Bone morphogenetic protein 3B silencing in non-small-cell lung cancer

Dai, Zunyan; Popkie, Anthony P.; Zhu, Wei‐Guo; Timmers, Cynthia; Raval, Aparna; Tannehill-Gregg, Sarah H.; Morrison, Carl; Auer, Herbert; Kratzke, Robert A.; Niehans, Gloria A.; Amatschek, Stefan; Sommergruber, Wolfgang; Leone, Gustavo; Rosol, Thomas J.; Otterson, Gregory A.; Plass, Christoph

doi:10.1038/sj.onc.1207441

Cited by 53 publications

(38 citation statements)

References 32 publications

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“…There are multiple BMPs with overlapping substrate specificity (Stott et al, 1998). Our data, showing that epigenetic inactivation of BMP3b (at a frequency similar to that previously reported (Dai et al, 2004)) and BMP6 tend to occur together in lung cancer, suggests that in NSCLC multiple BMPs may need to be silenced in order to abrogate their antigrowth signalling. Increasing evidence shows that there is a crosstalk between TGFb/BMP antigrowth signalling and Ras/MAP-K progrowth signalling, and it is likely that the interaction of these pathways is cell type and tissue specific.…”

Section: Discussionsupporting

confidence: 80%

“…However, additional signalling pathways are acknowledged to play important roles in malignant disease, with the bone morphogenetic protein (BMP) signalling pathway emerging as important in multiple cancers (Nagatake et al, 1996;Tamada et al, 2001;Baldus et al, 2004;Dai et al, 2004;Kim et al, 2004). It is well recognised that the BMP signalling pathways are crucial for all stages of embryonic development, including regulation of lung development and airway branching (Weaver et al, 1999;Lu et al, 2001;Rosendahl et al, 2002).…”

mentioning

confidence: 99%

“…It is well recognised that the BMP signalling pathways are crucial for all stages of embryonic development, including regulation of lung development and airway branching (Weaver et al, 1999;Lu et al, 2001;Rosendahl et al, 2002). The BMPs have been shown to be growth inhibitory by suppressing proliferation (Dai et al, 2004;Haudenschild et al, 2004). They act through upregulation of the cell cycle proteins p21 and p27 (Nakamura et al, 2003;Brubaker et al, 2004;Haudenschild et al, 2004).…”

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confidence: 99%

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Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

et al. 2005

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Bone morphogenetic proteins (BMPs) are an integral component of the TGFb superfamily, responsible for regulation of cell proliferation, differentiation, migration and programmed cell death in a variety of cell types. The BMPs transduce their signals directly through the SMAD family of proteins but they also have been reported to interact with the MAPK and Erk pathways. Inactivation of the BMP pathway genes has been implicated as important in several cancers. Recent work has shown that BMP3b is epigenetically inactivated in cancer and suggests that BMP6 can be epigenetically inactivated. We investigated whether BMP6 is epigenetically inactivated in cell lines and whether BMP3b and BMP6 are epigenetically inactivated in non-small-cell lung cancer (NSCLC). We also studied the relationship between BMP methylation and k-ras mutation. Here, we demonstrate that the BMP3b and BMP6 genes are common targets of epigenetic inactivation in NSCLC, and that they are significantly more likely to be concurrently inactivated (P ¼ 0.009). Furthermore, this coinactivation of BMP3b and BMP6 is significantly associated with mutation of k-ras codon 12 in lung cancer (P ¼ 0.003); those with a k-ras mutation were six times more likely to have concurrent methylation of these BMP loci. Hence, these data suggest that concurrent inactivation of the BMP and activation of the Ras signalling pathways are important in lung carcinogenesis.

