Abstract 2861: ACKR3 promotes cell metastasis via activating TGF-beta 1/Smad signaling in head and neck squamous cell carcinoma

Abstract

Abstract Background: The atypical chemokine receptor, ACKR3, has been shown to play as a tumor promoter, which is upregulated in various types of cancer. However, the biological role of ACKR3 and its underlying mechanism in head and neck squamous cell carcinoma (HNSCC) is still unknown. In this study, we investigated the functional role of ACKR3 and the underlying molecular mechanism of tumor progression in HNSCC. Methods: We examined the ACKR3 expression and its association with clinicopathological characteristics in 103 cases of HNSCC by immunohistochemical staining. The biological roles of ACKR3- and ACKR3-induced downstream signaling were investigated in HNSCC cell through ACKR3 overexpression and knockdown of ACKR3 in vitro and in vivo. Results: We detected differential expression of ACKR3 in HNSCC cells and tissues. High ACKR3 expression was significantly associated with invasion depth of tumor (T status; P = 0.007), lymph node involvement (N status; P = 0.004), and higher stage III/IV (P = 0.02). Overexpression of ACKR3 dramatically enhanced cell migration and invasion in HNSCC cells in vitro, and promoted lymph node metastasis in vivo. ACKR3 overexpression also induced the epithelial-mesenchymal transition. Vimentin, Slug, and Twist were increased but E-cadherin and Ep-CAM were decreased by ACKR3 expression. Upregulation of TGF-β1 was observed in ACKR3 overexpression, and TGF-β1/Smad signaling activation and Akt phosphorylation were induced in HNSCC cells with ACKR3 overexpression. Treatment with a PI3K inhibitor reduced Slug and Twist levels while suppression of Smad2/3 signaling by siRNA reduced Akt phosphorylation, as well as Slug and Twist. Furthermore, inhibition of Smad2/3 decreased tumor cell migration and invasion in HNSCC. ACKR3 knockdown using siRNA in HNSCC cells reduced the secretion of TGF-β1 and also recovered the cell migratory and invasive behavior of HNSCC cells. Conclusions: ACKR3 expression was associated with an aggressive tumor behavior in HNSCC. ACKR3 contributed to migration and invasion of HNSCC cell through the TGF-β1/Smad signaling axis and epithelial-mesenchymal transition in vitro, and was involved in lymph node metastasis in vivo, suggesting that ACKR3 plays an important role during HNSCC progression and metastasis. Citation Format: Nayoung Kim, Solbi Kim, Mina Joo, Heung Jin Jeon, Myung-Won Lee, Hyewon Ryu, Hyo Jin Lee. ACKR3 promotes cell metastasis via activating TGF-beta 1/Smad signaling in head and neck squamous cell carcinoma [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 2861.