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PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

ABSTRACT: The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/?-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation injury, genetic ablation of PAF impairs intestinal regeneration along with the severe loss of ISCs and Myc expression. Mechanistically, PAF conditionally occupies and transactivates the c-Myc promoter, which induces the expansion of ISCs/IPCs during intestinal regeneration. In mouse models, PAF knockout inhibits Apc inactivation-driven intestinal tumorigenesis with reduced tumor cell stemness and suppressed Wnt/?-catenin signaling activity, supported by transcriptome profiling. Collectively, our results unveil that the PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells.

SUBMITTER: Kim MJ

PROVIDER: S-EPMC5854208 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

Kim Moon Jong MJ Xia Bo B Suh Han Na HN Lee Sung Ho SH Jun Sohee S Lien Esther M EM Zhang Jie J Chen Kaifu K Park Jae-Il JI

Developmental cell 20180301 5

The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/β-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation inj ...[more]

PMID: 29533773

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Project description:BACKGROUND: Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/?-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5?N?cat previously generated by our team present a constitutive activation of Wnt/?-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5?N?cat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers. METHODS: Microarray analysis was used to compare K5?N?cat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5?N?cat mice. Stem cell amplification in K5?N?cat mouse mammary epithelium was assessed with 3D-culture and transplantation assays. RESULTS: Histological and microarray analyses of the mammary lesions of K5?N?cat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5?N?cat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5?N?cat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5?N?cat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis. CONCLUSIONS: These results strongly indicate that ?-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.

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PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

Publications

PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

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