Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

Hjortebjerg, Rikke; Espelund, Ulrick; Rasmussen, Torben Riis; Folkersen, Birgitte Holst; Steiniche, Torben; Georgsen, Jeanette Bæhr; Oxvig, Claus; Frystyk, Jan

doi:10.3389/fendo.2020.00614

Cited by 5 publications

(6 citation statements)

References 48 publications

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“…Pappalysin 2 (PAPPA2) is a protein-encoding gene associated with several disorders, including Down's syndrome and HELLP syndrome. High expression of PAPPA2 is associated with mortality in lung cancer patients (26). Coincidentally, PAPPA2 is also associated with multiple immune cell types in gastric cancer, similar to the present study, in which PAPPA2 exhibited a positive correlation with activated mast cells, eosinophils, and activated memory CD4 T cells, and negative correlation with macrophage M0, macrophage M1, and CD8 T cells.…”

Section: Discussionsupporting

confidence: 88%

Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

et al. 2021

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IntroductionGastric cancer is one of the most common malignant tumors of the digestive tract. However, there are no adequate prognostic markers available for this disease. The present study used bioinformatics to identify prognostic markers for gastric cancer that would guide the clinical diagnosis and treatment of this disease.Materials and MethodsGene expression data and clinical information of gastric cancer patients along with the gene expression data of 30 healthy samples were downloaded from the TCGA database. The initial screening was performed using the WGCNA method combined with the analysis of differentially expressed genes, which was followed by univariate analysis, multivariate COX regression analysis, and Lasso regression analysis for screening the candidate genes and constructing a prognostic model for gastric cancer. Subsequently, immune cell typing was performed using CIBERSORT to analyze the expression of immune cells in each sample. Finally, we performed laboratory validation of the results of our analyses using immunohistochemical analysis.ResultsAfter five screenings, it was revealed that only three genes fulfilled all the screening requirements. The survival curves generated by the prognostic model revealed that the survival rate of the patients in the high-risk group was significantly lower compared to the patients in the low-risk group (P-value < 0.001). The immune cell component analysis revealed that the three genes were differentially associated with the corresponding immune cells (P-value < 0.05). The results of immunohistochemistry also support our analysis.ConclusionCGB5, MKNK2, and PAPPA2 may be used as novel prognostic biomarkers for gastric cancer.

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Section: Discussionsupporting

confidence: 88%

Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

et al. 2021

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“…The PAPP-As are responsible for the proteolytic cleavage of specific IGFBPs, through which they increase tissue concentrations of free IGF, which becomes available for receptor activation [17][18][19]. In breast cancer, an elevated serum PAPP-A has been shown to be associated with low recurrence-free and overall survival [20], and recently, we demonstrated that serum PAPP-A2 is higher in patients with lung cancer and predictive of all-cause mortality [13]. In 2015, stanniocalcin-1 (STC1) and -2 (STC2) were discovered as potent inhibitors of PAPP-A and PAPP-A2 [21,22].…”

Section: Introductionmentioning

confidence: 94%

“…Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 constitute the pappalysin family of metalloproteases [11]. They have been shown to play key roles in regulating IGF signaling in cancers [12][13][14][15][16]. The PAPP-As are responsible for the proteolytic cleavage of specific IGFBPs, through which they increase tissue concentrations of free IGF, which becomes available for receptor activation [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

The IGF–PAPP-A–Stanniocalcin Axis in Serum and Ascites Associates with Prognosis in Patients with Ovarian Cancer

Hjortebjerg,

Høgdall,

Hansen

et al. 2024

IJMS

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Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 women with ovarian cancer and ascites accumulation, we determined corresponding serum and ascites levels of IGF-1, IGF-2, PAPP-A, PAPP-A2, STC1, and STC2 and assessed their relationship with mortality. As compared to serum, we found highly increased ascites levels of PAPP-A (51-fold) and PAPP-A2 (4-fold). Elevated levels were also observed for IGF-1 (12%), STC1 (90%) and STC2 (68%). In contrast, IGF-2 was reduced by 29% in ascites. Patients were followed for a median of 38.4 months (range: 45 days to 8.9 years), during which 73 patients (68.2%) died. Overall survival was longer for patients with high serum IGF-1 (hazard ratio (HR) per doubling in protein concentration: 0.60, 95% CI: 0.40–0.90). However, patients with high ascites levels of IGF-1 showed a poorer prognosis (HR: 2.00 (1.26–3.27)). High serum and ascites IGF-2 levels were associated with increased risk of mortality (HR: 2.01 (1.22–3.30) and HR: 1.78 (1.24–2.54), respectively). Similarly, serum PAPP-A2 was associated with mortality (HR: 1.26 (1.08–1.48)). Our findings demonstrate the presence and activity of the IGF system in the local tumor ecosystem, which is likely a characteristic feature of malignant disease and plays a role in its peritoneal dissemination. The potential clinical implications are supported by our finding that serum levels of the proteins are associated with patient prognosis.

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“…In literature, the involvement of PAPPA in cancer development and progression has been explored in multiple cancer types supporting its possible role as oncogene. PAPPA is overexpressed in ovarian cancer [6], lung cancer [7], breast cancer [8], Ewing sarcoma [9], testicular and prostate cancer [10] and hepatocellular carcinoma [11]. Moreover, evidences suggest that PAPPA activity promotes cancer proliferation, invasion, migration and metastasis [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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

Marzocchi

Capezzone

Sagnella

et al. 2021

J Endocrinol Invest

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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.

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Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

Cited by 5 publications

References 48 publications

Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

The IGF–PAPP-A–Stanniocalcin Axis in Serum and Ascites Associates with Prognosis in Patients with Ovarian Cancer

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

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