TY - JOUR
T1 - The role of oncogenic Ras in human skin tumorigenesis depends on the clonogenic potential of the founding keratinocytes
AU - Maurelli, Riccardo
AU - Tinaburri, Lavinia
AU - Gangi, Fabio Maria
AU - Bondanza, Sergio
AU - Severi, Anna Lisa
AU - Scarponi, Claudia
AU - Albanesi, Cristina
AU - Mesiti, Giuseppe
AU - Guerra, Liliana
AU - Capogrossi, Maurizio C.
AU - Dellambra, Elena
PY - 2016
Y1 - 2016
N2 - The role of Ras in human skin tumorigenesis induction is still ambiguous. Overexpression of oncogenic Ras causes premature senescence in cultured human cells and hyperplasia in transgenic mice. Here, we investigated whether the oncogenic insult outcome might depend on the nature of the founding keratinocyte. We demonstrate that overexpression of the constitutively active Ras- V12 induces senescence in primary human keratinocyte cultures, but that some cells escape senescence and proliferate indefinitely. Ras overexpression in transient-amplifying- or stem-cell-enriched cultures shows that p16 (encoded by CDKN2A) levels are crucial for the final result. Indeed, transient-amplifying keratinocytes expressing high levels of p16 are sensitive to Ras-V12-induced senescence, whereas cells with high proliferative potential, but that do not display p16, are resistant. The subpopulation that sustains the indefinite culture growth exhibits stem cell features. Bypass of senescence correlates with inhibition of the pRb (also known as RB1) pathway and resumption of telomerase reverse transcriptase (TERT) activity. Immortalization is also sustained by activation of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) and Akt pathways. Moreover, only transduced cultures originating from cultures bearing stem cells induce tumors in nude mice. Our findings demonstrate that the Ras overexpression outcome depends on the clonogenic potential of the recipient keratinocyte and that only the stem cell compartment is competent to initiate tumorigenesis.
AB - The role of Ras in human skin tumorigenesis induction is still ambiguous. Overexpression of oncogenic Ras causes premature senescence in cultured human cells and hyperplasia in transgenic mice. Here, we investigated whether the oncogenic insult outcome might depend on the nature of the founding keratinocyte. We demonstrate that overexpression of the constitutively active Ras- V12 induces senescence in primary human keratinocyte cultures, but that some cells escape senescence and proliferate indefinitely. Ras overexpression in transient-amplifying- or stem-cell-enriched cultures shows that p16 (encoded by CDKN2A) levels are crucial for the final result. Indeed, transient-amplifying keratinocytes expressing high levels of p16 are sensitive to Ras-V12-induced senescence, whereas cells with high proliferative potential, but that do not display p16, are resistant. The subpopulation that sustains the indefinite culture growth exhibits stem cell features. Bypass of senescence correlates with inhibition of the pRb (also known as RB1) pathway and resumption of telomerase reverse transcriptase (TERT) activity. Immortalization is also sustained by activation of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) and Akt pathways. Moreover, only transduced cultures originating from cultures bearing stem cells induce tumors in nude mice. Our findings demonstrate that the Ras overexpression outcome depends on the clonogenic potential of the recipient keratinocyte and that only the stem cell compartment is competent to initiate tumorigenesis.
KW - Clonogenic potential
KW - Primary human keratinocyte
KW - Ras
KW - Tumorigenesis
UR - http://www.scopus.com/inward/record.url?scp=84960384944&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84960384944&partnerID=8YFLogxK
U2 - 10.1242/jcs.176842
DO - 10.1242/jcs.176842
M3 - Article
AN - SCOPUS:84960384944
VL - 129
SP - 1003
EP - 1017
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 0021-9533
IS - 5
ER -