scholarly journals Pregnancy-associated plasma protein A mRNA expression as a marker for differentiated thyroid cancer: results from a “surgical” and a “cytological” series

2021 ◽  
Author(s):  
C. Marzocchi ◽  
M. Capezzone ◽  
A. Sagnella ◽  
A. Cartocci ◽  
M. Caroli Costantini ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Mrna Expression ◽  
Plasma Protein ◽  
Differentiated Thyroid Cancer ◽  
Binding Protein ◽  
Protein A ◽  
Needle Aspiration ◽  
Normal Tissues ◽  
Igf Binding ◽  
Igf Binding Protein

Abstract Purpose Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase initially described for its role during pregnancy. PAPPA regulates IGF ligands 1 (IGF1) bioavailability through the degradation of IGF-binding protein 4 (IGFBP4). After the cleavage of IGFBP4, free IGF1 is able to bind IGF1 receptors (IGF1R) triggering the downstream signaling. Recently, PAPPA expression has been linked with development of several cancers. No data have been published on thyroid cancer, yet. Methods We evaluated PAPPA, insulin-like growth factor (IGF1), IGF1 receptors (IGF1R) and IGF-binding protein 4 (IGFBP4) mRNA expression levels in a “Surgical series” of 94 thyroid nodules (64 cancers, 16 follicular adenomas and 14 hyperplastic nodules) and in a “Cytological series” of 80 nodules from 74 patients underwent to fine-needle aspiration cytology (FNAC). In tissues, PAPPA was also evaluated by western blot. Results We found that PAPPA expression was increased in thyroid cancer specimen at mRNA and protein levels and that, adenomas and hyperplastic nodules had an expression similar to normal tissues. When applied on thyroid cytologies, PAPPA expression was able to discriminate benign from malignant nodules contributing to pre-surgical classification of the nodules. We calculated a cut-off with a good specificity (91%) which reached 100% when combined with molecular biology. Conclusion These results show that PAPPA could represent a promising diagnostic marker for differentiated thyroid cancer.

scholarly journals Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease

2017 ◽  
Vol 102 (9) ◽  
pp. 3526-3534 ◽  
Author(s):  
Ulrick Skipper Espelund ◽  
Mette Bjerre ◽  
Rikke Hjortebjerg ◽  
Torben Riis Rasmussen ◽  
Anders Lundby ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pleural Fluid ◽  
Plasma Protein ◽  
Binding Protein ◽  
Protein A ◽  
Insulin Like Growth Factor ◽  
Igf System ◽  
Igf Binding ◽  
Stanniocalcin 2 ◽  
Igf Binding Protein

Abstract Context Members of the insulin-like growth factor (IGF) system are primarily produced in the liver and secreted into the circulation, but they are also produced, recruited, and activated locally in tissues. Objective To compare activity and concentrations of IGF system components in pleural fluid and blood. Design Pathological pleural fluid, secondary to lung cancer or nonmalignant disease, and matching blood samples were collected from 24 patients ages 66.7 to 81.9 years. Methods IGF-related proteins and cytokine levels were measured by immunoassays or immunoblotting. Bioactive IGF was measured by an IGF-1 receptor phosphorylation assay. Results Total IGF-1 concentration did not differ between the compartments, but concentrations of free IGF-1 and bioactive IGF were more than threefold higher in pleural fluid than in corresponding serum samples (P = 0.0004), regardless of etiology. Median pregnancy-associated plasma protein-A (PAPP-A) and interleukin (IL)-6 levels were increased 47-fold and 143-fold, respectively, in pleural fluid compared with plasma (P < 0.0001). PAPP-A and IL-6 concentrations correlated positively (r = 0.46; P = 0.02). In pleural fluid, levels of PAPP-A–generated IGF binding protein-4 fragments correlated inversely with that of stanniocalcin-2 (r ≤ −0.42; P ≤ 0.05), a PAPP-A inhibitor; such correlations were absent in plasma. Conclusion Pathological pleural fluid is characterized by increased in vitro IGF bioactivity and elevated concentrations of PAPP-A, an IGF-activating proteinase. Thus, the tissue activity of the IGF system may differ substantially from that of the circulating IGF system. The correlation between IL-6 and PAPP-A indicates that inflammation plays a role in promoting local tissue IGF activity.

