Gene Summary

Gene:BMP6; bone morphogenetic protein 6
Aliases: VGR, VGR1
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. This protein regulates a wide range of biological processes including iron homeostasis, fat and bone development, and ovulation. Differential expression of this gene may be associated with progression of breast and prostate cancer. Mutations in this gene may be associated with iron overload in human patients. [provided by RefSeq, Jul 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:bone morphogenetic protein 6
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Bone Morphogenetic Protein 2
  • Cell Proliferation
  • Cell Differentiation
  • Estrogen Receptors
  • Neoplasm Invasiveness
  • Young Adult
  • Sensitivity and Specificity
  • Gene Silencing
  • Signal Transduction
  • Breast Cancer
  • Risk Factors
  • DNA Methylation
  • Lung Cancer
  • Phenotype
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Bone Morphogenetic Protein 4
  • Smad1 Protein
  • Prostate Cancer
  • Promoter Regions
  • Software
  • Gene Expression Profiling
  • DNA Sequence Analysis
  • Down-Regulation
  • Epigenetics
  • Tumor Microenvironment
  • Chromosome 6
  • Neoplasm Metastasis
  • Immunohistochemistry
  • Bone Morphogenetic Protein 6
  • Case-Control Studies
  • Disease Progression
  • CpG Islands
  • Oligonucleotide Array Sequence Analysis
  • Transforming Growth Factor beta
  • Neoplasm Proteins
  • ras Proteins
  • MicroRNAs
  • Bone Morphogenetic Proteins
  • Colorectal Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BMP6 (cancer-related)

Pellatt AJ, Mullany LE, Herrick JS, et al.
The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs.
J Transl Med. 2018; 16(1):191 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The TGFβ-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression.
METHODS: In this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFβ-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months.
RESULTS: Thirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months.
CONCLUSION: These data support an interaction between miRNAs and genes in the TGFβ-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations.

Lee GT, Kwon SJ, Kim J, et al.
WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages.
Br J Cancer. 2018; 118(5):670-678 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although the standard treatment for the patients with recurrent and metastatic prostate cancer (CaP) is androgen deprivation therapy, castration-resistant prostate cancer (CRPC) eventually emerges. Our previous report indicated that bone morphogenetic protein 6 (BMP6) induced CRPC via tumour-infiltrating macrophages. In a separate line of study, we have observed that the WNT5A/BMP6 loop in CaP bone metastasis mediates resistance to androgen deprivation in tissue culture. Simultaneously, we have reported that BMP6 induced castration resistance in CaP cells via tumour-infiltrating macrophages. Therefore, our present study aims to investigate the mechanism of WNT5A and its interaction with macrophages on CRPC.
METHODS: Doxycycline inducible WNT5A overexpression prostate cancer cell line was used for detailed mechanical study.
RESULTS: WNT5A was associated with increased expression of chemokine ligand 2 (CCL2) in the human CaP cell line, LNCaP. Mechanistically, this induction of CCL2 by WNT5A is likely to be mediated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway. Our in vivo experiments demonstrated that the overexpression of WNT5A in LNCaP cells promoted castration resistance. Conversely, this resistance was inhibited with the removal of macrophages via clodronate liposomes. When patient-derived CaP LuCaP xenografts were analysed, high levels of WNT5A were correlated with increased levels of CCL2 and BMP6. In addition, higher levels of CCL2 and BMP6 were more commonly observed in intra-femoral transplanted tumours as compared to subcutaneous-transplanted tumours in the patient-derived PCSD1 bone-niche model.
CONCLUSIONS: These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.

Hasegawa D, Ochiai-Shino H, Onodera S, et al.
Gorlin syndrome-derived induced pluripotent stem cells are hypersensitive to hedgehog-mediated osteogenic induction.
PLoS One. 2017; 12(10):e0186879 [PubMed] Free Access to Full Article Related Publications
Gorlin syndrome is an autosomal dominant inherited syndrome that predisposes a patient to the formation of basal cell carcinomas, odontogenic keratocysts, and skeletal anomalies. Causative mutations in several genes associated with the sonic hedgehog (SHH) signaling pathway, including PTCH1, have been identified in Gorlin syndrome patients. However, no definitive genotype-phenotype correlations are evident in these patients, and their clinical presentation varies greatly, often leading to delayed diagnosis and treatment. We generated iPSCs from four unrelated Gorlin syndrome patients with loss-of-function mutations in PTCH1 using the Sendai virus vector (SeVdp(KOSM)302). The patient-derived iPSCs exhibited basic iPSC features, including stem cell marker expression, totipotency, and the ability to form teratomas. GLI1 expression levels were greater in fibroblasts and patient-derived iPSCs than in the corresponding control cells. Patient-derived iPSCs expressed lower basal levels than control iPSCs of the genes encoding the Hh ligands Indian Hedgehog (IHH) and SHH, the Hh acetyltransferase HHAT, Wnt proteins, BMP4, and BMP6. Most of these genes were upregulated in patient-derived iPSCs grown in osteoblast differentiation medium (OBM) and downregulated in control iPSCs cultured in OBM. The expression of GLI1 and GLI2 substantially decreased in both control and patient-derived iPSCs cultured in OBM, whereas GLI3, SHH, and IHH were upregulated in patient-derived iPSCs and downregulated in control iPSCs grown in OBM. Activation of Smoothened by SAG in cells grown in OBM significantly enhanced alkaline phosphatase activity in patient-derived iPSCs compared with control iPSC lines. In summary, patient-derived iPSCs expressed lower basal levels than the control iPSCs of the genes encoding Hh, Wnt, and bone morphogenetic proteins, but their expression of these genes strongly increased under osteogenic conditions. These findings indicate that patient-derived iPSCs are hypersensitive to osteogenic induction. We propose that Hh signaling is constituently active in iPSCs from Gorlin syndrome patients, enhancing their response to osteogenic induction and contributing to disease-associated abnormalities.

