Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation.
Yes-associated protein (YAP) is a transcriptional co-activator of hippo signaling pathway, which plays an important role in organ size control and tumorigenesis. Here we report that YAP and its downstream transcriptional targets CCN1 and CCN2 are markedly elevated in keratinocytes in human skin basal cell carcinoma tumor islands. In human keratinocytes, knockdown of YAP significantly reduced expression of CCN1 and CCN2, and repressed proliferation and survival. This inhibition of proliferation and survival was rescued by restoration of CCN1 expression, but not by CCN2 expression. In basal cell carcinoma stroma, CCN2-regulated genes type I collagen, fibronectin, and α-smooth muscle actin were highly expressed. Furthermore, atomic force microscopy revealed increased tissue stiffness in basal cell carcinoma stroma compared to normal dermis. These data provide evidence that up-regulation of YAP in basal cell carcinoma impacts both aberrant keratinocyte proliferation, via CCN1, and tumor stroma cell activation and stroma remodeling, via CCN2. Targeting YAP and/or CCN1 and CCN2 may provide clinical benefit in basal cell carcinoma.
Department of Dermatology, University of Michigan, Ann Arbor, Michigan. Electronic address: thquan@umich.edu.
Taihao
T
Quan
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Yiru
Y
Xu
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Zhaoping
Z
Qin
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Patrick
P
Robichaud
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Stephanie
S
Betcher
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Ken
K
Calderone
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Tianyuan
T
He
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Timothy M
TM
Johnson
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
John J
JJ
Voorhees
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Gary J
GJ
Fisher
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D055515:Cysteine-Rich Protein 61 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000473:pathology; D061346:Laser Capture Microdissection; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology; D014157:Transcription Factors; D014162:Transfection; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C501848:CCN1 protein, human; C526317:CCN2 protein, human; D055515:Cysteine-Rich Protein 61; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor