TY - JOUR
T1 - RhoB promotes cancer initiation by protecting keratinocytes from UVB-induced apoptosis but limits tumor aggressiveness
AU - Meyer, Nicolas
AU - Peyret-Lacombe, Alexis
AU - Canguilhem, Bruno
AU - Médale-Giamarchi, Claire
AU - Mamouni, Kenza
AU - Cristini, Agnese
AU - Monferran, Sylvie
AU - Lamant, Laurence
AU - Filleron, Thomas
AU - Pradines, Anne
AU - Sordet, Olivier
AU - Favre, Gilles
N1 - Funding Information:
This study was supported by Institut National de la Recherche Médicale (INSERM), Institut Claudius Regaud Comprehensive Cancer Center, Centre Hospitalier et Universitaire (CHU) de Toulouse, Université Paul-Sabatier, the Ligue Nationale de Lutte Contre le Cancer, Comité Haute-Garonne, and The Research and Therapeutic Innovation in Cancer (RTIC) Foundation. We thank GC Prendergast (The Lankenau Institute for Medical Research, Wynnewood, PA) for kindly providing the rhob-/- mice, Philippe Rochaix for his technical contribution and fruitful discussions, S Cabantous for reading the manuscript, and D Berg for technical assistance.
PY - 2014/1
Y1 - 2014/1
N2 - The role of UVB-induced apoptosis in the formation of squamous cell carcinoma (SCC) is recognized. We previously identified the small RhoB (Ras homolog gene family, member B) GTPase, an early response gene to cellular stress, as a critical protein controlling apoptosis of human keratinocytes after UVB exposure. Here we generated SKH1 (hairless immunocompetent mouse) mice invalidated for RhoB to evaluate its role in UVB-induced skin carcinogenesis in vivo. We show that rhob-/- mice have a lower risk of developing UVB-induced keratotic tumors and actinic keratosis that is associated with a higher sensitivity of UVB-exposed keratinocytes to apoptosis. We extend this observation to primary cultures of normal human keratinocytes in which RhoB was downregulated with small interfering RNA (siRNA) and further show that the hypersensitivity to apoptosis depends on B-cell lymphoma 2 (Bcl-2) downregulation. In rhob-/- mice, the UVB-induced tumors were preferentially undifferentiated and highly proliferative. Finally, we show in humans an almost constant loss of RhoB expression in undifferentiated SCCs. These undifferentiated and RhoB-deficient tumors have elevated phosphorylated histone H2AX (γH2AX) and 53BP1, two markers of DNA double-strand breaks. Together, our results indicate that UVB-induced RhoB expression participates in in vivo SCC initiation by increasing keratinocyte survival. Conversely, RhoB may limit tumor aggressiveness as loss of RhoB expression in tumor cells is associated with tumor progression.
AB - The role of UVB-induced apoptosis in the formation of squamous cell carcinoma (SCC) is recognized. We previously identified the small RhoB (Ras homolog gene family, member B) GTPase, an early response gene to cellular stress, as a critical protein controlling apoptosis of human keratinocytes after UVB exposure. Here we generated SKH1 (hairless immunocompetent mouse) mice invalidated for RhoB to evaluate its role in UVB-induced skin carcinogenesis in vivo. We show that rhob-/- mice have a lower risk of developing UVB-induced keratotic tumors and actinic keratosis that is associated with a higher sensitivity of UVB-exposed keratinocytes to apoptosis. We extend this observation to primary cultures of normal human keratinocytes in which RhoB was downregulated with small interfering RNA (siRNA) and further show that the hypersensitivity to apoptosis depends on B-cell lymphoma 2 (Bcl-2) downregulation. In rhob-/- mice, the UVB-induced tumors were preferentially undifferentiated and highly proliferative. Finally, we show in humans an almost constant loss of RhoB expression in undifferentiated SCCs. These undifferentiated and RhoB-deficient tumors have elevated phosphorylated histone H2AX (γH2AX) and 53BP1, two markers of DNA double-strand breaks. Together, our results indicate that UVB-induced RhoB expression participates in in vivo SCC initiation by increasing keratinocyte survival. Conversely, RhoB may limit tumor aggressiveness as loss of RhoB expression in tumor cells is associated with tumor progression.
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U2 - 10.1038/jid.2013.278
DO - 10.1038/jid.2013.278
M3 - Article
C2 - 23792460
AN - SCOPUS:84891041861
SN - 0022-202X
VL - 134
SP - 203
EP - 212
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 1
ER -