Growth Differentiation Factor 15 Overexpression Research Articles

Growth differentiation factor 15 promotes cell viability, invasion, migration, and angiogenesis in human liver carcinoma cell line HepG2

This study was aimed to explore the role of growth differentiation factor 15 (GDF15) in hepatocellular carcinoma (HCC). Human liver carcinoma cell line HepG2 was used and transfected with vector and/or short hairpin RNA (shRNA) against GDF15. Then, the transfection efficiency was ascertained by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Cell viability was measured by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide (MTT). Cell invasion and migration were measured by Transwell assay and Scratch assay. In addition, human umbilical vein endothelial cell (HUVEC) tube formation assay was performed to analysis the angiogenesis. Further, the protein expressions of epithelial-mesenchymal transition (EMT)-related factors were measured by Western blot. We found that GDF15 overexpression significantly facilitated cell viability, cell invasion, migration, and angiogenesis (P<0.05 or P<0.01). The protein expressions of N-Cadherin, Vimentin and Twist1 were up-regulated by GDF15 overexpression, while E-Cadherin was down-regulated. Reciprocally, using a GDF15-shRNA strategy, we observed that GDF15 downregulation inhibited both basal and GDF15-induced cell viability, migration, invasion and angiogenesis in HepG2 cells. GDF15 could promote cell viability, invasion, migration, and angiogenesis of HepG2 cells. GDF15 overexpression might be a potential risk factor of HCC.

P38 MAPK Contributes to Resistance and Invasiveness of HER2- Overexpressing Breast Cancer

Intrinsic or acquired resistance to the HER2-targeted therapy trastuzumab is a clinical concern in the treatment of patients with HER2-over-expressing metastatic breast cancers. We demonstrate here that multiple models of intrinsic and acquired resistance exhibit increased phosphorylation of p38 MAPK. Kinase inhibition of p38 rescued trastuzumab sensitivity in cells with acquired resistance. In addition, knockdown of p38 increased sensitivity to trastuzumab in an intrinsically resistant cell line. We previously reported that expression of growth differentiation factor 15 (GDF15) is increased in trastuzumab-resistant HER2-overexpressing breast cancer cells. In this study, we found that exogenous GDF15 or stable overexpression of GDF15 stimulated p38 phosphorylation in HER2-positive cells, suggesting a possible mechanism by which p38 is activated in resistant cells.GDF15 stable clones showed significantly increased invasiveness, which was rescued by p38 kinase inhibition, suggesting that p38 plays a role in the pro-invasive phenotype conferred by GDF15. Importantly, immunohistochemical analysis of a breast tumor tissue array indicated a significant (p=0.0053) correlation between HER2 and phosphorylated p38 specifically in GDF15-positive tissues. Our results suggest that p38 signaling drives trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer. Upstream growth factor signals that have previously been implicated in trastuzumab resistance, such as GDF15, may contribute to the increased phosphorylation of p38 found in resistant cells.

Growth differentiation factor-15 as a prognostic biomarker in ovarian cancer

Objectives There is a need for identification of new biomarkers improving our understanding, diagnosis, and follow-up of ovarian cancer. Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily, and GDF-15 overexpression has been found in several cancer forms but has not been explored in ovarian cancer. The aim of the study was to explore preoperative plasma concentration and tissue expression of growth differentiation factor (GDF)-15 in ovarian tumors. Methods GDF-15 concentration was measured by immunoradiometric assay in plasma samples from patients with invasive ovarian cancer ( n = 125), borderline ovarian tumor (BOT, n = 43), and benign ovarian tumor ( n = 144), from healthy women ( n = 40), as well as in effusion samples ( n = 44) from women with advanced ovarian cancer. Sections of ovarian carcinoma ( n = 20), BOT ( n = 9), and cystadenoma ( n = 7) were immunostained for GDF-15. Results Median plasma GDF-15 concentration was elevated in ovarian cancer as compared to healthy controls and women with benign ovarian tumors or BOT ( p < 0.001). GDF-15 plasma concentration correlated inversely with survival time and was an independent predictor of survival, after correction for FIGO stage and age ( p = 0.01). GDF-15 protein was cytoplasmatically expressed in serous tumor cells and detectable in high concentrations in effusion samples. Conclusion GDF-15 emerges as a new potential biomarker in ovarian cancer.

Behavioral, biochemical, and genetic analysis of iron metabolism in high‐intensity blood donors

Individuals donating whole blood 13 times in a 2-year period without development of iron deficiency anemia (superdonors) are a self-selected population that is deferred for low hematocrit (Hct) level less frequently than other donors. Iron metabolism was assessed in 138 superdonors through a questionnaire and measurement of Hct, serum ferritin, serum hepcidin, and serum growth differentiation factor 15 (GDF15). Genetic testing for HFE and JAK-2 mutations was also performed. Iron deficiency (ferritin level, <30 microg/L) is present in more than 60 percent of superdonors. Behaviors altering iron status included casual use of iron supplements in males, but not in females, and cigarette smoking that produced increased Hct associated with decreased ferritin. The striking biochemical characteristic of superdonors is greatly decreased serum hepcidin, consistent with their need to absorb maximal amounts of dietary iron to replace that lost from blood donation. GDF15 is normal in most superdonors, indicating that GDF15 overexpression arising from the expanded erythroid pool necessary to replace donated red cells is not the biochemical mechanism for the decreased serum hepcidin. Mutations in JAK-2 were not found, indicating that undiagnosed polycythemia vera is not a common cause for successful repeated blood donation by superdonors. Mutations in HFE associated with hemochromatosis were present in superdonors at the same frequency as the normal population. However, superdonors heterozygous for the H63D mutation in HFE had significantly decreased hepcidin : ferritin ratios demonstrating for the first time that the heterozygous state for HFE mutations is associated with alterations in hepcidin expression.

High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin

In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.