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Loss of the transforming growth factor-? effector ?2-Spectrin promotes genomic instability.

ABSTRACT: Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ?/mothers against decapentaplegic homolog 3 adaptor ?2-Spectrin (?2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ?2SP supports DNA repair through ?2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ?2SP leads to decreased Fancd2 levels and sensitizes ?2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ? stimulation is regulated by the ?2SP/mothers against decapentaplegic homolog 3 complex.Conclusion: Dysfunctional transforming growth factor ?/?2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

SUBMITTER: Chen J

PROVIDER: S-EPMC5432427 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability.

Chen Jian J Shukla Vivek V Farci Patrizia P Andricovich Jaclyn J Jogunoori Wilma W Kwong Lawrence N LN Katz Lior H LH Shetty Kirti K Rashid Asif A Su Xiaoping X White Jon J Li Lei L Wang Alan Yaoqi AY Blechacz Boris B Raju Gottumukkala S GS Davila Marta M Nguyen Bao-Ngoc BN Stroehlein John R JR Chen Junjie J Kim Sang Soo SS Levin Heather H Machida Keigo K Tsukamoto Hidekazu H Michaely Peter P Tzatsos Alexandros A Mishra Bibhuti B Amdur Richard R Mishra Lopa L

Hepatology (Baltimore, Md.) 20161224 2

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor β/mothers against decapentaplegic homolog 3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi a ...[more]

PMID: 28114741

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Project description:Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor-suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild-type (WT) and β2-spectrin (β2SP)+/- (SPTBN1) mice. CD133+ LSCs derived from preneoplastic livers of β2SP+/- mice treated with interleukin-6 (pIL6; IL6 β2SP+/- LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6 WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6 β2SP+/- LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial-mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFκB; RELA). Knockdown of NFκB decreased the EMT phenotypes and metastatic capacity of these cells. NFκB in IL6 β2SP+/- LSCs was activated by transforming growth factor β (TGFβ)-activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin-6 (IL6) expression. The amount of constitutively activated NFκB increased dramatically from normal to cirrhotic to HCC tissues from human patients.ConclusionIL6-mediated inflammation programs constitutive activation of the TAK1-NFκB signaling cascade in CD133+ LSCs, and this program interacts with deficient TGFβ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT-positive mCSCs in HCC-free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222-1236).

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Loss of the transforming growth factor-? effector ?2-Spectrin promotes genomic instability.

Publications

Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability.

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