RESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Carcinoma Basocelular/patologia , Proliferação de Células , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Proteína Rica em Cisteína 61/biossíntese , Fosfoproteínas/biossíntese , Neoplasias Cutâneas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Biomarcadores Tumorais/análise , Western Blotting , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/genética , Proteína Rica em Cisteína 61/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Imuno-Histoquímica , Queratinócitos/patologia , Microdissecção e Captura a Laser , Pessoa de Meia-Idade , Fosfoproteínas/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Células Estromais/patologia , Fatores de Transcrição , Transfecção , Proteínas de Sinalização YAPRESUMO
Microscopic colitis (MC) is a chronic inflammation condition of the colon characterized by watery diarrhea and normal appearing mucosa. A 75-year-old female presented with one-year history of chronic diarrhea while taking cannabidiol (CBD) for pain. Colonoscopy with random colon biopsies revealed collagenous colitis. She started budesonide and stopped CBD. At six-week follow-up, her diarrhea improved, and the budesonide dose was decreased. She restarted CBD oil twice but had diarrhea both times. Her diarrhea resolved after taking budesonide and stopping CBD. We report a case of CBD-associated MC to make clinicians aware of this potential adverse effect in patients who chronically use CBD.