Gelbrich N, Ahrend H, Kaul A, et al.
Different Cytokine and Chemokine Expression Patterns in Malignant Compared to Those in Nonmalignant Renal Cells.
Anal Cell Pathol (Amst). 2017; 2017:7190546 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Cytokines and chemokines are widely involved in cancer cell progression and thus represent promising candidate factors for new biomarkers.
METHODS: Four renal cell cancer (RCC) cell lines (Caki-1, 786-O, RCC4, and A498) and a nonmalignant renal cell line (RC-124) were examined with respect to their proliferation. The cytokine and chemokine expression pattern was examined by a DNA array (Human Cytokines & Chemokines RT
RESULTS: Caki-1 and 786-O cells exhibited significantly increased proliferation rates, whereas RCC4 and A498 cells demonstrated attenuated proliferation, compared to nonmalignant RC-124 cells. Expression analysis revealed 52 cytokines and chemokines primarily involved in proliferation and inflammation and differentially expressed not only in malignant and nonmalignant renal cells but also in the four RCC cell lines.
CONCLUSION: This is the first study examining the expression of 84 cytokines and chemokines in four RCC cell lines compared to that in a nonmalignant renal cell line. VEGFA, NODAL, and BMP6 correlated with RCC cell line proliferation and, thus, may represent putative clinical biomarkers for RCC progression as well as for RCC diagnosis and prognosis.

Makondi PT, Chu CM, Wei PL, Chang YJ
Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer.
PLoS One. 2017; 12(7):e0180616 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients' therapy.
METHODS: Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA).
RESULTS: The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients' survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation.
CONCLUSION: Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.

Hu M, Cui F, Liu F, et al.
BMP signaling pathways affect differently migration and invasion of esophageal squamous cancer cells.
Int J Oncol. 2017; 50(1):193-202 [PubMed] Related Publications
Bone morphogenetic proteins (BMPs) are broadly involved in normal embryo development and abnormal pathological process such as cancer. The complexity and diversity of BMPs and their signaling pathways impose quite different or even conflicting effects on clinical traits of tumors. The aim of the present study was to investigate whether different BMPs, including BMP2, BMP4, BMP6 and BMP7, influence esophageal squamous cancer cell (ESCC) growth, invasion and metastasis. BMP6 and type I receptor ALK2 and type II receptor BMPRII, ActRIIA and ActRIIB were expressed in all ESCC cell lines. In addition, adenovirus-mediated BMP overexpression did not affect ECA-109 cell growth. BMP6/7 overexpression increased ECA-109 cell invasion and metastasis, activated SMAD1/5/8 signal pathway and induced downstream gene ID1 expression. While BMP2/4 overexpression reduced ECA-109 cell invasion and metastasis and obviously promoted ERK1/2, P-38 and JNK activation with weak SMAD1/5/8 phosphorylation. When BMP6/7 favorite type I receptor ALK2 or type II receptor BMPRII was interfered with by dominant-negative mutation, BMP6/7-induced invasion and metastasis augmentation disappeared. Further investigation on clinical ESCC samples and non-tumorous adjacent tissue found that tumors with triple-positive BMP6, ALK2 and BMPRII had deeper growth than tumors with only BMP6 expression. These results suggested that different BMPs distinctly affected esophageal squamous cancer cell invasion and metastasis by employing different signal pathways.

de Boeck M, Cui C, Mulder AA, et al.
Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model.
Sci Rep. 2016; 6:24968 [PubMed] Free Access to Full Article Related Publications
The transforming growth factor-β (TGF-β) family is known to play critical roles in cancer progression. While the dual role of TGF-β is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo.

