Promoter Hypermethylation of the Bone Morphogenetic Protein-6 Gene in Malignant Lymphoma

Daibata, Masanori; Nemoto, Yuiko; Bandobashi, Kentaro; Kotani, Norihiro; Kuroda, Masayuki; Tsuchiya, Masato; Okuda, Heiwa; Takakuwa, Tetsuya; Imai, Shosuke; Shuin, Taro; Taguchi, Hirokuni

doi:10.1158/1078-0432.ccr-06-2766

Cited by 27 publications

(40 citation statements)

References 34 publications

(16 reference statements)

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“…Collectively, our results indicated that hypermethylation of promoter downregulated the expression of BMP6 and then induced the cells to undergo EMT during the acquisition of drug resistance of breast cancer cells. BMP6 is a member of the signaling molecules of the TGF-β superfamily that are important regulators of cell proliferation and apoptosis in various types of cells including breast cancer, myeloma and lymphoma (16,20,21). BMP6 transfer signals through ligation of type Ⅰ and type Ⅱ serine-threonine kinase receptor, which then propagate the signal downstream by phosphorylating receptor-activated Smad protein (22).…”

Section: Discussionmentioning

confidence: 99%

Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells

Liu

Lian

et al. 2014

Oncology Reports

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Abstract. 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.

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Section: Discussionmentioning

confidence: 99%

Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells

Liu

Lian

et al. 2014

Oncology Reports

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“…It has been reported that the BMP gene family is inactivated in a number of cancer types, including lung cancer, breast cancer, prostate cancer, colon cancer, lymphoma, and mesothelioma and BMP proteins are of great importance in tumorigenesis of these cancers (9)(10)(11)(12)(13)(14)(15). As an antagonist of BMP proteins likely through direct binding to BMP proteins (6), Gremlin has recently been shown to be deregulated during tumorigenesis of several types of cancers such as lung, breast, ovarian and cervical cancers (20)(21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…BMP family proteins are members of the transforming growth factor-β (TGF-β) superfamily and critical mediators of early embryonic patterning involved in skeletal development and bone formation (7,8). Inactivation of the BMP genes has been reported in several cancer types, including lung, breast, prostate and colon cancers, lymphomas and mesotheliomas (9)(10)(11)(12)(13)(14)(15), suggesting the importance of BMPs in tumorigenesis of these cancers. As an antagonist of BMP proteins, Gremlin also plays important roles during early development (16)(17)(18)(19), as well as tumorigenesis of several types of cancers (20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

et al. 2011

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Abstract.Gremlin is a member of the bone morphogenetic protein (BMP) antagonist family and its antagonistic effect is likely through direct binding to BMP proteins. As an antagonist of BMP, Gremlin plays a role in regulating organogenesis, body patterning and tissue differentiation. Recent studies have shown a deregulation of Gremlin in several types of human cancers. However, the role of Gremlin in human malignant mesothelioma (MM) is still unknown. In this study, we investigated the expression of Gremlin in human MM. We found that Gremlin mRNA and protein were both overexpressed in the majority of primary MM tissue samples that we examined. We also observed high level expression of the Gremlin gene in 4 of the 6 MM cell lines. Consistently, we found that the Gremlin promoter activity was significantly elevated in those MM cell lines expressing the Gremlin gene. On the other hand, no activity of the Gremlin promoter was detected in the two MM cell lines lacking Gremlin expression. Moreover, to examine the functional significance of the Gremlin overexpression in MM, we used shRNA to knock down Gremlin expression in MM cell lines expressing Gremlin and found that inhibition of Gremlin expression significantly suppressed proliferation of those MM cells. Taken together, our results suggest that the BMP antagonist Gremlin is overexpressed in MM and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of human MM.

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“…Normal fizyolojik süreçlerde önemli işlevlere sahip olmalarının yanında, KMP sinyallerindeki regülasyon bozukluğu ciddi patofizyolojik sonuçlara yol açabilmektedir. Kemik morfogenetik protein seviyelerindeki değişimlerin pek çok kanser türüyle ilişkili olduğu bulunmuştur (12)(13)(14)(15)(16)(17)(18)(19). Ayrıca romatoid artritli hastaların sinovyal sıvılarında KMP düzeylerinde artış saptanmıştır (11).…”

Section: Bulgularunclassified

Bone Morphogenetic Protein Levels in Osteoarthritis

Bozkurt¹,

Karasu²,

Dinçel³

et al. 2014

Turk J Phys Med Rehab

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Objective: The modern treatment approach for osteoarthritis aims at suppressing the inflammation by antagonizing such proinflammatory cytokines. More complicated approaches are expected to come to the forefront in the future that focus on such signals as bone morphogenetic proteins (BMPs) of the transforming growth factor (TGF)-beta superfamily and alleviate or antagonize the destruction process. These proteins are associated with many cellular functions, such as proliferation, differentiation, and apoptosis. We investigated the BMP levels in the serum and urine samples of patients with osteoarthritis. Material and Methods: A total of 41 patients with gonarthrosis, with grade 3 or 4 knees according to Kellgren-Lawrence Grading, and 50 healthy volunteers were included in the study. Visual analog scale was used for the assessment of pain. Levels of BMP7, BMP6, BMP4, and TGF-β1 were determined by ELISA method based on the serums obtained from the blood samples routinely taken from the patients as well as urine samples of 24 hours. Results: We evaluated the serum and urine samples of 37 patients with gonarthrosis and 29 healthy controls. There was no significant difference between the two groups with regard to age, weight, and height. Levels of serum TGFβ-1 and BMP6 were significantly higher in the patients compared to healthy controls (p=0.004, 0.002, respectively). As to urine samples, it was found that levels of TGFβ-1 and BMP7 were below the minimum detection limit proposed by the ELISA method in the patients. There was no statistically significant difference between the two groups with regard to levels of BMP4 and BMP6 in the urine (p>0.05). Conclusion: Levels of TGFβ-1 and BMP6 were higher in the patients compared to the controls. We think that more frequent examination of BMP levels in serum and urine samples, which are closely associated with the overall process of osteoarthritis, may guide future treatment studies.

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Promoter Hypermethylation of the Bone Morphogenetic Protein-6 Gene in Malignant Lymphoma

Cited by 27 publications

References 34 publications

Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells

Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

Bone Morphogenetic Protein Levels in Osteoarthritis

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