Gene Summary

Gene:GDF15; growth differentiation factor 15
Aliases: PDF, MIC1, PLAB, MIC-1, NAG-1, PTGFB, GDF-15
Summary:This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. [provided by RefSeq, Aug 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:growth/differentiation factor 15
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: GDF15 (cancer-related)

Glorie N, Baert T, VAN DEN Bosch T, Coosemans AN
Circulating Protein Biomarkers to Differentiate Uterine Sarcomas from Leiomyomas.
Anticancer Res. 2019; 39(8):3981-3989 [PubMed] Related Publications
Uterine sarcomas are rare but very aggressive. Uterine myomas, on the other hand, are the most common benign tumors of the uterus. Currently there is no diagnostic technique available to distinguish them with certainty. This study aimed to summarize the published literature concerning protein-based biomarkers in the peripheral blood that can assist in this difficult differential diagnosis. In total, 48 articles, published between 1990 and 2017, were included. Most studies (n=37) concerned soft tissue sarcomas, while 11 discussed uterine sarcomas specifically. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukins (IL), cancer antigen 125 (CA 125), lactate dehydrogenase, gangliosides (LDH) and growth differentiation factor 15 (GDF-15) are the most studied proteins in soft tissue sarcomas, including uterine sarcomas. Future research on improving sarcoma diagnosis should include these proteins.

Jia H, Xu M, Bo Y, et al.
Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac.
Life Sci. 2019; 230:89-96 [PubMed] Related Publications
AIMS: Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) is a key downstream gene of Ras pathway. Activation of Ras-ERK1/2 has been testified to be linked to the progression of diverse cancers. Nonetheless, whether Ras-ERK1/2-tumorigenic pathway is mediated by epigenetic factors remains indistinct. The purpose of the research attempted to disclose the functions of H2BK5ac in Ras-ERK1/2-evoked CRC cell phenotypes.
MATERIALS AND METHODS: Western blot assay was implemented for exploration of the relevancy between Ras-ERK1/2 and H2BK5ac. H2BK5Q was established and its functions in cell viability, colony formation and migration were appraised via utilizing MTT, soft-agar colony formation and Transwell assays. The mRNA and transcription of ERK1/2 downstream genes were estimated via RT-qPCR and ChIP assays. HDAC2 functions in SW48 cell phenotypes were evaluated after co-transfection with pEGFP-Ras
KEY FINDINGS: H2BK5ac expression was evidently repressed by Ras-ERK1/2 pathway in SW48 cells. Moreover, Ras-ERK1/2-elevated cell viability, the number of colonies and migration were both impeded by H2BK5ac. The mRNA and transcriptions of CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16 were both mediated by H2BK5ac. Additionally, HDAC2 silence overtly recovered H2BK5ac expression inhibited by Ras-ERK1/2, meanwhile abated Ras-ERK1/2-affected SW48 cell phenotypes. Beyond that, restrained H2BK5ac induced by Ras-ERK1/2 was concerned with MDM2-mediated ATF2 degradation.
SIGNIFICANCE: These investigations testified that Ras-ERK1/2 pathway affected SW48 cell phenotypes through repressing H2BK5ac expression. Otherwise, declined H2BK5ac might be linked to MDM2-mediated ATF2 degradation.

Duan L, Pang HL, Chen WJ, et al.
The role of GDF15 in bone metastasis of lung adenocarcinoma cells.
Oncol Rep. 2019; 41(4):2379-2388 [PubMed] Related Publications
Lung cancer is the most common malignant tumor in China. It often metastasizes to bone, thereby significantly shortening the lives of patients, and reducing their quality of life. However, the efficacy of treatment for bone metastasis of lung cancer at this stage is very limited. The development and clinical application of molecular‑targeted drugs for the effective targeted therapy of bone metastasis of lung cancer are urgently required. The growth differentiation factor 15 (GDF15) gene which may be associated with bone metastasis of lung cancer, was screened out by whole‑genome sequencing. In the present study, we used a recombinant GDF15 lentivirus technique to upregulate the expression of GDF15 in lung adenocarcinoma A549 cells, and the results revealed that GDF15 could inhibit the proliferation, migration and invasion, while promoting apoptosis of A549 cells. In addition, GDF15 significantly decreased the number and sites of lung metastases and bone metastases in vivo compared to the control group. Finally, it was revealed that Smad2 and phospho‑Smad2 protein expression was lower in the GDF15‑overexpressing A549 cells. This result indicated that the tumor suppressive effect of GDF15 may be related to the TGF‑β/Smad signaling pathway, although more studies are still required for confirmation. In summary, GDF15 inhibited the growth and bone metastasis of lung adenocarcinoma A549 cells, and this effect may be achieved through the TGF‑β/Smad signaling pathway.

