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A cross section of a mouse esophagus. The dark brown staining shows
epithelial cells containing NANOG protein. Image Credit: CNIO
The esophagus (American English) or oesophagus (British English),
Gene essential in embryos, toxic in adult cell division
A gene factor called NANOG is essential to pluripotency in the embryo as it implants in the womb. It also regulates cell proliferation in skin, epithelia cells, and the esophagus of adult organisms. In fact, blocking NANOG reduces division in tumor cells.
Scientists from the Spanish National Cancer Research Centre (CNIO) have discovered that NANOG, an essential gene for embryonic stem cells, also regulates cell division in stratified epithelia cells — those cells that form part of the epidermis of the skin or cover the esophagus and even line the vagina — of adult organisms.
According to the conclusions of a study, published in the journal Nature Communications, this factor could also play a role in the formation of tumors arising from stratified epithelia cells in the esophagus and skin.
NANOG is essential to cell pluripotency. It is active during a period just two days prior to the embryo implanting in the uterus (day 5 to day 7 post (following) fertilization).
In this critical period of embryo development, NANOG contributes to the extraordinary capacity of embryonic stem cells to become all of the tissues of an adult organism, an ability technically known as pluripotency.
Up until now, it was thought that the function of NANOG was limited to the 2 days immediately prior to an egg implanting in the uterine wall. Now, the CNIO study led by Manuel Serrano and Daniela Piazzolla shows that NANOG also plays a role in adult cells.
Researchers studied a line of mice that can be programmed to turn on NANOG for a limited period of time. When NANOG was increased, epithelia cells, hyperplasia, and the amount of DNA damage also increased.
"Interestingly, the effects of NANOG were only observed in stratified epithelia, whereas other tissues, such as the liver or kidney, were completely unaffected," says Serrano. This reinforces the idea that NANOG operates only in stratified epithelial cells.
"Using genome-wide analysis, we found that NANOG is able to specifically regulate cell proliferation in these tissues using the protein AURKA, which partly controls cell division," says Serrano. When the researchers blocked the action of NANOG, the cell proliferation index was reduced. "This tells us that these cancerous cells depend on NANOG activity to maintain their high proliferation rate and cancerous properties," adds Serrano.
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.
Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia. Piazzolla D, Palla AR, Pantoja C, Cañamero M, de Castro IP, Ortega S, Gómez-López G, Dominguez O, Megías D, Roncador G, Luque-Garcia JL, Fernandez-Tresguerres B, Fernandez AF, Fraga MF, Rodriguez-Justo M, Manzanares M, Sánchez-Carbayo M, García-Pedrero JM, Rodrigo JP, Malumbres M, Serrano M. Nature Communications (2014). doi: 10.1038/ncomms5226.
The study has benefitted from the participation of CNIO researchers Marcos Malumbres and Ignacio Pérez de Castro, who are experts on protein AURKA and its role in the cell cycle. This work has been funded by the Ministry of Economy and Competitiveness, the European Union, the Community of Madrid, the Botín Foundation, the Ramón Areces Foundation, and the AXA Foundation.
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