Riddiough Georgina E, Fifis Theodora, Walsh Katrina A, Muralidharan Vijayaragavan, Christophi Christopher, Tran Bang M, Vincan Elizabeth, Perini Marcos V
Department of Surgery, Austin Health Precinct, The University of Melbourne, Austin Health, Lance Townsend Building, Level 8, 145 Studley Road, Heidelberg, VIC 3084, Australia.
Department of Infectious Diseases, The Peter Doherty Institute, The University of Melbourne, Melbourne, VIC 3000, Australia.
Cancers (Basel). 2021 May 31;13(11):2734. doi: 10.3390/cancers13112734.
(1) Background: Recent clinical and experimental data suggests that the liver's regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.
(1) 背景：近期临床和实验数据表明，部分肝切除术后肝脏的再生反应可刺激肝残余组织中的肿瘤复发。Wnt/β-连环蛋白信号通路在结直肠癌发生和肝脏再生过程中均发挥重要作用。研究表明，Wnt/β-连环蛋白信号通路调控多个肾素-血管紧张素系统（RAS）基因，而抑制RAS（RASi）可减轻肿瘤负荷并延缓肿瘤进展。本研究探讨RASi是否通过调节Wnt/β-连环蛋白信号传导来减轻肝切除术后再生肝脏中肿瘤进展的特征。(2) 方法：雄性CBA小鼠先诱导发生结直肠癌肝转移（CRLM），1周后行70%部分肝切除术。从实验第4天起，小鼠每天接受250 mg/kg/d的RASi卡托普利治疗或溶剂对照。使用qRT-PCR和免疫组织化学分析肿瘤和肝脏样本中的RAS和Wnt信号标志物。(3) 结果：卡托普利治疗降低了下游Wnt靶基因的表达，包括c-myc和细胞周期蛋白D1均显著降低，尽管激活了Wnt信号。这是一种肿瘤特异性反应，在相应的肝脏样本中未出现。(4) 结论：我们首次报道了体内RASi治疗后结直肠癌肿瘤中c-myc表达降低。尽管Wnt信号增强，但c-myc表达降低伴随着侵袭表型的减弱。
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