Abstract LB-091: Tumor suppressor WW domain-containing oxidoreductase controls epidermal keratinocyte growth

Abstract

Abstract Human fragile WWOX gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase. Ectopically overexpressed WWOX protein induces apoptosis in cancer cells and suppresses tumor growth both in vitro and in vivo. Functional suppression of WWOX by antisense mRNA, dominant negatives, and small interfering RNA protects cells from apoptosis induced by tumor necrosis factor, anticancer drugs, UV light, and ectopic p53 in vitro. Interestingly, substantial studies have revealed that progression of various cancers to a pre-metastatic stage positively correlates with upregulation of WWOX protein expression, suggesting that WWOX may act more than a tumor suppressor. In normal human epidermis, WWOX is abundant in proliferating epithelial cells of the skin, and its expression is increased in intensity toward the superficial layers. In this study, we determined a reduced number of Ki67-positive proliferating keratinocytes in the epidermis of our newly developed Wwox gene knockout (Wwox-/-) mice. A marked reduction in the basal (K5-positive) and suprabasal (K10-positive) keratinocyte numbers was examined in the keratinized squamous epithelium of the Wwox-/- mouse skin. Apparent decreases in Wwox-/- epidermal and dermal thickness were found. To further verify whether WWOX regulates keratinocyte growth, we detected significantly decreased cell proliferation in both Wwox-/- primary keratinocyte cultures and WWOX-knockdown HaCaT cells as compared to the control cells. No significant increases in the number of TUNEL-positive cells were observed in the Wwox-/- epidermal tissues. Taken together, our results clearly demonstrated a crucial role of tumor suppressor WWOX in regulating normal keratinocyte proliferation for maintaining skin homeostasis. Note: This abstract was not presented at the meeting. Citation Format: Li-Jin Hsu. Tumor suppressor WW domain-containing oxidoreductase controls epidermal keratinocyte growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-091.