Targeting PADI2 as a potential therapeutic strategy against metastasis in oral cancer via suppressing EMT-mediated migration and invasion and CCL3/5-induced angiogenesis.

IF 4.2 3区 医学 Q2 ONCOLOGY
Shih-Kai Hung, Chih-Chia Yu, Hon-Yi Lin, Wen-Yen Chiou, Moon-Sing Lee, Ru-Inn Lin, Ming-Chi Lu
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Abstract

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy, with metastasis being the leading cause of death in patients. Unfortunately, therapeutic options for metastatic OSCC remain limited. Peptidylarginine deiminases (PADI) are implicated in various tumorigenesis and metastasis processes across multiple cancers. However, the role of PADI2, a type of PADI, in OSCC is not well understood. This study aimed to explore the impact of PADI2 on epithelial-mesenchymal transition (EMT), angiogenesis, and OSCC metastasis. The effect of PADI2 on EMT was evaluated using cell lines by Western blot analysis with shRNA targeting PADI2. In addition, the selective PADI2 inhibitor AFM32a was used to assess the effect of PADI2 on cancer metastasis and angiogenesis in animal models. Our findings indicated that PADI2 expression correlated with EMT changes, and PADI2 knockdown reversed these changes, reducing cell proliferation, cell migration, and invasion. PADI2 inhibition also diminished tube formation in HUVECs and decreased secretion of angiogenesis-related chemokines CCL3, CCL5 and CCL20. In a mouse model, AFM32a markedly reduced lung metastasis and production of CCL3 and CCL5. Our in vitro and in vivo studies suggested inhibiting PADI2 could prevent OSCC metastasis by impeding EMT and angiogenesis via AKT/mTOR signaling pathway. These results highlight PADI2 as a potential therapeutic target for combating OSCC metastasis.

Abstract Image

通过抑制 EMT 介导的迁移和侵袭以及 CCL3/5 诱导的血管生成,以 PADI2 为靶点作为抗口腔癌转移的潜在治疗策略。
口腔鳞状细胞癌(OSCC)是一种常见的侵袭性恶性肿瘤,转移是导致患者死亡的主要原因。遗憾的是,转移性 OSCC 的治疗方案仍然有限。肽基精氨酸脱氨酶(PADI)与多种癌症的各种肿瘤发生和转移过程有关。然而,PADI2(PADI的一种)在OSCC中的作用尚不十分清楚。本研究旨在探讨PADI2对上皮-间质转化(EMT)、血管生成和OSCC转移的影响。研究利用细胞系,通过针对PADI2的shRNA进行Western印迹分析,评估了PADI2对EMT的影响。此外,还使用选择性PADI2抑制剂AFM32a评估了PADI2对动物模型中癌症转移和血管生成的影响。我们的研究结果表明,PADI2的表达与EMT变化相关,而PADI2的敲除可逆转这些变化,减少细胞增殖、细胞迁移和侵袭。抑制 PADI2 还能减少 HUVECs 中的管形成,并减少血管生成相关趋化因子 CCL3、CCL5 和 CCL20 的分泌。在小鼠模型中,AFM32a 能显著减少肺转移以及 CCL3 和 CCL5 的产生。我们的体外和体内研究表明,抑制 PADI2 可通过 AKT/mTOR 信号通路阻碍 EMT 和血管生成,从而防止 OSCC 转移。这些结果突显了PADI2是对抗OSCC转移的潜在治疗靶点。
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来源期刊
CiteScore
7.80
自引率
5.00%
发文量
55
审稿时长
12 months
期刊介绍: The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.
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