Hu F, Zhang Y, Li M, et al.
BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression.
Oncol Rep. 2016; 35(3):1823-30 [PubMed] Related Publications
Bone morphogenetic protein-6 (BMP-6) is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis. In the present study, our results showed that the rate of BMP-6-negative expression was 30.56% in breast cancer tissues, but was 9.58% in normal tissues by immunohistochemical staining. This implied that BMP-6 expression is absent in breast cancer tissues and may suppress breast cancer metastasis. In addition, stable overexpression of BMP-6 in MDA-MB‑231 cells was established to analyze the metastatic ability. The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MDA-MB-231 cells. Moreover, real-time PCR analysis showed that BMP-6 markedly downregulated matrix metalloproteinase-1 (MMP-1) expression at both the mRNA and protein levels in the MDA-MB‑231 cells. Importantly, the results of luciferase and CHIP assays revealed that BMP-6 inhibited MMP-1 promoter activity through the AP-1 response element. In MDA-MB-231 cells treated with BMP-6, a significant decrease in the recruitment of AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter was noted. We also demonstrated that BMP-6 inhibited the invasion of MDA-MB-231 cells, and this effect was significantly attenuated by overexpression of MMP-1. In contrast, MMP-1 knockdown by RNA interference or MMP-1 inhibitor exhibited an opposite effect. These observations suggest a novel role of BMP-6 in the inhibition of breast cancer metastasis by regulating secretion of MMPs in the tumor microenvironment.

Cuttano R, Rudini N, Bravi L, et al.
KLF4 is a key determinant in the development and progression of cerebral cavernous malformations.
EMBO Mol Med. 2016; 8(1):6-24 [PubMed] Free Access to Full Article Related Publications
Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5-MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFβ/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.

Yang F, Chen Y, Shen T, et al.
Stromal TGF-β signaling induces AR activation in prostate cancer.
Oncotarget. 2014; 5(21):10854-69 [PubMed] Free Access to Full Article Related Publications
AR signaling is essential for the growth and survival of prostate cancer (PCa), including most of the lethal castration-resistant PCa (CRPC). We previously reported that TGF-β signaling in prostate stroma promotes prostate tumor angiogenesis and growth. By using a PCa/stroma co-culture model, here we show that stromal TGF-β signaling induces comprehensive morphology changes of PCa LNCaP cells. Furthermore, it induces AR activation in LNCaP cells in the absence of significant levels of androgen, as evidenced by induction of several AR target genes including PSA, TMPRSS2, and KLK4. SD-208, a TGF-β receptor 1 specific inhibitor, blocks this TGF-β induced biology. Importantly, stromal TGF-β signaling together with DHT induce robust activation of AR. MDV3100 effectively blocks DHT-induced, but not stromal TGF-β signaling induced AR activation in LNCaP cells, indicating that stromal TGF-β signaling induces both ligand-dependent and ligand-independent AR activation in PCa. TGF-β induces the expression of several growth factors and cytokines in prostate stromal cells, including IL-6, and BMP-6. Interestingly, BMP-6 and IL-6 together induces robust AR activation in these co-cultures, and neutralizing antibodies against BMP-6 and IL-6 attenuate this action. Altogether, our study strongly suggests tumor stromal microenvironment induced AR activation as a direct mechanism of CRPC.

Sangplod P, Kanngurn S, Boonpipattanapong T, et al.
Expression of BMP6 is associated with its methylation status in colorectal cancer tissue but lacks prognostic significance.
Asian Pac J Cancer Prev. 2014; 15(17):7091-5 [PubMed] Related Publications
BACKGROUND: The study aimed to evaluate the incidence of CpG island promoter methylation of BMP6, a member of the transforming growth factor beta family, in tissue samples from colorectal cancers (CRC) and look for its association with BMP6 expression and clinicopathological correlation.
MATERIALS AND METHODS: Methylation specific PCR for the BMP6 promoter region was performed with 85 frozen tissue samples of CRC and 45 of normal colon. Methylation status of MLH1 was also determined by the same method. Expression of BMP6 was evaluated by immunohistochemistry (IHC), using Allred's scoring system. The methylation status was analyzed against clinical and pathological parameters in CRC.
RESULTS: The study revealed BMP6 hypermethylation in 34 of 85 tumor specimens (40%), and 15 out of 45 normal tissue samples from CRC (33%). The incidence of hypermethylation was inversely correlated with IHC score. Allred's scores of 7 or more were correlated with lower frequency of BMP6 hypermethylation (29% compared to 50% in the remaining, p-value 0.049). However, there was no association between hypermethylation status and any clinicopathological parameters. The methylation status of BMP6 was not correlated with that of MLH1, a key methylation determinant in CRC. On survival analysis, there was no significant difference in progress-free survival (PFS) between the cases with and without hypermethylation (2-year PFS 74% and 76%, respectively).
CONCLUSIONS: CpG island methylation of BMP6 is found in high frequency in CRC and this epigenetic event is associated with suppressed protein expression in the tumor tissue. However, the marker is not associated with tumor progression of the disease.

