<b>TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells</b>

Cárdenas, Horacio; Vieth, Edyta; Lee, Jiyoon; Segar, Matthew W.; Liu, Yunlong; Nephew, Kenneth P.; Matei, Daniela

doi:10.4161/15592294.2014.971608

Cited by 140 publications

(122 citation statements)

References 53 publications

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“…Previously, GPR135 has been reported to be hypermethylated in epithelial-mesenchymal transition induced by TGF-beta in ovarian cancer cells. 35 ZSCAN31 is thought to act as a transcription factor; it is claimed to be involved in airway structure or remodeling, with genetic variants leading to lowered lung function. 36 Differential methylation was shown in T versus N also for the first time within zinc finger proteins ZNF311, ZNF831 and ZIC5.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 3 10 219 , mean change in beta [D] 20.09), GPR135 (FDR 1.87 3 10 28 , mean D 20.09) and TPO (FDR 8.58 3 10 25 , mean D 20.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.Lung cancer is the leading cause of cancer-related deaths, accounting for around every fifth global cancer death. 1 While tobacco smoking remains the principal risk factor for lung carcinogenesis, exposure to asbestos, a group of naturally occurring fibrous silicate minerals with multiple commercial applications, is the most important occupational risk factor for lung cancer. 2 Asbestos exposure causes 6 to 23% of all male lung cancers (estimates depending on the exposure and population), and >107,000 deaths annually from asbestosrelated diseases. 3,4 All forms of asbestos are carcinogenic to

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Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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“…TGFβ promotes OC invasion [26], a process often linked to EMT, and further affects gene methylation during EMT [27]. The involvement of the TGFβ pathway in EMT has been studied in different models.…”

Section: Discussionmentioning

confidence: 99%

TGFβ splicing and canonical pathway activation in high-grade serous carcinoma

et al. 2017

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The present study analyzed the expression and clinical role of the transforming growth factor-β (TGFβ) pathway in high-grade serous carcinoma (HGSC), with focus on malignant effusions. TGFβ1-3 and TGFβRI-III mRNA expression by qRT-PCR was analyzed in 70 HGSC effusions and 55 solid specimens (28 ovarian, 27 abdominal metastases). Protein expression of Smad2 and Smad3 and their phosphorylated forms by Western blotting was analyzed in 73 specimens (42 effusions, 13 ovarian carcinomas, 18 solid metastases). Expression was analyzed for association with anatomic site and clinical parameters, including survival. TGFβRI and TGFβRII mRNA was overexpressed in effusions and solid metastases, particularly the former, compared to that in the ovarian tumors (p < 0.001 to p = 0.05), with anatomic site-dependent expression of splice variants. Conversely, Smad2, p-Smad2, and p-Smad3 were overexpressed in solid specimens (ovarian and peritoneal) compared to those in effusions (p < 0.001 for all). In univariate survival analysis, higher TGFβRI variant 1 and TGFβRIII mRNA levels were associated with a trend for shorter overall survival in patients with post-chemotherapy effusions (p = 0.066 and p = 0.087, respectively), and the latter was an independent prognostic marker in Cox multivariate analysis (p = 0.041). Smad3 protein expression was associated with a trend for shorter overall survival in univariate survival analysis (p = 0.052). TGFβ receptor splice variant expression is anatomic site-dependent in HGSC. Elevated levels of TGFβ signaling pathway mRNAs are seen in metastatic HGSC, but are not accompanied by increased Smad expression and activation in HGSC effusions, evidence of failure to activate canonical TGFβ signaling. Assessment of the prognostic role of this pathway in HGSC effusions merits further research.

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“…It is possible that miR-30d transcription is under the control of TGF-A1Ystimulated promoter methylation. 29 In addition, it was found that TGF-A down-regulated miR-30s in a Smad2-dependent rather than Smad3-dependent manner in podocytes. 30 Elucidating the molecular underpinnings of TGF-AYinduced miR-30s reduction will contribute to understanding the regulatory network in TGF-AYtriggered EMT.…”

Section: Discussionmentioning

confidence: 99%