Depot-specific and GH-dependent regulation of IGF binding protein-4, pregnancy-associated plasma protein-A, and stanniocalcin-2 in murine adipose tissue

2018 ◽  
Vol 39 ◽  
pp. 54-61 ◽  
Author(s):  
Rikke Hjortebjerg ◽  
Darlene E. Berryman ◽  
Ross Comisford ◽  
Edward O. List ◽  
Claus Oxvig ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasma Protein ◽  
Binding Protein ◽  
Protein A ◽  
Igf Binding ◽  
Stanniocalcin 2 ◽  
Igf Binding Protein

IGF dependent modulation of IGF binding protein (IGFBP) proteolysis by pregnancy-associated plasma protein-A (PAPP-A): Multiple PAPP-A–IGFBP interaction sites

2013 ◽  
Vol 1830 (3) ◽  
pp. 2701-2709 ◽  
Author(s):  
Ervinas Gaidamauskas ◽  
Claus Gyrup ◽  
Henning B. Boldt ◽  
Vivien R. Schack ◽  
Michael T. Overgaard ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Binding Protein ◽  
Protein A ◽  
Interaction Sites ◽  
Igf Binding ◽  
Igf Binding Protein

scholarly journals Actions of GnRH antagonists on IGF-II, IGF-binding protein-2 and pregnancy-associated plasma protein-A in human granulosa-lutein cells

2003 ◽  
pp. 31-37 ◽  
Author(s):  
JM Weiss ◽  
B Krautmacher ◽  
S Polack ◽  
K Diedrich ◽  
O Ortmann
Keyword(s):  
Plasma Protein ◽  
Ovarian Function ◽  
Binding Protein ◽  
Protein A ◽  
University Hospital ◽  
Gnrh Antagonists ◽  
Cell Culture Study ◽  
Igf System ◽  
Igf Binding ◽  
Igf Binding Protein

OBJECTIVE: Recently, GnRH antagonists (GnRHants) have been introduced for the prevention of premature LH surges during controlled ovarian hyperstimulation (COH). Here we investigated whether the GnRHants cetrorelix and ganirelix exert effects on the human ovarian IGF system. Since controversy exists on the action of GnRH agonists in the human ovary, we also tested the effect of triptorelin on IGF-II, IGF-binding protein-2 (IGFBP-2) and pregnancy-associated plasma protein-A (PAPP-A) in cultured human granulosa-lutein cells. DESIGN: In vitro cell culture study in a research laboratory of a university hospital. PATIENTS: Cells were obtained from patients treated with different protocols of COH. In addition to gonadotropins they received triptorelin or cetrorelix. Cells were treated with triptorelin, cetrorelix or ganirelix, 1 nmol/l each, for 48 h. IGF-II, IGFBP-2 and PAPP-A were measured by RIA and enzyme immunoassay respectively. RESULTS: GnRHants and triptorelin did not affect IGF-II, IGFBP-2 or PAPP-A. CONCLUSIONS: We conclude that GnRHants do not exert any significant effects on the IGF system of granulosa-lutein cells and therefore their introduction into protocols of COH is unlikely to impair ovarian function.

scholarly journals Selection of the Dominant Follicle and Insulin-Like Growth Factor (IGF)-Binding Proteins: Evidence that Pregnancy-Associated Plasma Protein A Contributes to Proteolysis of IGF-Binding Protein 5 in Bovine Follicular Fluid

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 437-446 ◽  
Author(s):  
G. M. Rivera ◽  
J. E. Fortune
Keyword(s):  
Proteolytic Activity ◽  
Plasma Protein ◽  
Follicular Fluid ◽  
Binding Proteins ◽  
Protein A ◽  
Positive Control ◽  
Dominant Follicle ◽  
Igf Binding Proteins ◽  
Igf Binding ◽  
Igf Binding Protein