Zhang S, Chen Y, Guo W, et al.
Disordered hepcidin-ferroportin signaling promotes breast cancer growth.
Cell Signal. 2014; 26(11):2539-50 [PubMed] Related Publications
Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth.

Liu G, Liu YJ, Lian WJ, et al.
Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells.
Oncol Rep. 2014; 32(2):581-8 [PubMed] Related Publications
Bone morphogenetic protein 6 (BMP6) is an important regulator of cell growth, differentiation and apoptosis in various types of tumor. In breast cancer, it was considered as a tumor suppressor. Our previous study also confirmed that BMP6 was a critical regulator of breast cancer drug resistance. However, little is known about how its expression is regulated and its mechanisms in breast cancer drug resistance. In the present study, we assessed the DNA methylation regulation of BMP6 based on the presence of a large CpG island in the BMP6 gene promoter. Quantitative DNA methylation analyses showed a significantly increased DNA methylation level in the drug-resistant cell line MCF-7/ADR compared to their parental cells MCF-7. Moreover, the drug-resistant cell line MCF-7/ADR showed an EMT phenotype confirmed by morphology and the expression of EMT marker gene. MCF-7 cells transfected with BMP6-specific shRNA vector also showed an EMT phenotype. The MCF-7/ADR cells treated with the recombinant BMP6 proteins reversed their EMT phenotype. These data indicated that hypermethylation modifications contributed to the regulation of BMP6 and induced an EMT phenotype of breast cancer during the acquisition of drug resistance.

Pei N, Jie F, Luo J, et al.
Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.
PLoS One. 2014; 9(3):e92253 [PubMed] Free Access to Full Article Related Publications
Increased expression of angiotensin II type 2 receptor (AT2R) induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2), 2 cytokine genes (IL6 and IL8) and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7) in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.

Lee GT, Kang DI, Ha YS, et al.
Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction.
Br J Cancer. 2014; 110(6):1634-44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases.
METHODS: We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model.
RESULTS: In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2-17.8 months) vs 57 months (95% CI, 19.4-94.6 months)). These results suggest that bone-tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines.
CONCLUSIONS: These observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.

He Y, Cui Y, Xu B, et al.
Hypermethylation leads to bone morphogenetic protein 6 downregulation in hepatocellular carcinoma.
PLoS One. 2014; 9(1):e87994 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In the liver, bone morphogenetic protein 6 (BMP-6) maintains balanced iron metabolism. However, the mechanism that underlies greater BMP-6 expression in hepatocellular carcinoma (HCC) tissue than adjacent non-cancerous tissue is unclear. This study sought to investigate the epigenetic mechanisms of BMP-6 expression by analysing the relationship between the DNA methylation status of BMP-6 and the expression of BMP-6.
METHODS: Methylation-specific polymerase chain reaction (PCR), bisulphite sequencing PCR, the MethyLight assay, and quantitative real-time PCR were performed to examine BMP-6 methylation and mRNA expression levels. Immunohistochemistry (IHC) was performed on tissue arrays to evaluate the BMP-6 protein level.
RESULTS: BMP-6 mRNA expression was approximately 84.09% lower in HCC tissues than in adjacent non-cancerous tissues, and this low level of expression was associated with a poor prognosis. Moreover, the hypermethylation observed in HCC cell lines and HCC tissues was correlated with the BMP-6 mRNA expression level, and this correlation was validated following treatment with 5-aza-CdR, a demethylation agent. In addition, BMP-6 DNA methylation was upregulated by 68.42% in 114 clinical HCC tissue samples compared to adjacent normal tissues, whereas the BMP-6 staining intensity was downregulated by 77.03% in 75 clinical HCC tissue samples in comparison to adjacent normal tissues. Furthermore, elevated expression of BMP-6 in HCC cell lines inhibited cell colony formation.
CONCLUSIONS: Our results suggest that BMP-6 CpG island hypermethylation leads to decreased BMP-6 expression in HCC tissues.

