PMC:5608921 / 1478-4663 JSONTXT

{"project":"2_test","denotations":[{"id":"28846079-21376230-79081889","span":{"begin":95,"end":96},"obj":"21376230"},{"id":"28846079-25554788-79081890","span":{"begin":98,"end":99},"obj":"25554788"},{"id":"28846079-25554788-79081891","span":{"begin":203,"end":204},"obj":"25554788"},{"id":"28846079-15549094-79081892","span":{"begin":356,"end":357},"obj":"15549094"},{"id":"28846079-24926024-79081893","span":{"begin":463,"end":464},"obj":"24926024"},{"id":"28846079-25554788-79081894","span":{"begin":607,"end":608},"obj":"25554788"},{"id":"28846079-19741607-79081895","span":{"begin":750,"end":751},"obj":"19741607"},{"id":"28846079-20804975-79081896","span":{"begin":753,"end":754},"obj":"20804975"},{"id":"28846079-24813615-79081897","span":{"begin":877,"end":878},"obj":"24813615"},{"id":"28846079-23715544-79081898","span":{"begin":1046,"end":1047},"obj":"23715544"},{"id":"28846079-23715544-79081899","span":{"begin":1354,"end":1355},"obj":"23715544"},{"id":"28846079-16921403-79081900","span":{"begin":1357,"end":1358},"obj":"16921403"},{"id":"28846079-25305068-79081901","span":{"begin":1521,"end":1523},"obj":"25305068"},{"id":"28846079-20682446-79081902","span":{"begin":1525,"end":1527},"obj":"20682446"},{"id":"28846079-17342777-79081903","span":{"begin":1886,"end":1888},"obj":"17342777"},{"id":"28846079-24018418-79081904","span":{"begin":2009,"end":2011},"obj":"24018418"},{"id":"28846079-16456137-79081905","span":{"begin":2013,"end":2015},"obj":"16456137"},{"id":"28846079-18026629-79081906","span":{"begin":2176,"end":2178},"obj":"18026629"},{"id":"28846079-16597322-79081907","span":{"begin":2440,"end":2442},"obj":"16597322"},{"id":"28846079-8411377-79081908","span":{"begin":2546,"end":2548},"obj":"8411377"},{"id":"28846079-16597322-79081909","span":{"begin":2652,"end":2654},"obj":"16597322"},{"id":"28846079-15767402-79081910","span":{"begin":2656,"end":2658},"obj":"15767402"},{"id":"28846079-8610145-79081911","span":{"begin":2820,"end":2822},"obj":"8610145"},{"id":"28846079-15699322-79081912","span":{"begin":2824,"end":2826},"obj":"15699322"},{"id":"28846079-18548112-79081913","span":{"begin":3071,"end":3073},"obj":"18548112"}],"text":"Introduction\nGrowth is a condition that predisposes tissues to initiate a carcinogenic process.1, 2 Accordingly, tissues that carry out continuous renewal during adult life have high incidence of tumors,2 and their specific stem cells are the main candidates for cancer initiation. In addition, injury, another condition associated with cancer development,3 forces tissues to recruit cells from other niches to fulfill the high demand of cells needed for healing.4 The self-renewal capacity of stem cells places them as the major target for the accumulation of mutations that trigger a carcinogenic process.2 However, recent studies have shown the emergence of tumors from transient proliferating progenitors or from postmitotic differentiated cells.5, 6\nA hallmark of tissue renewal, repair and regeneration is the activation of cell proliferation, differentiation and growth.7 Thus, it is not surprising that proto-oncogenes and tumor suppressors participate in these processes by promoting cell proliferation and differentiation, respectively.8 In this context, it is interesting the evolution of the Ink4a locus encoding in mammals for Arf and p16Ink4a, key regulators of the p53 and pRb1 pathways; this locus in lower vertebrates, including amphibians, encodes exclusively for p16Ink4a, possibly causing a marked difference in cell cycle regulation.8, 9 Furthermore, in addition to the increase in cell proliferation, reducing the activity of these tumor suppressors facilitates cell reprogramming/dedifferentiation,10, 11 a process common to regeneration and cancer.\nCervical–uterine cancer is the cause of many deaths worldwide. Cervical–uterine endometrium is a continuously renewing tissue during the whole reproductive life. The estrous cycle is a hormonally regulated process whose phases can be distinguished by the marked growth changes occurring in the reproductive tract.12 Slow dividing stem cells have been identified in this tissue, which proliferate upon estrogen receptor (ER) stimulation.13, 14 Infection by human papillomavirus (HPV) is a major etiological factor associated with cervical–uterine cancer, though cancer incidence in infected women is low.15 Although, it is predicted that stem cells are the target of HPV oncogenes during cancer initiation, viral replication and expression of major HPV oncogenes (e.g., E6, E7) occur in the suprabasal layers of the growing epithelium to ensure a productive infection.16 Accordingly, LacZ expression driven by the Long-Control-Region of HPV was located in suprabasal layers.17 Actually, it has been proposed that E6/E7 could promote cell cycle re-entry in upper epithelial layers.16, 18\nMouse models of cervical–uterine cancer have been developed previously by directing the expression of HPV oncogenes to the basal layer of epithelia (K14+ cells).19, 20 Here, we determined the effect of E6/E7 HPV oncogenes on cervical epithelium renewal when expressed in suprabasal layers (K6b+ cells) during the growing phases. In addition, taking advantage of the increased regenerative capacity of these mice,21 we compared the growth effect on ear regeneration and cervix renewal in response to oncogenes and/or estradiol."}