Development of a dominant follicle is associated with decreased intrafollicular low molecular weight IGF-binding proteins (namely IGFBP-2, -4, and -5) and increased proteolysis of IGFBP-4 by pregnancy-associated plasma protein A (PAPP-A). In addition to IGFBP-4 proteolytic activity, bovine follicular fluid contains strong proteolytic activity for IGFBP-5, but not for IGFBP-2. Here we show that the IGFBP-5 protease present in bovine follicular fluid is a neutral/basic pH-favoring, Zn2+ metalloprotease very similar to the previously described IGFBP-4 protease. We hypothesized that immunoneutralization and immunoprecipitation with anti-PAPP-A antibodies would result in abrogation of the IGFBP-4, but not the IGFBP-5, proteolytic activity in follicular fluid. As expected, anti-PAPP-A antibodies were able to neutralize and precipitate the IGFBP-4, but not the IGFBP-5, proteolytic activity of human pregnancy serum, which was used as a positive control for PAPP-A. Surprisingly, immunoneutralization and immunoprecipitation of follicular fluid from bovine preovulatory follicles with anti-PAPP-A antibodies abrogated both IGFBP-4 and IGFBP-5 proteolysis. Quantitative results derived from phosphorimaging revealed a complete inhibition of both IGFBP-4 and -5 proteolysis by follicular fluid incubated for 2 or 5 h in the presence of anti-PAPP-A antibodies. After 18 h of incubation, anti-PAPP-A antibodies still inhibited IGFBP-5 degradation, although with an efficiency lower than that for IGFBP-4 degradation. Both proteolytic activities have identical electrophoretic mobility, and a single band (∼400 kDa) was detected by Western immunoblotting of bovine follicular fluid with anti-PAPP-A antibodies. Proteolysis of IGFBP-5 was readily detectable in follicular fluid from dominant follicles and was negligible in subordinate follicles from the same cohort. These results suggest that an active intrafollicular IGFBP-4/-5 proteolytic system, in which PAPP-A is the major protease involved, is an important determinant of follicular fate.

scholarly journals Proteolytic degradation of IGF-binding protein (IGFBP)-2 in equine ovarian follicles: involvement of pregnancy-associated plasma protein-A (PAPP-A) and association with dominant but not subordinated follicles

2004 ◽  
Vol 182 (3) ◽  
pp. 457-466 ◽  
Author(s):  
N Gerard ◽  
T Delpuech ◽  
C Oxvig ◽  
MT Overgaard ◽  
P Monget
Keyword(s):  
Proteolytic Activity ◽  
Plasma Protein ◽  
Follicular Fluid ◽  
Protein A ◽  
Binding Domain ◽  
Proteolytic Degradation ◽  
Heparin Binding ◽  
Heparin Binding Domain ◽  
Igf Binding ◽  
Igf Binding Protein

In the ovary of mammalian species, terminal follicular growth is accompanied by a decrease in intrafollicular levels of IGF-binding protein-2 (IGFBP-2) and IGFBP-4. The decrease in IGFBP-4 levels is essentially due to an increase in proteolytic cleavage by intrafollicular pregnancy-associated plasma protein-A (PAPP-A) in growing healthy follicles. The decrease in IGFBP-2 levels is partly due to a decrease in mRNA expression by follicular cells. In addition, we have recently shown that IGFBP-2 is also proteolytically cleaved by PAPP-A in bovine and porcine growing follicles. In the present work, we showed that follicular fluid from late dominant equine follicles (35 mm diameter) contains a proteolytic activity against IGFBP-2. First follicular fluid from dominant follicles contained lower levels of native IGFBP-2 than the corresponding serum, as assessed by Western ligand blotting. In contrast, immunoblotting experiments showed much higher levels of a 12 kDa proteolytic fragment in dominant follicular fluid than in the serum. Moreover, equine dominant follicular fluid was able to induce proteolysis of exogenous recombinant bovine (rb)IGFBP-2, this degradation being dose-dependently enhanced by IGFs. The proteolytic activity against IGFBP-2 in equine follicles was partially immunoneutralized by a polyclonal antibody raised against human PAPP-A. Moreover, cleavage of rbIGFBP-2 by equine follicular fluid was dose-dependently inhibited by a peptide derived from the heparin-binding domain of IGFBP-5, as well as by peptides derived from other heparin-binding domain-containing proteins such as connective tissue growth factor, vitronectin and heparin-interacting protein, previously shown to inhibit PAPP-A. Finally, the proteolytic activity was very low in subordinate follicles, was high in both early (25 mm diameter) and late (35 mm diameter) dominant follicles, and was slightly lower in preovulatory follicles recovered 35 h after human chorionic gonadotropin (hCG) treatment.Overall, these data show that in the equine ovary, the selection of dominant follicles is associated with an increase of the proteolytic degradation of IGFBP-2 by PAPP-A, as for IGFBP-4, and potentially other protease(s), probably contributing to the increase in IGF bioavailability. In atretic subordinate follicles, the decrease in the proteolytic degradation of IGFBP-2, probably due in part to a direct inhibition by peptides containing heparin-binding domains, contributes to the increase in IGFBP-2 levels and the decrease in IGF bioavailability. The expression of PAPP-A and IGFBP-2 mRNA during folliculogenesis remain to be investigated in the mare.