Eberlein C, Rooney C, Ross SJ, et al.
E-Cadherin and EpCAM expression by NSCLC tumour cells associate with normal fibroblast activation through a pathway initiated by integrin αvβ6 and maintained through TGFβ signalling.
Oncogene. 2015; 34(6):704-16 [PubMed] Related Publications
Fibroblasts in the tumour stroma (cancer-associated fibroblasts) influence tumour progression and response to therapeutics; little is known about the mechanisms through which the tumour cell co-opts a normal fibroblast. To study the activation of fibroblasts by tumour cells, a panel of non-small cell lung cancer (NSCLC) cell lines and normal human dermal fibroblasts were co-cultured. A subset of the NSCLC cells induced an activated cancer-associated fibroblast-like fibroblast phenotype defined by induction of fibroblast α-smooth muscle actin expression. Tumour cells that activated fibroblasts were associated with E-Cadherin and EpCAM expression and expression of integrin αvβ6. Co-culture of activating tumour cells with fibroblasts resulted in induction of transcripts associated with tumour cell invasion and growth, TGFβ1 and TGFBR1, SERPINE-1, BMP6, SPHK1 and MMP9. Fibroblast activation was inhibited by an αvβ6/8 integrin blocking antibody (264RAD) and a small molecule inhibitor of the TGF-beta type I receptor activin-like kinase (ALK5) (SB431542), demonstrating that transactivation of the TGFβ pathway initiates fibroblast activation. Both integrin and ALK5 antagonists inhibited initiation. Only ALK5 was effective when added after 3 days of co-culture. This suggests that although activation is αvβ6-dependent, once fibroblasts are activated alternative TGFβ pathway regulators maintain an activation loop. In co-culture activating cells had reduced sensitivity to selumetinib, AZD8931 and afatinib compared with mono-culture. In contrast, non-activating cells were insensitive to selumetinib and AZD8931 in both mono-culture and co-culture. In conclusion NSCLC cell lines, positive for E-Cadherin, EpCAM and αvβ6 expression, activate normal fibroblasts through avβ6/TGFβ signalling in vitro, and influence both gene expression and response to therapeutic agents.

Slattery ML, Lundgreen A, Stern MC, et al.
The influence of genetic ancestry and ethnicity on breast cancer survival associated with genetic variation in the TGF-β-signaling pathway: The Breast Cancer Health Disparities Study.
Cancer Causes Control. 2014; 25(3):293-307 [PubMed] Free Access to Full Article Related Publications
The TGF-β signaling pathway regulates cellular proliferation and differentiation. We evaluated genetic variation in this pathway, its association with breast cancer survival, and survival differences by genetic ancestry and self-reported ethnicity. The Breast Cancer Health Disparities Study includes participants from the 4-Corners Breast Cancer Study (n = 1,391 cases) and the San Francisco Bay Area Breast Cancer Study (n = 946 cases) who have been followed for survival. We evaluated 28 genes in the TGF-β signaling pathway using a tagSNP approach. Adaptive rank truncated product (ARTP) was used to test the gene and pathway significance by Native American (NA) ancestry and by self-reported ethnicity (non-Hispanic white (NHW) and Hispanic/NA). Genetic variation in the TGF-β signaling pathway was associated with overall breast cancer survival (P ARTP = 0.05), especially for women with low NA ancestry (P ARTP = 0.007) and NHW women (P ARTP = 0.006). BMP2, BMP4, RUNX1, and TGFBR3 were significantly associated with breast cancer survival overall (P ARTP = 0.04, 0.02, 0.002, and 0.04, respectively). Among women with low NA, ancestry associations were as follows: BMP4 (P ARTP = 0.007), BMP6 (P ARTP = 0.001), GDF10 (P ARTP = 0.05), RUNX1 (P ARTP = 0.002), SMAD1 (P ARTP = 0.05), and TGFBR2 (P ARTP = 0.02). A polygenic risk model showed that women with low NA ancestry and high numbers of at-risk alleles had twice the risk of dying from breast cancer as did women with high NA ancestry. Our data suggest that genetic variation in the TGF-β signaling pathway influences breast cancer survival. Associations were similar when the analyses were stratified by genetic ancestry or by self-reported ethnicity.

Schmidt J, Weijdegård B, Mikkelsen AL, et al.
Differential expression of inflammation-related genes in the ovarian stroma and granulosa cells of PCOS women.
Mol Hum Reprod. 2014; 20(1):49-58 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder. Ovarian changes in PCOS women are well characterized by ultrasound. However, the ovarian pathophysiology is not fully understood. The aim of this study was to characterize the expression, in both the central ovarian stroma and in granulosa cells (GCs), of a number of genes, including several inflammation-related genes, which have been hypothesized to be involved in the pathophysiology of PCOS. Biopsies of the central ovarian stroma were obtained from PCOS women (Rotterdam criteria) and from normally ovulating women in follicular phase. GCs were retrieved from PCOS-women and non-PCOS women, undergoing in vitro maturation. The expressions of 57 genes were analyzed by quantitative-PCR using a low-density-gene array. The main outcome measures were over-expression or under-expression of the specific genes. The results showed that in the central stroma of PCOS ovaries, five inflammation-related genes (CCL2, IL1R1, IL8, NOS2, TIMP1), the leukocyte marker CD45, the inflammation-related transcription factor RUNX2 and the growth factor AREG were under-expressed. The growth factor DUSP12 and the coagulation factor TFPI2 were over-expressed. In the GC of PCOS, all of the differentially expressed genes were over-expressed; the inflammation-related IL1B, IL8, LIF, NOS2 and PTGS2, the coagulation-related F3 and THBS1, the growth factors BMP6 and DUSP12, the permeability-related AQ3 and the growth-arrest-related GADD45A. In conclusion, the results indicate major alterations in the local ovarian immune system of PCOS ovaries. This may have implications for the PCOS-related defects in the inflammation-like ovulatory process and for the susceptibility to acquire the inflammatory state of ovarian hyperstimulation syndrome.

