Ciszewski Wojciech M, Wozniak Lucyna A, Sobierajska Katarzyna
Department of Molecular Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
Department of Structural Biology, Medical University of Lodz, Zeligowskiego 7/9, 90-752, Lodz, Poland.
Biochim Biophys Acta Mol Cell Res. 2023 Oct;1870(7):119541. doi: 10.1016/j.bbamcr.2023.119541. Epub 2023 Jul 17.
The COVID-19 pandemic led to the delay of colorectal cancer (CRC) diagnosis, which causes CRC to be treated at more advanced, often metastatic stages. Unfortunately, there is no effective treatment for metastatic CRC stages, which are considered the leading cause of patients' death. The mortality induced by SARS-CoV-2 is significantly higher in cancer patients than in patients with other diseases. Interestingly, COVID-19 patients often develop fibrosis which depends on epithelial-mesenchymal transition (EMT) - the process also involved in cancer progression. The study aimed to verify whether SARS-CoV-2 induces EMT and consequently increases the invasion potential of colon cancer cells. CRC cells were stimulated with SARS-CoV-2 S and N protein peptides and epithelial and mesenchymal markers were analysed with Western blotting to detect the occurrence of the EMT. The migration, invasion assays and MMP-7 secretion were employed to evaluate the potential of SARS-CoV-2 to stimulate the cells invasion in vitro. ELISA assay, TGF-β1 neutralizing antibodies, TGF-βR silencing and inhibitors were used to investigate the role of the TGF-β1 signalling pathways in the SARS-CoV-2-dependent CRC stimulation. The SARS-CoV-2 induced EMT, which increased the invasion ability of CRC cells. Moreover, the SARS-CoV-2 proteins drive colon cancer cell invasion through TGF-β1. Additionally, secreted TGF-β1 induced a bystander effect in colon cancer cells. However, blocking TGF-β1/Smad- and -non-Smad-dependent pathways suppressed the SARS-CoV-2-induced invasiveness of CRC. In conclusion, we revealed that SARS-CoV-2 stimulates the invasion abilities of CRC by regulating TGF-β1-induced EMT. Our results provide a theoretical basis for using anti-TGF-β1 therapy to reduce the risk of CRC metastasis during SARS-CoV-2 infection.
新冠疫情导致结直肠癌（CRC）诊断延迟，致使CRC在更晚期（通常为转移期）才得以治疗。不幸的是，对于转移性CRC阶段尚无有效治疗方法，而这被认为是患者死亡的主要原因。SARS-CoV-2所致死亡率在癌症患者中显著高于其他疾病患者。有趣的是，新冠患者常出现纤维化，这依赖于上皮-间质转化（EMT）——该过程也参与癌症进展。本研究旨在验证SARS-CoV-2是否诱导EMT，进而增加结肠癌细胞的侵袭潜能。用SARS-CoV-2的S和N蛋白肽刺激CRC细胞，并用蛋白质免疫印迹法分析上皮和间质标志物以检测EMT的发生。采用迁移、侵袭实验及MMP-7分泌检测来评估SARS-CoV-2在体外刺激细胞侵袭的潜能。运用ELISA检测、TGF-β1中和抗体、TGF-βR沉默及抑制剂来研究TGF-β1信号通路在SARS-CoV-2依赖的CRC刺激中的作用。SARS-CoV-2诱导了EMT，增加了CRC细胞的侵袭能力。此外，SARS-CoV-2蛋白通过TGF-β1驱动结肠癌细胞侵袭。另外，分泌的TGF-β1在结肠癌细胞中诱导旁观者效应。然而，阻断TGF-β1/Smad和非Smad依赖的信号通路可抑制SARS-CoV-2诱导的CRC侵袭性。总之，我们揭示了SARS-CoV-2通过调节TGF-β1诱导的EMT刺激CRC的侵袭能力。我们的结果为使用抗TGF-β1疗法降低SARS-CoV-2感染期间CRC转移风险提供了理论依据。