Bouaouiche S, Magadoux L, Dondaine L, et al.
Glyceryl trinitrate‑induced cytotoxicity of docetaxel‑resistant prostatic cancer cells is associated with differential regulation of clusterin.
Int J Oncol. 2019; 54(4):1446-1456 [PubMed] Related Publications
Metastatic castration resistant prostate cancer (mCRPC) relapse due to acquired resistance to chemotherapy, such as docetaxel, remains a major threat to patient survival. Resistance of mCRPC to docetaxel can be associated with elevated levels of soluble clusterin (sCLU) and growth differentiation factor‑15 (GDF‑15). Any strategies aiming to modulate sCLU and/or GDF‑15 in docetaxel‑resistant prostate cancer cells present a therapeutic interest. The present study reports the cytotoxic effect of a nitric oxide donor, glyceryl trinitrate (GTN), on docetaxel‑resistant mCRPC human cell lines and demonstrates that GTN displays greater inhibition of cell viability toward docetaxel‑resistant mCRPC cells than on mCRPC cells. It is also demonstrated that GTN modulates the level of expression of clusterin (CLU) which is dependent of GDF‑15, two markers associated with docetaxel resistance in prostate cancer. The results indicate that GTN represses the level of expression of the cytoprotective isoform of CLU (sCLU) and can increase the level of expression of the cytotoxic isoform (nuclear CLU) in docetaxel resistant cells. Furthermore, it was observed that GTN differentially regulates the level of the precursor form of GDF‑15 between resistant and parental cells, and that recombinant GDF‑15 can modulate the expression of CLU isoforms and counteract GTN‑induced cytotoxicity in resistant cells. A link was established between GDF‑15 and the expression of CLU isoforms. The present study thus revealed GTN as a potential therapeutic strategy to overcome docetaxel‑resistant mCRPC.

Gkretsi V, Louca M, Stylianou A, et al.
Inhibition of Breast Cancer Cell Invasion by Ras Suppressor-1 (RSU-1) Silencing Is Reversed by Growth Differentiation Factor-15 (GDF-15).
Int J Mol Sci. 2019; 20(1) [PubMed] Free Access to Full Article Related Publications
Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of

Reyes I, Reyes N, Suriano R, et al.
Gene expression profiling identifies potential molecular markers of papillary thyroid carcinoma.
Cancer Biomark. 2019; 24(1):71-83 [PubMed] Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases.
OBJECTIVE: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease.
METHODS: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response.
RESULTS: In this study we found that upregulation of extracellular activities, such as proteoglycans, ECM-receptor interaction, and cell adhesion molecules, were the most prominent feature of PTC. Significantly over-expressed genes included SDC1 (syndecan 1), SDC4 (syndecan 4), KLK7 (kallikrein-related peptidase 7), KLK10 (kallikrein-related peptidase 10), SLPI (secretory leukocyte peptidase inhibitor), GDF15 (growth/differentiation factor-15), ALOX5 (arachidonate 5-lipoxygenase), SFRP2 (secreted Frizzled-related protein 2), among others. Further, elevated KLK10 levels were detected in patients with PTC. Many of these genes belong to KEGG pathway "Proteoglycans in cancer".
CONCLUSIONS: Using DNA microarray analysis allowed the identification of genes and pathways with known important roles in malignant transformation, and also the discovery of novel genes that may be potential biomarkers for PTC.

Muller DC, Larose TL, Hodge A, et al.
Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium.
BMJ. 2019; 364:k4981 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.
DESIGN: Nested case-control study.
SETTING: 20 population based cohort studies in Asia, Europe, Australia, and the United States.
PARTICIPANTS: 5299 patients with incident lung cancer, with individually incidence density matched controls.
EXPOSURE: Circulating hsCRP concentrations in prediagnostic serum or plasma samples.
MAIN OUTCOME MEASURE: Incident lung cancer diagnosis.
RESULTS: A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.
CONCLUSIONS: Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.

