sera of cancer-negative pregnant women who are known to have high levels of plasma oestrogens.ResultsOur results demonstrated that the 35 kDa fragment of ITIH4 was overexpressed in healthy pregnant women and patients with hydatidiform mole, relative to the controls. The serum oestradiol levels of both groups of pregnant subjects were also confirmed to be higher than those of the control women who were not pregnant.ConclusionsOverexpression of the 35 kDa fragment of ITIH4 was not restrictive to patients with cancers but also occurred in women who were pregnant and those diagnosed with hydatidiform mole. Our data implicate the limitation of the 35 kDa ITIH4 fragment as a cancer biomarker and its correlation with serum oestrogen levels.

iTRAQ-proteomics and bioinformatics analyses of mammary tissue from cows with clinical mastitis due to natural infection with Staphylococci aureus

“…APP including serum amyloid A, haptoglobin, alpha-1-acid glycoprotein, alpha-1-proteinase inhibitor (alpha-1-antitrypsin) and ITIH4 have been shown to increase in different inflammatory processes, in both in vivo and in vitro models, and involved several inflammatory diseases, such as Crohn’s disease and ulcerative colitis [ 39 – 41 ]. ITIH4 protein is a 120KD glycoprotein, which is prone to be cleaved to produce fragments of different length, such as 100 kDa and 35 kDa fragment, which have been identified as the biomarkers for Down syndrome [ 41 ], amyotrophic lateral sclerosis [ 42 ], and cancer [ 43 ]. A report showed that all heifers responded to the mastitis with increased ITIH4 concentrations [ 44 ].…”

Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer

“…Several methods, including lectin affinity chromatography [ 21 ] and lectin blotting [ 22 , 23 ], have earlier been used in studies identifying the composition of O- glycosylated proteins in sample fractions. However, these methods require substantial glycoprotein samples.…”

Opposing roles of inter-α-trypsin inhibitor heavy chain 4 in recurrent pregnancy loss

“…Furthermore, the high level of STAT3 expression in the luminal epithelium and stromal cells during pre-implantation period might be essential for establishing uterine receptivity [15]. ITI-H4 is the only member of the ITI family which harbors a kallikrein-released bradykinin-like domain in its C-terminal sequence, making its plasma kallikrein sensitive [16]. The cleaved form detected in the various subjects with enhanced estrogen levels may contribute to increased cleavage of ITI-H4 by elevating levels of circulating kallikrein in the serum [16].…”

“…ITI-H4 is the only member of the ITI family which harbors a kallikrein-released bradykinin-like domain in its C-terminal sequence, making its plasma kallikrein sensitive [16]. The cleaved form detected in the various subjects with enhanced estrogen levels may contribute to increased cleavage of ITI-H4 by elevating levels of circulating kallikrein in the serum [16]. In addition, plasma kallikrein is known to be expressed in hormone-dependent tissues such as the breast and ovary [17].…”