title: RhoB promotes cancer initiation by protecting keratinocytes from UVB-induced apoptosis but limits tumor aggressiveness.
abstract: 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.
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France; Department of Dermatology, Hôpital Larrey, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meyer
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Peyret-Lacombe
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Canguilhem
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Médale-Giamarchi
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Kenza
authors.initials: K
authors.lastname: Mamouni
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Agnese
authors.initials: A
authors.lastname: Cristini
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monferran
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France; Department of Pathology, Hôpital Purpan, Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.affiliation: Department of Biostatistics, Institut Claudius Regaud, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France; Department of Biopathology, Institut Claudius Regaud, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Pradines
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sordet
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France; Université Paul Sabatier, Toulouse, France; Department of Biopathology, Institut Claudius Regaud, Toulouse, France. Electronic address: favre.gilles@claudiusregaud.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008812:Mice, Hairless; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000473:pathology*; D014466:Ultraviolet Rays / Q000009:adverse effects; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D020743:rhoB GTP-Binding Protein