Kong J, Sun W, Zhu W, et al.
Long noncoding RNA LINC01133 inhibits oral squamous cell carcinoma metastasis through a feedback regulation loop with GDF15.
J Surg Oncol. 2018; 118(8):1326-1334 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Long noncoding RNAs (lncRNAs) play key roles in carcinoma metastasis. We aimed to investigate lncRNA LINC01133 in oral squamous cell carcinoma (OSCC) metastasis.
METHODS: The RNA levels of LINC01133 and growth and differentiation factor 15 (GDF15) in tissue samples from OSCC patients, and OSCC cell lines were tested by real-time quantitative polymerase chain reaction (RT-qPCR). SPSS20.0 was used to perform statistical analysis of LINC01133 expression in clinical samples and correlate expression of LINC01133 and GDF15. Cell migration/invasion was assessed via transwell assays. Downstream genes of LINC01133 were screened using RNA-seq and validated by RT-qPCR. GDF15 protein levels were evaluated via Western blot analysis.
RESULTS: LINC01133 was downregulated in OSCCs; higher expression of LINC01133 in OSCCs was correlated with less metastasis and better prognosis. LINC01133 inhibited OSCC cell migration and invasion. RNA-seq data showed that LINC01133 inhibited GDF15, and GDF15 could rescue inhibition of OSCC cell migration and invasion caused by LINC01133. Interestingly, GDF15 also inhibited LINC01133. Furthermore, a significant negative correlation between expression of LINC01133 and GDF15 was validated in the clinical study.
CONCLUSIONS: Collectively, these data indicate that LINC01133 inhibited OSCC metastasis via a feedback regulation loop of reciprocal inhibition with GDF15, suggesting a new diagnostic and therapeutic target for OSCC.

Wu K, Na K, Chen D, et al.
Effects of non-steroidal anti-inflammatory drug-activated gene-1 on Ganoderma lucidum polysaccharides-induced apoptosis of human prostate cancer PC-3 cells.
Int J Oncol. 2018; 53(6):2356-2368 [PubMed] Free Access to Full Article Related Publications
Ganoderma lucidum polysaccharides (GLP) has been demonstrated to elicit antitumorigenic and proapoptotic activities in cancer; however, the molecular mechanisms underlying the anticancer effects of GLP have yet to be elucidated. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) has been reported to exert proapoptotic effects and therefore, may serve an important role in cancer prevention. The present study aimed to elucidate the molecular mechanism by which GLP stimulates anticancer activity in human prostate cancer (PCa) PC-3 cells. In addition, the role of NAG-1 in GLP-induced cancer inhibition was examined. The results of the present study demonstrated that GLP significantly inhibited cell viability in a time- and dose-dependent manner in PC-3 cells. Flow cytometry indicated that GLP induced late apoptosis, which was accompanied by poly (ADP-ribose) polymerase 1 (PARP) cleavage, and inhibition of pro-caspase-3, -6 and -9 protein expression. Furthermore, it was observed that the expression levels of NAG-1, and its transcriptional factor early growth response-1, were upregulated in a time- and dose-dependent manner upon GLP treatment. The results of a luciferase assay demonstrated that GLP induced the promoter activity of NAG-1, thus indicating that NAG-1 may be transcriptionally regulated by GLP. The secretion of NAG-1 proteins into the cell culture medium was also upregulated upon GLP treatment. Furthermore, inhibition of NAG-1 expression by small interfering RNA significantly, but not completely, prevented GLP-induced apoptosis, and reversed the effects of GLP on PARP and pro-caspase expression. It was further demonstrated that GLP inhibited the phosphorylation of protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in PC-3 cells. The present study is the first, to the best of our knowledge, to report that GLP may induce apoptosis of PCa cells, which is partially mediated through NAG-1 induction. The present findings may be helpful in elucidating the anticancer mechanisms of GLP through NAG-1 induction for its chemopreventive potential in PCa.

Niu B, Coslo DM, Bataille AR, et al.
In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets.
Nucleic Acids Res. 2018; 46(16):8385-8403 [PubMed] Free Access to Full Article Related Publications
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.

