EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

Bornachea, Olga; Santos, Mirentxu; Martínez-Cruz, Ana Belén; García‐Escudero, Ramón; Dueñas, Marta; Costa, Clotilde; Segrelles, Carmen; Lorz, Corina; Buitrago, Agueda; Sáiz-Ladera, Cristina; Agirre, Xabier; Grande, Teresa; Paradela, Beatriz; Maraver, Antonio; Ariza, José M.; Prósper, Felipe; Serrano, Manuel; Sanchez-Cespedes, Montse; Paramio, Jesús M.

doi:10.1038/srep00434

Cited by 78 publications

(87 citation statements)

References 88 publications

(145 reference statements)

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“…Adenovirus expressing Cre recombinase was obtained from University of Iowa's Vector Core Facility (www.uiowa.edu) and surgically delivered to the bladder lumen as previously described (13). At the time of sacrifice, tissues were collected and processed as previously reported (16, 17, 21). …”

Section: Methodsmentioning

confidence: 99%

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

et al. 2014

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Bladder cancer (BC) is a highly prevalent human disease in which retinoblastoma (Rb) pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here we show that the in vivo inactivation of all Retinoblastoma (Rb) family genes in the mouse urothelium is sufficient to initiate BC development. The characterization of the mouse tumors revealed multiple molecular features of human BC, including the activation of E2F transcription factor and subsequent Ezh2 expression, and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. These mice represent a genetically defined model for human high-grade superficial BC. Whole transcriptional characterizations of mouse and human bladder tumors revealed a significant overlap and confirm the predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, the increased tumor recurrence and progression in human superficial BC patients is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial BC and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.

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Section: Methodsmentioning

confidence: 99%

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

et al. 2014

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“…Although loss of p53 does not sensitize the skin to early tumorigenesis, it accelerates cancer progression (Kemp et al, 1993;Bornachea et al, 2012). Interestingly, genomic instability appears to contribute to the spontaneous tumors developed in p53 knockout mouse epidermis (Martínez-Cruz et al, 2009).…”

Section: Implications Into Skin Homeostasis and Cancermentioning

confidence: 96%

Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage

et al. 2014

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Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.

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“…Primary mouse embryonic fibroblasts were obtained from E13.5 C57BL/6 embryos. Mouse embryonic fibroblasts, murine-transformed keratinocyte cell line PB 33,34 (a kind gift of Jesus Paramio), human NTERA2 teratocarcinoma cells, oesophageal cancer cell lines TE1 and TE2 (ref. 55) (a kind gift of Anil Rustgi), and human HNSCC cell lines Cal27, Cal33 and HN6 (refs 56,57) (a kind gift of J. Paramio) and SCC40, SCC38, SCC29, SCC42B and SCC2 (ref.…”

Section: Methodsmentioning

confidence: 99%

“…To further explore the link between NANOG and aurora kinases, we recapitulated the above in vivo observations in a mouse keratinocyte cell line, PB 33,34 . Indeed, overexpression of NANOG resulted in a significant transcriptional upregulation of Aurka and Aurkb mRNA levels (Fig.…”

Section: Sa-2xpamentioning

confidence: 99%

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

et al. 2014

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NANOG is a pluripotency transcription factor in embryonic stem cells; however, its role in adult tissues remains largely unexplored. Here we show that mouse NANOG is selectively expressed in stratified epithelia, most notably in the oesophagus where the Nanog promoter is hypomethylated. Interestingly, inducible ubiquitous overexpression of NANOG in mice causes hyperplasia selectively in the oesophagus, in association with increased cell proliferation. NANOG transcriptionally activates the mitotic programme, including Aurora A kinase (Aurka), in stratified epithelia, and endogenous NANOG directly binds to the Aurka promoter in primary keratinocytes. Interestingly, overexpression of Nanog or Aurka in mice increased proliferation and aneuploidy in the oesophageal basal epithelium. Finally, inactivation of NANOG in cell lines from oesophageal or head and neck squamous cell carcinomas (ESCCs or HNSCCs, respectively) results in lower levels of AURKA and decreased proliferation, and NANOG and AURKA expression are positively correlated in HNSCCs. Together, these results indicate that NANOG has a lineage-restricted mitogenic function in stratified epithelia.

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EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

Cited by 78 publications

References 88 publications

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

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