Maddaluno L, Rudini N, Cuttano R, et al.
EndMT contributes to the onset and progression of cerebral cavernous malformations.
Nature. 2013; 498(7455):492-6 [PubMed] Related Publications
Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.

Lian WJ, Liu G, Liu YJ, et al.
Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer.
Oncol Rep. 2013; 30(1):193-200 [PubMed] Related Publications
Previous studies indicate that bone morphogenetic protein (BMP) 6 is involved in breast cancer development and progression. However, the mechanism underlying the role of BMP6 in breast cancer cell proliferation, differentiation and chemoresistance remains unknown. In this study, we confirmed that BMP6 expression was downregulated in breast cancer tissues compared with the adjacent normal breast tissues. We further demonstrated that the downregulation of BMP6 was correlated with the estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade and enhanced proliferation (Ki67 proliferation index). In vitro functional experiments showed that the suppression of BMP6 expression by a specific small hairpin (sh)RNA vector led to increased proliferation in the MCF7 breast cancer cell line. Furthermore, knockdown of BMP6 in MCF7 cells enhanced the chemoresistance to doxorubicin by upregulation of mdr-1/P-gp expression and activation of the ERK signaling pathway. Taken together, our data suggest that BMP6 plays a critical role in breast cancer cell aberrant proliferation and chemoresistance and may serve as a novel diagnostic biomarker or therapeutic target for breast cancer.

Topić I, Ikić M, Ivčević S, et al.
Bone morphogenetic proteins regulate differentiation of human promyelocytic leukemia cells.
Leuk Res. 2013; 37(6):705-12 [PubMed] Related Publications
We investigated the role of bone morphogenetic proteins (BMPs) in suppression of all-trans retinoic acid (ATRA)-mediated differentiation of leukemic promyelocytes. In NB4 and HL60 cell lines, BMPs reduced the percentage of differentiated cells, and suppressed PU.1 and C/EBPε gene expression induced by ATRA. BMP and ATRA synergized in the induction of ID genes, causing suppression of differentiation. In primary acute promyelocytic leukemia bone-marrow samples, positive correlation of PML/RARα and negative of RARα with the expression of BMP-4, BMP-6 and ID genes were found. We concluded that BMPs may have oncogenic properties and mediate ATRA resistance by a mechanism that involves ID genes.

Väänänen RM, Lilja H, Cronin A, et al.
Association of transcript levels of 10 established or candidate-biomarker gene targets with cancerous versus non-cancerous prostate tissue from radical prostatectomy specimens.
Clin Biochem. 2013; 46(7-8):670-4 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: The benefits of PSA (prostate specific antigen)-testing in prostate cancer remain controversial with a consequential need for validation of additional biomarkers. We used highly standardized reverse-transcription (RT)-PCR assays to compare transcript levels of 10 candidate cancer marker genes - BMP6, FGF-8b, KLK2, KLK3, KLK4, KLK15, MSMB, PCA3, PSCA and Trpm8 - in carefully ascertained non-cancerous versus cancerous prostate tissue from patients with clinically localized prostate cancer treated by radical prostatectomy.
DESIGN AND METHODS: Total RNA was isolated from fresh frozen prostate tissue procured immediately after resection from two separate areas in each of 87 radical prostatectomy specimens. Subsequent histopathological assessment classified 86 samples as cancerous and 88 as histologically benign prostate tissue. Variation in total RNA recovery was accounted for by using external and internal standards and enabled us to measure transcript levels by RT-PCR in a highly quantitative manner.
RESULTS: Of the ten genes, there were significantly higher levels only of one of the less abundant transcripts, PCA3, in cancerous versus non-cancerous prostate tissue whereas PSCA mRNA levels were significantly lower in cancerous versus histologically benign tissue. Advanced pathologic stage was associated with significantly higher expression of KLK15 and PCA3 mRNAs. Median transcript levels of the most abundantly expressed genes (i.e. MSMB, KLK3, KLK4 and KLK2) in prostate tissue were up to 10(5)-fold higher than those of other gene targets.
CONCLUSIONS: PCA3 expression was associated with advanced pathological stage but the magnitude of overexpression of PCA3 in cancerous versus non-cancerous prostate tissue was modest compared to previously reported data.

