Targeting Integrin αvβ3 by Liposome-Tetrac Induce Dual Inhibitory Effects on Proliferation in Cholangiocarcinoma

Cell surface receptors play vital roles in cancer growth and metastasis. Overexpressed integrin αvβ3 in various cancer cells and crosstalk with the epidermal growth factor receptor further stimulated cancer progression. Thyroid hormone binds to integrin αvβ3 to activate signal transduction and cell proliferation. However, thyroxine (T ₄ ) deaminated analogue, tetraiodothyronine (tetrac), competes for the binding on integrin and inhibits cancer cell growth and metastasis. The current study investigated the pathogenic effect of thyroid hormone and EGF in cholangiocarcinoma and the potential of a novel therapeutic strategy. Pathogenetic studies of clinical samples revealed integrin αvβ3, EGFR, and (PD-ligand 1) PD-L1 related to the progression of cholangiocarcinoma malignancy. EGF and thyroxine stimulated PD-L1 expression. The thyroxine-induced PD-L1 accumulated in the nuclei and colocalized with p300. Alternatively, EGF increased PD-L1 and nuclear accumulation of β-catenin. Clinical evidence supported the potential targeting roles of integrin αvβ3 and EGFR for cancer therapy. Targeting integrin αvβ3 with liposome-tetrac inhibited EGFR-dependent signal transduction, PD-L1 expression, and cancer growth in xenograft model. Liposome-tetrac and its Dox-derivative targeted integrin αvβ3 performed dual targeting inhibitory effects on integrin αvβ3 and EGFR to inhibit cholangiocarcinoma growth. Our research provides significant findings that will inform and enlighten the field of cholangiocarcinoma treatment.