Meyer Ulrike, Rönnpagel Vincent, Grammbauer Sophie, von Lucadou Mirjam, Rauch-Kröhnert Ursula, Schwedhelm Edzard, Dombrowski Frank, Ritter Christoph, Rauch Bernhard H
Pharmacology and Toxicology, University Medicine Oldenburg, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
Department of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
Front Oncol. 2025 Jul 21;15:1631350. doi: 10.3389/fonc.2025.1631350. eCollection 2025.
Colon cancer is among the most common cancer types worldwide. Signaling pathways that control cell proliferation and migration play a crucial role in its progression. The G-protein-coupled protease-activated receptors (PARs) are associated mediators in this process. Both activated coagulation factors thrombin and FXa are capable of activating PARs. While thrombin, beyond its intrinsic role in hemostasis, primarily activates PAR1, FXa mediates its cellular effects independently via PAR2. Although the role of thrombin and PAR1 activation in cancer development has been established for some time, the impact of FXa-PAR2 on tumor progression represents a relatively novel area of investigation. Therefore, the current study was conducted to examine the role of FXa and PAR2 signaling in colon cancer progression using the murine colon cancer cell line MC38. Proliferation and migration assays were performed in vitro and signaling pathways analyzed by Western blot. In vivo, tumor growth and health status were investigated in WT and PAR2-KO mice. The findings demonstrate that FXa considerably augments the proliferation and migration of colon cancer (CC) cells . A molecular mechanism of action has been identified in the activation of PAR2 by FXa. The coagulation factor significantly induces MAPK- and AKT-signaling with EGFR transactivation in the murine MC38 cells utilized. Although oral treatment with a direct FXa inhibitor (Apixaban) at a dosage of up to 50 mg/kg did not significantly affect tumor growth , PAR2 deficiency resulted in significantly reduced tumor growth and enhanced health condition status, indicating a key role of PAR2 in the progression of colon cancer.
结肠癌是全球最常见的癌症类型之一。控制细胞增殖和迁移的信号通路在其进展过程中起着至关重要的作用。G蛋白偶联蛋白酶激活受体（PARs）是这一过程中的相关介质。活化的凝血因子凝血酶和FXa都能够激活PARs。凝血酶除了在止血中具有内在作用外，主要激活PAR1，而FXa则通过PAR2独立介导其细胞效应。尽管凝血酶和PAR1激活在癌症发展中的作用已经确立了一段时间，但FXa-PAR2对肿瘤进展的影响是一个相对较新的研究领域。因此，本研究使用小鼠结肠癌细胞系MC38来研究FXa和PAR2信号在结肠癌进展中的作用。进行了体外增殖和迁移试验，并通过蛋白质印迹分析信号通路。在体内，研究了野生型和PAR2基因敲除小鼠的肿瘤生长和健康状况。研究结果表明，FXa显著增强了结肠癌细胞（CC）的增殖和迁移。已经确定了FXa激活PAR2的分子作用机制。在所用的小鼠MC38细胞中，凝血因子通过表皮生长因子受体（EGFR）反式激活显著诱导丝裂原活化蛋白激酶（MAPK）和蛋白激酶B（AKT）信号通路。虽然以高达50mg/kg的剂量口服直接FXa抑制剂（阿哌沙班）对肿瘤生长没有显著影响，但PAR2缺陷导致肿瘤生长显著减少，健康状况得到改善，这表明PAR2在结肠癌进展中起关键作用。
