Background: Beckwith-Wiedemann syndrome (BWS) is a hereditary human cancer stem cell syndrome with an 800 fold risk of multiple cancers, is currently linked to deregulated imprinting at chromosome 11p15, IGF2, CDKN1C and others. Yet, causal molecular defects and genetic models of this overgrowth syndrome have remained elusive to date in the majority of cases. CCCTC-Binding Factor CTCF is a highly conserved zinc finger protein that has diverse regulatory functions, including transcriptional ctivation/repression/imprinting of molecules such as TERT, IGF-2 and c-Myc.
Recent studies demonstrate a high frequency of TERT promoter mutations in early stage of multiple cancers, suggesting that these promoter mutations may function as driver events that contribute to oncogenesis through TERT deregulation. However, telomerase remains a challenge to target effectively. We have recently discovered identified a mouse model for BWS with loss of TGF-β signaling with multiple liver and GI cancers. CTCF expression is markedly decreased, with concomitantly high TERT levels in these cancers. Therefore, we hypothesize that TGF-β/β2SP/Smad3/ signaling regulates CTCF and TERT regulation. Rescuing TGF-β signaling may successfully reduce tumor burden with inhibition of telomerase.
Materials & Methods: Generation of β2SP+/-/Smad3+/- mice and genotype analysis. Database of Genomics (COSMIC) and transcriptomics (TCGA) were analyzed. BWS tumors and mice liver, pancreas and stomach tissue specimens were immunostained with anti-TERT antibody. ChIP assays were to demonstrate the recruitment of β2SP/Smad3/CTCF at the promoter of TERT.
Results: (1) β2SP+/-/Smad3+/- heterozygote mice spontaneously develop visceromegaly, multiple cancers, phenocopy a hereditary human cancer stem cell syndrome BWS. (2) Genomics and transcriptomics analyses revealed aberrant TGF-β signaling in β2SP+/-/Smad3+/- mice and human BWS. (3) Increased TERT expression in β2SP+/-/Smad3+/- mice is similar to that observed in human BWS. (4) CTCF levels are markedly decreased in β2SP+/-/Smad3+/- mice tissues. (5) CTCF interacts with β2SP/Smad3 in cell nucleus in a TGF-β-dependent manner. (6) TGF-β promotes the complex of β2SP/Smad3/CTCF at TERT promoter region. Conclusions: Loss of TGF-β signaling pathway leads to dysfunctional chromosome modulation through TERT deregulation. Smad3/β2SP/CTCF complex regulates TERT transcriptional activity. Our results provide a better mechanistic understanding of this dysfunctional stem cells cancer syndrome. Importantly, this study may lead to identify new treatment strategies and functional markers for the early detecting lethal cancers.
Citation Format: Jian Chen, Jiun-Sheng Chen, Zhixing Yao, Wilma Jogunoori, Bibhuti Mishra, Lopa Mishra. Telomerase modulation in a human cancer stem cell syndrome with loss of TGF-β signaling is a promising treatment strategy in liver and gastrointestinal cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 115. doi:10.1158/1538-7445.AM2014-115