Benkheil M, Paeshuyse J, Neyts J, et al.
HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis.
Biochem Pharmacol. 2018; 155:305-315 [PubMed] Related Publications
HCV is a major risk factor for hepatocellular carcinoma (HCC). HCC development in chronically infected HCV patients has until now been attributed to persistent inflammation and interference of viral proteins with host cell signaling. Since activation of the epidermal growth factor receptor (EGFR) presents a crucial step in HCV entry, we aimed at investigating whether EGFR signaling may contribute to the pathogenesis of HCV-related HCC. By applying microarray analysis, we generated a gene expression signature for secreted proteins in HCV-infected hepatoma cells. This gene signature was enriched for inflammatory and angiogenic processes; both crucially involved in HCC development. RT-qPCR analysis, conducted on the entire list of upregulated genes, confirmed induction of 11 genes (AREG, IL8, CCL20, CSF1, GDF15, IGFBP1, VNN3, THBS1 and PAI-1) in a virus titer- and replication-dependent manner. EGFR activation in hepatoma cells largely mimicked the gene signature seen in the infectious HCV model. Further, the EGFR-ERK pathway, but not Akt signaling, was responsible for this gene expression profile. Finally, microarray analysis conducted on clinical data from the GEO database, revealed that our validated gene expression profile is significantly represented in livers of patients with HCV-related liver pathogenesis (cirrhosis and HCC) compared to healthy livers. Taken together, our data indicate that persistent activation of EGFR-ERK signaling in chronically infected HCV patients may induce a specific pro-inflammatory and pro-angiogenic signature that presents a new mechanism by which HCV can promote liver cancer pathogenesis. A better understanding of the key factors in HCV-related oncogenesis, may efficiently direct HCC drug development.

Keam SP, Gulati T, Gamell C, et al.
Biodosimetric transcriptional and proteomic changes are conserved in irradiated human tissue.
Radiat Environ Biophys. 2018; 57(3):241-249 [PubMed] Related Publications
Transcriptional dosimetry is an emergent field of radiobiology aimed at developing robust methods for detecting and quantifying absorbed doses using radiation-induced fluctuations in gene expression. A combination of RNA sequencing, array-based and quantitative PCR transcriptomics in cellular, murine and various ex vivo human models has led to a comprehensive description of a fundamental set of genes with demonstrable dosimetric qualities. However, these are yet to be validated in human tissue due to the scarcity of in situ-irradiated source material. This represents a major hurdle to the continued development of transcriptional dosimetry. In this study, we present a novel evaluation of a previously reported set of dosimetric genes in human tissue exposed to a large therapeutic dose of radiation. To do this, we evaluated the quantitative changes of a set of dosimetric transcripts consisting of FDXR, BAX, BCL2, CDKN1A, DDB2, BBC3, GADD45A, GDF15, MDM2, SERPINE1, TNFRSF10B, PLK3, SESN2 and VWCE in guided pre- and post-radiation (2 weeks) prostate cancer biopsies from seven patients. We confirmed the prolonged dose-responsivity of most of these transcripts in in situ-irradiated tissue. BCL2, GDF15, and to some extent TNFRSF10B, were markedly unreliable single markers of radiation exposure. Nevertheless, as a full set, these genes reliably segregated non-irradiated and irradiated tissues and predicted radiation absorption on a patient-specific basis. We also confirmed changes in the translated protein product for a small subset of these dosimeters. This study provides the first confirmatory evidence of an existing dosimetric gene set in less-accessible tissues-ensuring peripheral responses reflect tissue-specific effects. Further work will be required to determine if these changes are conserved in different tissue types, post-radiation times and doses.

Zhao C, Li Y, Qiu W, et al.
C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation.
Oncogene. 2018; 37(35):4821-4837 [PubMed] Free Access to Full Article Related Publications
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (-103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5-GCN5-GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

Zhang Y, Wang X, Zhang M, et al.
GDF15 promotes epithelial-to-mesenchymal transition in colorectal [corrected].
Artif Cells Nanomed Biotechnol. 2018; 46(sup2):652-658 [PubMed] Related Publications
Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily that has been associated with colorectal cancers (CRC). However, the role of GDF15 in the progression of CRC remains unknown. We demonstrated that GDF15 expression was higher in fresh CRC tissues than in adjacent normal tissues. Moreover, we found that GDF15 overexpression significantly facilitated cell viability, cell invasion and migration (p < .01 or p < .05). The protein expression 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 GDF16-induced cell viability, invasion and migration in LoVo cells. In conclusion, GDF15 could promote cell viability, invasion and migration of LoVo cells through EMT induction.

