Thyroid hormone receptor-interacting protein 13 (TRIP13) is involved in cancer progression, but its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. Thus, we assessed the expression, functional role, and mechanism of action of TRIP13 in PDAC. We further examined the efficacy of TRIP13 inhibitor, DCZ0415, alone or in combination with gemcitabine on malignant phenotypes, tumor progression, and immune response. We found that TRIP13 was overexpressed in human PDACs relative to corresponding normal pancreatic tissues. TRIP13 knockdown or treatment of PDAC cells with DCZ0415 reduced proliferation and colony formation, and induced G2/M cell cycle arrest and apoptosis. Additionally, TRIP13 knockdown or targeting with DCZ0415 reduced the migration and invasion of PDAC cells by increasing E-cadherin and decreasing N-cadherin and vimentin. Pharmacologic targeting or silencing of TRIP13 also resulted in reduce expression of FGFR4 and STAT3 phosphorylation, and downregulation of the Wnt/β-catenin pathway. In immunocompromised mouse models of PDAC, knockdown of TRIP13 or treatment with DCZ0415 reduced tumor growth and metastasis. In an immunocompetent syngeneic PDAC model, DCZ0415 treatment enhanced the immune response by lowering expression of PD1/PDL1, increasing granzyme B/perforin expression, and facilitating infiltration of CD3/CD4 T-cells. Further, DCZ0415 potentiated the anti-metastatic and anti-tumorigenic activities of gemcitabine by reducing proliferation and angiogenesis and by inducing apoptosis and the immune response. These preclinical findings show that TRIP13 is involved in PDAC progression and targeting of TRIP13 augments the anticancer effect of gemcitabine.

甲状腺激素受体相互作用蛋白 13 (TRIP13) 参与癌症进展，但其在胰腺导管腺癌 (PDAC) 中的作用尚不清楚。因此，我们评估了 TRIP13 在 PDAC 中的表达、功能作用和作用机制。我们进一步检查了 TRIP13 抑制剂 DCZ0415 单独或与吉西他滨联合使用对恶性表型、肿瘤进展和免疫反应的功效。我们发现 TRIP13 在人 PDAC 中相对于相应的正常胰腺组织过度表达。TRIP13 敲低或用 DCZ0415 处理 PDAC 细胞可减少增殖和集落形成，并诱导 G2/M 细胞周期停滞和凋亡。此外，TRIP13 敲低或 DCZ0415 靶向通过增加 E-钙粘蛋白并减少 N-钙粘蛋白和波形蛋白来减少 PDAC 细胞的迁移和侵袭。TRIP13 的药理学靶向或沉默还导致 FGFR4 和 STAT3 磷酸化表达减少，以及 Wnt/β-catenin 通路下调。在免疫功能低下的 PDAC 小鼠模型中，敲低 TRIP13 或使用 DCZ0415 治疗可减少肿瘤生长和转移。在具有免疫活性的同基因 PDAC 模型中，DCZ0415 治疗通过降低 PD1/PDL1 的表达、增加颗粒酶 B/穿孔素的表达以及促进 CD3/CD4 T 细胞的浸润来增强免疫反应。此外，DCZ0415 通过减少增殖和血管生成以及诱导细胞凋亡和免疫反应，增强了吉西他滨的抗转移和抗肿瘤发生活性。这些临床前研究结果表明 TRIP13 参与 PDAC 进展，并且 TRIP13 的靶向增强了吉西他滨的抗癌作用。