TY - JOUR

T1 - Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors

AU - Villarejo, Ana

AU - Molina-Ortiz, Patricia

AU - Montenegro, Yenny

AU - Moreno-Bueno, Gema

AU - Morales, Saleta

AU - Santos, Vanesa

AU - Gridley, Tom

AU - Perez-Moreno, Mirna

AU - Peinado, Héctor

AU - Portillo, Francisco

AU - Calés, Carmela

AU - Cano, Amparo

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015

Y1 - 2015

N2 - Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression.

AB - Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression.

KW - 9,10-Dimethyl-1,2-benzanthracene

KW - Animals

KW - Apoptosis

KW - Blotting, Western

KW - Carcinogens

KW - Cell Differentiation

KW - Cell Proliferation

KW - Cells, Cultured

KW - Fluorescent Antibody Technique

KW - Hematopoiesis

KW - Immunoenzyme Techniques

KW - Inflammation

KW - Keratinocytes

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Myeloid Progenitor Cells

KW - Neoplasms, Experimental

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Skin Neoplasms

KW - Snail Family Transcription Factors

KW - Transcription Factors

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/carcin/bgv021

DO - 10.1093/carcin/bgv021

M3 - Journal article

C2 - 25784375

VL - 36

SP - 585

EP - 597

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 5

ER -