Juan C, Hua Q, Ruping Z, Tingting W
miRNA-489 as a biomarker in diagnosis and treatment of cervical cancer.
Bratisl Lek Listy. 2018; 119(5):278-283 [PubMed] Related Publications
miRNA-489 was shown to be a suppressor factor in many cancers, however, evidence on the effects and mechanism of miRNA-489 in progression of cervical cancer is limited. So we aimed to determine the function of miRNA-489 in cervical cancer proliferation and apoptosis in our present study. Interestingly, we found that miRNA-489 was significantly down-regulated in cervical cancer tissues. miRNA-489 overexpression inhibited the cell proliferation and improved the cell apoptosis of cervical cancer cells. Further, miRNA-489 over-expression suppressed the activation of PI3K and AKT, and stimulated P53 proteins expression. In conclusion, our results suggested that miRNA-489 may be considered as a biomarker in cervical cancer and had suppressed the cell proliferation and stimulated cell apoptosis via PI3K/AKT/P53 signaling pathway (Fig. 5, Ref. 26). Text in PDF

Freedman JA, Wang Y, Li X, et al.
Single-nucleotide polymorphisms of stemness genes predicted to regulate RNA splicing, microRNA and oncogenic signaling are associated with prostate cancer survival.
Carcinogenesis. 2018; 39(7):879-888 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single-nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with PCa survival. SNPs within stemness-related genes were analyzed for association with overall survival of PCa in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with PCa survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of PCa and support a contribution of the stemness pathway to PCa patient outcome.

Guo RQ, Xiong GY, Yang KW, et al.
Detection of urothelial carcinoma, upper tract urothelial carcinoma, bladder carcinoma, and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective, single-center study.
Urol Oncol. 2018; 36(7):342.e15-342.e23 [PubMed] Related Publications
INTRODUCTION: Hematuria is the most common symptom of urothelial carcinomas (UC) but is often idiopathic. Cystoscopy is expensive which involves considerable patient discomfort, and conventional urine cytology for noninvasive UC detection and disease monitoring suffers from poor sensitivity. We aim to evaluate the performance of genes selected from a previous study in detecting UC, especially among patients with gross hematuria, as well as upper tract urothelial carcinoma (UTUC) and bladder carcinoma separately, in voided urine samples.
METHODS: Using methylation-specific polymerase chain reaction, we examined the promoter methylation status of 10 genes in voided urine samples among 473 patients at our institution, including 217 UC patients and 256 control subjects.
RESULTS: The final combination of VIM, CDH1, SALL3, TMEFF2, RASSF1A, BRCA1, GDF15, and ABCC6 identified UC with a sensitivity of 0.83 and a specificity of 0.60. Additionally, a panel of selected genes (CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15) identified UTUC with a sensitivity of 0.82 and a specificity of 0.68, while a panel of selected genes (VIM, RASSF1A, GDF15, and TMEFF2) identified bladder carcinoma with a sensitivity of 0.82 and a specificity of 0.53. Remarkably, a different panel (CDH1, SALL3, THBS1, TMEFF2, VIM, and GDF15) identified UC in patients with gross hematuria with 0.89 sensitivity and 0.74 specificity, and sensitivity (0.91) and specificity (0.92) could be achieved when cytology was included.
CONCLUSIONS: The selected urine-DNA methylation biomarkers are reliable, noninvasive, and cost-effective diagnostic tools for bladder carcinoma and UTUC, especially among patients with gross hematuria.

Baroni M, Marie SKN, Fedatto PF, et al.
Distinct response to GDF15 knockdown in pediatric and adult glioblastoma cell lines.
J Neurooncol. 2018; 139(1):51-60 [PubMed] Related Publications
INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary brain tumor affecting adults. In pediatric patients, GBM exhibits genetic variations distinct from those identified in the adult GBM phenotype. This tumor exhibits complex genetic changes leading to malignant progression and resistance to standard therapies including radiotherapy and temozolomide treatment. The GDF15 gene codes for a growth factor whose expression is altered in the presence of inflammations and malignancies. GDF15 is associated with a poor prognosis and with radio- and chemoresistance in a variety of tumors. The aim of this study was to compare the response to GDF15 knockdown in adult (U343) and pediatric (KNS42) GBM cell line models.
METHODS: The expression of the GDF15 gene was investigated by qRT-PCR and overexpression was identified in both GBM cell lines. The KNS42 and U343 cell lines were submitted to lentiviral transduction with shRNA of GDF15 and validated at the protein level. To understand the difference between cell lines, RNAseq was performed after GDF15 knockdown.
RESULTS: The data obtained demonstrated that the pathways were differentially expressed in adult GBM and pediatric GBM cell lines. This was confirmed by functional assays perfomed after independent treatments (radiotherapy and TMZ).
CONCLUSION: These results demonstrated that GBM cell lines had distinct responses to GDF15 knockdown, a fact that can be explained by the different molecular profile of pediatric and adult GBM.