Khalaf M, Morera J, Bourret A, et al.
BMP system expression in GCs from polycystic ovary syndrome women and the in vitro effects of BMP4, BMP6, and BMP7 on GC steroidogenesis.
Eur J Endocrinol. 2013; 168(3):437-44 [PubMed] Related Publications
BACKGROUND: The bone morphogenetic proteins (BMPs) are growth factors involved in the folliculogenesis. Alteration in their expression may compromise the reproductive process in disease such as the polycystic ovary syndrome (PCOS). This study investigated the expression and role of granulosa cell (GC) BMP from normal cycling and PCOS women.
METHODS AND RESULTS: This prospective study was performed in GCs obtained from 14 patients undergoing IVF: i) six women with normal ovulatory cycles and tubal or male infertility and ii) eight women with PCOS. BMP2, BMP4, BMP5, BMP6, BMP7, and BMP8A and their receptors BMPR1A, BMPR1B, and BMPR2 were identified by RT-PCR in GCs from normally cycling and PCOS women. BMP4, BMP6, and BMP7 expressions were confirmed by immunohistochemistry. Quantitative transcript analysis showed the predominant expression of BMP6. In GCs from PCOS women, an overexpression of BMP6 (P<0.01) and BMPR1A mRNA (P<0.05) was observed. GC culture experiments demonstrated that basal estradiol (E₂) production was threefold higher but FSH-induced E₂ increment was twofold lower in PCOS compared with controls. In PCOS, BMP6 and BMP7 exerted a stimulatory effect on basal E₂ production while BMP4 and BMP6 inhibited FSH-induced E₂ production. FSH receptor and aromatase expression were not different between both groups.
CONCLUSION: The BMP system is expressed in human GCs from normal cycling and PCOS women. The BMP may be involved in reproductive abnormalities found in PCOS.

Slattery ML, John EM, Torres-Mejia G, et al.
Genetic variation in bone morphogenetic proteins and breast cancer risk in hispanic and non-hispanic white women: The breast cancer health disparities study.
Int J Cancer. 2013; 132(12):2928-39 [PubMed] Free Access to Full Article Related Publications
Bone morphogenetic proteins (BMP) are thought to be important in breast cancer promotion and progression. We evaluated genetic variation in BMP-related genes and breast cancer risk among Hispanic (2,111 cases, 2,597 controls) and non-Hispanic White (NHW) (1,481 cases, 1,586 controls) women who participated in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study. BMP genes and their receptors evaluated include ACVR1, AVCR2A, ACVR2B, ACVRL1, BMP1, BMP2, BMP4, BMP6, BMP7, BMPR1A, BMPR1B, BMPR2, MSTN and GDF10. Additionally, 104 ancestral informative markers were assessed to discriminate between European and native American ancestry. The importance of estrogen on BMP-related associations was suggested through unique associations by menopausal status and estrogen (ER) and progesterone (PR) receptor status of tumors. After adjustment for multiple comparisons ACVR1 (8 SNPs) was modestly associated with ER+PR+ tumors [odds ratios (ORs) between 1.18 and 1.39 padj < 0.05]. ACVR1 (3 SNPs) and BMP4 (3 SNPs) were associated with ER+PR- tumors (ORs 0.59-2.07; padj < 0.05). BMPR2 was associated with ER-PR+ tumors (OR 4.20; 95% CI 1.62, 10.91; padj < 0.05) as was GDF10 (2 SNPs; ORs 3.62 and 3.85; padj < 0.05). After adjustment for multiple comparisons several SNPs remained associated with ER-PR- tumors (padj < 0.05) including ACVR1 BMP4 and GDF10 (ORs between 0.53 and 2.12). Differences in association also were observed by percentage of native ancestry and menopausal status. Results support the hypothesis that genetic variation in BMPs is associated with breast cancer in this admixed population.

Barekati Z, Radpour R, Lu Q, et al.
Methylation signature of lymph node metastases in breast cancer patients.
BMC Cancer. 2012; 12:244 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers.
METHODS: The quantitative methylation analysis was performed using the SEQUENOM's EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).
RESULTS: The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis.
CONCLUSIONS: The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.

Hashida Y, Nemoto Y, Imajoh M, et al.
Promoter methylation of the bone morphogenetic protein 6 gene in multiple myeloma.
Oncol Rep. 2012; 27(3):825-30 [PubMed] Related Publications
Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β superfamily, are multifunctional signaling molecules that have become of increasing interest in cancer research. Recent observations suggest that alterations in BMPs and BMP signaling are associated with tumorigenesis and disease progression in various types of malignancies. This study investigated the methylation status of the BMP6 gene promoter in various types of plasma cell proliferative disorders by combined bisulfite restriction analysis. While BMP6 methylation was not detected in any samples from monoclonal gammopathies of undetermined significance, intramedullary multiple myeloma (MM), plasma cell leukemia or solitary plasmacytoma, both case studies and cell line studies showed that multiple extramedullary plasmacytoma (MEP) consistently carried a methylated BMP6 promoter. The BMP6 methylation-positive MEP was an aggressive form of MM with extremely high levels of serum lactate dehydrogenase (LDH). Bisulfite sequencing analysis confirmed intensive methylation at CpG sites of the BMP6 promoter region. The methylation of BMP6 was correlated with decreased levels of mRNA transcripts. Expression of BMP6 was restored by the demethylating agent 5-aza-2'-deoxycytidine, suggesting that the methylation is associated with transcriptional silencing. Our study implied that BMP6 promoter methylation is not a common event in MMs, but occurs in aggressive MEP. These findings warrant further investigation to clarify whether BMP6 methylation together with elevated LDH could be a marker of poor prognosis in MEP patients who should be considered for early intensive treatment.