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Section: Discussionsupporting

confidence: 80%

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confidence: 99%

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confidence: 99%

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Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

et al. 2005

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“…Bisulfite modification of genomic DNA was done as described (48,49). Briefly, 1 g of genomic DNA (50-l volume) was denatured by using mild heat at alkaline pH by adding 3.5 l of 3 M NaOH and incubating for 10 min at 37°C.…”

Section: Bisulfite Modification Of Genomic Dna and Sequencingmentioning

confidence: 99%

Eicosapentaenoic Acid Demethylates a Single CpG That Mediates Expression of Tumor Suppressor CCAAT/Enhancer-binding Protein δ in U937 Leukemia Cells

Ceccarelli

Racanicchi

Martelli

et al. 2011

Journal of Biological Chemistry

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Polyunsaturated fatty acids (PUFAs) inhibit proliferation and induce differentiation in leukemia cells. To investigate the molecular mechanisms whereby fatty acids affect these processes, U937 leukemia cells were conditioned with stearic, oleic, linolenic, ␣-linolenic, arachidonic, eicosapentaenoic, and docosahexaenoic acids. PUFAs affected proliferation; eicosapentaenoic acid (EPA) was the most potent on cell cycle progression. EPA enhanced the expression of the myeloid lineage-specific transcription factors CCAAT/enhancer-binding proteins (C/EBP␤ and C/EBP␦), PU.1, and c-Jun, resulting in increased expression of the monocyte lineage-specific target gene, the macrophage colony-stimulating factor receptor. Indeed, it is known that PU.1 and C/EBPs interact with their consensus sequences on a small DNA fragment of macrophage colony-stimulating factor receptor promoter, which is a determinant for expression. We demonstrated that C/EBP␤ and C/EBP␦ bind the same response element as a heterodimer. We focused on the enhanced expression of C/EBP␦, which has been reported to be a tumor suppressor gene silenced by promoter hypermethylation in U937 cells. After U937 conditioning with EPA and bisulfite sequencing of the ؊370/؊20 CpG island on the C/EBP␦ promoter region, we found a site-specific CpG demethylation that was a determinant for the binding activity of Sp1, an essential factor for C/EBP␦ gene basal expression. Our results provide evidence for a new role of PUFAs in the regulation of gene expression. Moreover, we demonstrated for the first time that re-expression of the tumor suppressor C/EBP␦ is controlled by the methylation state of a site-specific CpG dinucleotide.

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“…Silencing of genes by DNA hypermethylation could be the sole mechanism of gene inactivation, or cooperate with genetic mechanisms to inactivate putative tumor suppressor genes in tumors. Recently, it was reported that BMP3B, a member of the BMP family, was methylated in non-small-cell lung cancer (Dai et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas

Akiyama

et al. 2005

Oncogene

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Recently, it was reported that exogenous bone morphogenetic protein (BMP)-2 acted as an antiproliferative agent in a variety of cell lines, including normal and cancerous gastric cell lines, indicating that BMP-2 plays an important role during cell growth. However, despite the loss of BMP-2 expression in several cancers, the underlying mechanism remains unknown. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. In this study, we found, through analysis by the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in gastric and colon cancer cell lines. BMP-2 mRNA was found to be activated after 5-aza-2 0 -deoxycytidine treatment of the methylation-positive cells. Moreover, 24 of the 56 (42.9%) gastric cancer tissues exhibited promoter methylation. Immunohistochemical staining revealed that 18 of the 24 (75%) gastric cancer tissues without methylation signals exhibited BMP-2 expression, whereas among 20 cancer tissues with strong methylation signals only four (20%) expressed BMP-2 (P ¼ 0.0003). These findings indicate that BMP-2 methylation is strongly associated with the loss of BMP-2 protein expression in the primary gastric carcinomas. BMP-2 methylation was more often observed in diffuse type (60.7%) than in intestinal type (25%) gastric carcinomas (P ¼ 0.007). Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to gastric carcinogenesis, particularly in the diffuse type.

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Bone morphogenetic protein 3B silencing in non-small-cell lung cancer

Cited by 53 publications

References 32 publications

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

Eicosapentaenoic Acid Demethylates a Single CpG That Mediates Expression of Tumor Suppressor CCAAT/Enhancer-binding Protein δ in U937 Leukemia Cells

Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas

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