Li S, Ma YM, Zheng PS, Zhang P
GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2.
J Exp Clin Cancer Res. 2018; 37(1):80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported.
METHODS: Immunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2.
RESULTS: GDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells.
CONCLUSIONS: Our data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2.

Fang D, He S, Xiong G, et al.
Comparison of clinicopathologic characteristics, epigenetic biomarkers and prognosis between renal pelvic and ureteral tumors in upper tract urothelial carcinoma.
BMC Urol. 2018; 18(1):22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There's no consensus about the difference between renal pelvic and ureteral tumors in terms of clinical features, pathological outcomes, epigenetic biomarkers and prognosis.
METHODS: The data of 341 patients with renal pelvic tumors and 271 patients with ureteral tumors who underwent radical nephroureterectomy between 1999 and 2011 were retrospectively reviewed. The clinicopathologic features, gene promoters methylation status and oncologic outcomes were compared. Regression analysis was performed to identify oncologic prognosticators.
RESULTS: Patients with ureteral tumors were relatively older (p = 0.002), and had higher likelihood of pre-operative renal insufficiency (p < 0.001), hypertension (p = 0.038) and hydronephrosis (P < 0.001), while in patients with renal pelvic tumors gross hematuria was more prevalent (p < 0.001). Renal pelvic tumors tended to exhibit non-organ-confined disease (p = 0.004) and larger tumor diameter (p = 0.001), while ureteral tumors had a higher likelihood of exhibiting high grade (p < 0.001) and sessile architecture (p = 0.023). Hypermethylated gene promoters were significantly more prevalent in renal pelvic tumors (p < 0.001), specifically for TMEFF2, GDF15, RASSF1A, SALL3 and ABCC6 (all p < 0.05). Tumor location failed to independently predict cancer-specific survival, overall survival, intravesical or contralateral recurrence (all p > 0.05), while gene methylation status was demonstrated to be an independent prognostic factor.
CONCLUSION: Renal pelvic tumors and ureteral tumors exhibited significant differences in clinicopathologic characteristics and epigenetic biomarkers. Gene promoter methylation might be an important mechanism in explaining distinct tumor patterns and behaviors in UTUC.

Huang EY, Chang JC, Chen HH, et al.
Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: a potential role of macrophages.
BMC Cancer. 2018; 18(1):321 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.
METHODS: From July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.
RESULTS: Preoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.
CONCLUSION: Pretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.

Lu W, Wan Y, Li Z, et al.
Growth differentiation factor 15 contributes to marrow adipocyte remodeling in response to the growth of leukemic cells.
J Exp Clin Cancer Res. 2018; 37(1):66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The adipocyte remodeling, including of the morphological change, might indicate special pathological function. Our previous study found that the morphological remodeling of larger marrow adipocytes into small marrow adipocytes correlates with a poor prognosis for acute myeloid leukemia (AML) patients. However, the mechanisms contributed to the marrow adipocyte remodeling are still poorly understood.
METHODS: GDF15 expression was analyzed by RT-qPCR and western blotting assays in the leukemic cells. The enhancing and antibody neutralization tests in vitro were employed to evaluate the effect of GDF15 on the morphology of mature adipocytes. CCK8 test was used to detect the proliferation of leukemic cells after co-cultivation with small marrow adipocytes. Flow cytometry was used to analysis the proportion of cell cycle of leukemic cells. Immunofluorescence staining and linear analysis were applied to verify the GDF15 expression and the relationship between GDF15 and small marrow adipocytes in AML patients.
RESULTS: In this study, we found that leukemic cell lines not only expressed significantly higher growth differentiation factor 15 (GDF15) than the other three cytokines associated with adipocyte differentiation in RNA level but also secreted GDF15 factor. Furthermore, the in vitro experiments demonstrated that GDF15 was involved in the conversion of small marrow adipocytes from larger marrow adipocytes. Correspondingly, the leukemic cells proliferated more rapidly through regulating the cell cycle when co-cultured with GDF15-induced small marrow adipocytes. The immunofluorescence staining on the bone marrow sections of AML patients further exhibited that GDF15 was partly produced by leukemic cells. The positive correlation between the concentration of GDF15 in the marrow aspirates and the number and the volume of small marrow adipocytes might suggest the contribution of GDF15 in AML patients (r = 0.72, r = 0.67).
CONCLUSIONS: GDF15 secreted by leukemic cells was involved in the morphological remodeling of marrow adipocytes, which can in turn promote leukemic cell growth, indicating that GDF15 may be a promising treatment target for AML patients.