Maegdefrau U, Bosserhoff AK
BMP activated Smad signaling strongly promotes migration and invasion of hepatocellular carcinoma cells.
Exp Mol Pathol. 2012; 92(1):74-81 [PubMed] Related Publications
Several of the different bone morphogenetic proteins (BMPs) are involved in development and progression of specific tumors. For hepatocellular carcinoma (HCC) only BMP4 and BMP6 are described to be important for carcinogenesis. However, up to now neither the influence of other BMPs on tumor progression, nor the responsible signaling pathways to mediate target gene expression in HCC are known. In order to characterize BMP expression pattern in HCC cell lines, we performed RT-PCR analysis and revealed enhanced expression levels of several BMPs (BMP4, 6, 7, 8, 9, 10, 11, 13 and 15) in HCC. Thus, we treated HCC cells with the general BMP inhibitors chordin and noggin to determine the functional relevance of BMP overexpression and observed decreased migration and invasion of HCC cells. A cDNA microarray of noggin treated HCC cells was performed to analyze downstream targets of BMPs mediating these oncogenic functions. Subsequent analysis identified collagen XVI as 'Smad signaling specific' and nidogen-2 as 'MAPK/ERK signaling specific' BMP-target genes. To examine which signaling pathway is mainly responsible for the oncogenic role of BMPs in HCC, we treated HCC cells with dorsomorphin to determine the influence of BMP activated Smad signaling. Interestingly, also migratory and invasive behavior of dorsomorphin treated HCC cells was diminished. In summary, our findings demonstrate enhanced expression levels of several BMPs in HCC supporting enhanced migratory and invasive phenotype of HCC cells mainly via activation of Smad signaling.

Markić D, Ćelić T, Gršković A, et al.
mRNA expression of bone morphogenetic proteins and their receptors in human renal cell carcinoma.
Urol Int. 2011; 87(3):353-8 [PubMed] Related Publications
INTRODUCTION: Bone morphogenetic proteins (BMPs) have been studied in several cancers, but only limited information is available about renal cell carcinomas (RCCs). We determined the expression of mRNA of several BMP ligands and BMP receptors (BMPRs) in healthy kidney tissue and RCCs, and data were compared to clinicopathological parameters.
MATERIAL AND METHODS: Sixty-four samples of RCCs and healthy renal tissues were prospectively examined. The expression of BMP2, BMP4, BMP6, BMP7, BMPRIA, BMPRIB and BMPRII mRNA was determined using semiquantitative reverse transcriptase-polymerase chain reaction.
RESULTS: The expression levels of different BMP ligands and BMPRs were considerably higher in RCCs than in normal kidney tissue. BMP ligands showed elevated expression in clear-cell RCCs, whereas all three BMPRs showed higher expression levels in non-clear-cell RCCs. In clear-cell RCCs, the expression levels of BMP2 progressively increased and expression levels of BMP6, BMP7 and BMPRIB were lost with higher tumor stage.
CONCLUSIONS: All BMPs and their receptors have stronger expression levels in RCC. The expression level of BMP2 is strongly elevated in kidney cancer.

Maegdefrau U, Arndt S, Kivorski G, et al.
Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma.
Lab Invest. 2011; 91(11):1615-23 [PubMed] Related Publications
Recently, we revealed that bone morphogenetic protein (BMP) 4 is increased in hepatocellular carcinoma (HCC). Furthermore, latest reports described BMPs, in particular BMP6, as important regulators of hepcidin expression in iron homeostasis. Therefore, we aimed to unravel why enhanced BMP expression in HCC patients does not lead to severe changes in iron metabolism. Initial analysis of the BMP4 and BMP6 expression patterns revealed enhanced expression on mRNA and protein level in HCC cell lines and tissue samples compared with primary human hepatocytes (PHHs) and normal liver tissues. However and interestingly, hepcidin expression was reduced in HCC cell lines and tissues. Analysis of BMP6 receptor expression revealed loss of BMP6-specific receptor subunit in HCC. To identify a possible regulatory mechanism causing lack of reaction to BMP4 we analyzed the expression of hemojuvelin (HJV), which is involved in iron metabolism as BMP co-receptor. HJV expression was markedly decreased in HCC cell lines and tissues. HJV promoter analysis revealed potential HNF-1α and snail-binding sites, but functional analysis ruled out that these transcriptional regulators or promoter methylation are the cause of HJV downregulation in HCC. However, we identified AU-rich elements in the HJV 3'-untranslated region and revealed significantly faster decay of HJV mRNA in HCC cells as compared with PHH indicating decreased mRNA-stability as the reason for the loss of HJV expression in HCC.

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