scholarly journals The ovarian expression of mRNAs for aromatase, IGF-I receptor, IGF-binding protein-2, -4 and -5, leptin and leptin receptor in cycling ewes after three days of leptin infusion

Reproduction ◽  
2005 ◽  
Vol 130 (6) ◽  
pp. 869-881 ◽  
Author(s):  
M Muñoz-Gutiérrez ◽  
P A Findlay ◽  
C L Adam ◽  
G Wax ◽  
B K Campbell ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Granulosa Cells ◽  
Leptin Receptor ◽  
Binding Protein ◽  
Control Group ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Oestradiol Production

An experiment was carried out to determine the pattern of follicular expression of mRNAs for aromatase, IGF-I receptor (IGF-IR), IGF-binding protein (IGFBP)-2, -4 and -5, leptin and the long form of the leptin receptor (Ob-Rb) in ten ewes infused with human recombinant leptin (n= 5; 1 μg/h) or saline (n= 5) for 72 h in the luteal phase of the oestrous cycle. At the end of infusion a follicular phase was induced with a luteolytic dose of a prostaglandin F2α analogue and the ovaries were collected 32 h later. One ovary from each ewe was serially sectioned at 10 μm using a cryostat at −20 °C. All follicles >1 mm in diameter were counted and probed with specific oligoprobes for aromatase, IGF-IR and IGFBP-2, -4 and -5 and specific riboprobes for leptin and Ob-Rb. Leptin mRNA was detected in theca and granulosa cells and Ob-Rb mRNA was detected only in granulosa cells, of some, but not all antral follicles. Leptin doubled the number of follicles with a diameter ≥3.5 mm (1.0 ± 0.36 (s.e.m.) vs 2.4 ± 0.24; control vs leptin;P< 0.02) but had no effect on the number of ≥1 < 3.5 mm follicles. Leptin had no effect on the number of follicles expressing aromatase mRNA but it decreased significantly the number of follicles expressing mRNA for IGF-IR (10.7 ± 0.79 vs 7.4 ± 0.81; control vs leptin;P< 0.05), IGFBP-2 (10.0 ± 0.82 vs 5.2 ± 0.87; control vs leptin;P< 0.05) and IGFBP-5 (5.2 ± 1.60 vs 1.2 ± 0.30; control vs leptin;P< 0.05). Leptin increased the diameter of IGFBP-2 mRNA-positive follicles (1.5 ± 0.15 vs 2.2 ± 0.31 mm; control vs leptin;P< 0.05) and increased follicular mRNA expression for IGFBP-2 (0.30 ± 0.021 vs 0.39 ± 0.027 arbitrary units; control vs leptin;P< 0.05) and IGFBP-5 (0.46 ± 0.019 vs 0.25 ± 0.053 arbitary units; control vs leptin;P< 0.05). The mRNA for IGFBP-4 was detected in the theca of only two follicles from the control group. Leptin increased the number of follicles expressing Ob-Rb mRNA (0.25 ± 0.25 vs 1.40 ± 1.17; control vs leptin;P< 0.05) but had no effect on the number expressing leptin mRNA. Leptin decreased plasma concentrations of oestradiol (P< 0.05) and increased concentrations of FSH (P< 0.001) and insulin (P< 0.001), with no effect on glucose concentrations. These data show that: (i) ovine granulosa cells express mRNA for Ob-Rb and leptin and (ii) leptin increased the number of follicles ≥3.5 mm. Furthermore, the data suggest that suppression of oestradiol production by leptin is not mediated by inhibition of aromatase gene expression. Finally, the data indicate that the action of leptin in ovarian follicles is mediated by the IGF system, because leptin increased mRNA expression of IGFBP-2 and -5. Leptin also decreased the number of follicles expressing IGF-IR and IGFBP-2 and -5. We suggest that these actions of leptin on the IGF system decrease the bioavailability of IGF-I, resulting in decreased oestradiol production.

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