Li P, You S, Nguyen C, et al.
Genes involved in prostate cancer progression determine MRI visibility.
Theranostics. 2018; 8(7):1752-1765 [PubMed] Free Access to Full Article Related Publications
MRI is used to image prostate cancer and target tumors for biopsy or therapeutic ablation. The objective was to understand the biology of tumors not visible on MRI that may go undiagnosed and untreated.

Wang T, Mao B, Cheng C, et al.
YAP promotes breast cancer metastasis by repressing growth differentiation factor-15.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(5 Pt A):1744-1753 [PubMed] Related Publications
The transcriptional co-activator Yes-associated protein (YAP) has been implicated as an oncogene and is found to promote breast cancer metastasis. However, the pro-metastatic mechanism of YAP remains unclear. Here, we demonstrated that YAP functions as a transcriptional repressor of growth differentiation factor-15 (GDF15), a divergent member of the transforming growth factor superfamily, in several breast cancer cell lines. Functionally, knockdown of YAP decreased, whereas knockdown of GDF15 increased, the metastatic potential of breast cancer cells. More than that, the reduced metastasis in YAP-depleted cells could be reversed by simultaneous knockdown of GDF15. Mechanistically, the repressive effect of YAP on GDF15 requires its transcriptional factor TEAD (TEA domain family). In addition, YAP recruits polycomb repressive complex 2 (PRC2) to tri-methylate histone H3 lysine 27 in the promoter region of GDF15. Co-immunoprecipitation experiments demonstrated that YAP and enhancer of zeste 2 PRC2 subunit (EZH2) physically interact with each other. In conclusion, our data reveal that YAP promotes metastasis of breast cancer cells by repressing GDF15 transcription and present a novel molecular mechanism underlying the pro-metastasis function of YAP oncoprotein, with the implication of a therapeutic avenue for breast cancer treatment.

Bian Y, Guo J, Qiao L, Sun X
miR-3189-3p Mimics Enhance the Effects of S100A4 siRNA on the Inhibition of Proliferation and Migration of Gastric Cancer Cells by Targeting CFL2.
Int J Mol Sci. 2018; 19(1) [PubMed] Free Access to Full Article Related Publications

Li Y, Wang M, Huang BW, et al.
Transcriptome-wide elucidation of liposomal formulations for anticancer drug delivery.
Int J Nanomedicine. 2017; 12:8557-8572 [PubMed] Free Access to Full Article Related Publications
Although widely used in chemotherapy, free doxorubicin (Dox) might enhance cell malignancy undesirably. Liposomal Dox (Doxlipo) has been clinically approved for the treatment of breast cancer due to reduced systematical toxicity and increased tumor targeting, yet the transcriptome-wide elucidation of the Doxlipo formulations remains elusive. To this end, we explored the impact of two Dox liposomal formulations, Doxlipo mainly containing hydrogenated soy phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, on the transcriptional pattern of MCF-7 cells. The two types of Dox liposomal formulations with different drug release kinetics were investigated to reveal the relationship between the formulation and tumor malignancy. Interestingly, we found that liposomal formulation significantly altered the transcriptional pattern of a wide range of genes. Under equivalent dosage of Dox, free Dox substantially changed the expression of ANK1, ACTA2, GPR87, GDF15, FZD6, and WNT4 in MCF-7 cells. Notably, free Dox induced much higher expression of ABCB1 and significantly enhanced the cell migration behavior in comparison with HSPC Doxlipo under a similar level of cytotoxicity. Finally, siRNA targeting GPR87 was codelivered with cationic Doxlipo to reduce the expression of malignancy-related genes. Our study, for the first time, provides an overview of the influence of formulation on the malignancy at transcriptional level and reveals the relationship between cytotoxicity and cell malignancy from the formulation aspect, offering valuable reference for the future formulation design for anticancer drug delivery.

Li K, Na K, Sang T, et al.
The ethanol extracts of sporoderm-broken spores of Ganoderma lucidum inhibit colorectal cancer in vitro and in vivo.
Oncol Rep. 2017; 38(5):2803-2813 [PubMed] Free Access to Full Article Related Publications
The medicinal mushroom Ganoderma lucidum (G. lucidum) has been reported to possess a variety of pharmacological activities including anticancer effects. However, the anti-colorectal cancer effects and the potential molecular mechanisms of the ethanol extracts of sporoderm-broken spores of G. lucidum (BSGLEE), which mainly contains triterpenoids, have not been reported. The aim of the present study was to investigate the anticancer effects and molecular mechanisms exerted by BSGLEE on colorectal cancer in vitro and in vivo. MTT assay revealed that BSGLEE at 1.6 to 10 mg/ml significantly inhibited HCT116 cell proliferation in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BSGLEE induces apoptosis and cell cycle arrest at G0/G1 phase, which are associated with deregulation of the expression of key genes and proteins (p21, p16, cyclin D1, Bcl-2, bax, NAG-1, PARP and caspase-3) that regulate apoptosis and cell cycle cascades. Moreover, BSGLEE significantly inhibited HCT116 cell migration via downregulating MMP-1, MMP-2 and upregulating E-cadherin expression at mRNA levels. Oral gavage of 75 and 150 mg/kg BSGLEE significantly inhibited HCT116 xenograft tumor growth in nude mice, which was accompanied by suppressed Ki-67 staining as determined by immunochemistry. Collectively, we found that BSGLEE effectively inhibits colorectal cancer carcinogenesis through induction of apoptosis, inhibition of migration and promotion of cell cycle arrest. Our results suggest that triterpenoids of sporoderm-broken spores of G. lucidum ethanol extracts may serve as a promising anticancer agent for colorectal cancer chemoprevention and therapy.

Chakravarthi BVSK, Chandrashekar DS, Agarwal S, et al.
miR-34a Regulates Expression of the Stathmin-1 Oncoprotein and Prostate Cancer Progression.
Mol Cancer Res. 2018; 16(7):1125-1137 [PubMed] Free Access to Full Article Related Publications
In aggressive prostate cancers, the oncoprotein STMN1 (also known as stathmin 1 and oncoprotein 18) is often overexpressed. STMN1 is involved in various cellular processes, including cell proliferation, motility, and tumor metastasis. Here, it was found that the expression of STMN1 RNA and protein is elevated in metastatic prostate cancers. Knockdown of STMN1 resulted in reduced proliferation and invasion of cells and tumor growth and metastasis

Couture F, Sabbagh R, Kwiatkowska A, et al.
PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer.
Cancer Res. 2017; 77(24):6863-6879 [PubMed] Related Publications
Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer.

Lu Y, Ma J, Li Y, et al.
CDP138 silencing inhibits TGF-β/Smad signaling to impair radioresistance and metastasis via GDF15 in lung cancer.
Cell Death Dis. 2017; 8(9):e3036 [PubMed] Free Access to Full Article Related Publications
CDP138, a CDK5 binding partner, regulates cell proliferation and migration. However, the mechanisms by which CDP138 functions in these processes remain unclear. In this study, we show that CDP138 is frequently overexpressed and that high levels of CDP138 are correlated with lymph node metastasis in lung cancer. Furthermore, we provide evidence that CDP138-depleted lung cancer cells exhibit enhanced radiosensitivity as well as reduced migration and invasion. Mechanistically, we identify GDF15, a member of the TGF-β superfamily, as a key downstream effector of CDP138. CDP138 silencing attenuates TGF-β/Smad signaling activation at least in part through the downregulation of GDF15. More importantly, the observed phenotypes caused by CDP138 knockdown are partially dependent on GDF15 inhibition. Together, our findings demonstrate that CDP138 positively modulates the TGF-β/Smad signaling pathway via GDF15 to promote radioresistance and metastasis, suggesting CDP138 as a potential oncogenic biomarker and a promising therapeutic target in the treatment of lung cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. GDF15, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 30 August, 2019     Cancer Genetics Web, Established 1999