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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., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Fibrotic disorders, which are caused by long-term inflammation, are observed in numerous organs. These disorders are regulated mainly through transforming growth factor (TGF)-β family proteins by a fundamental cellular mechanism, known as the endothelial-mesenchymal transition. Therefore, there is a pressing need to identify the mechanisms and potential therapeutic targets that enable the inhibition of endothelial transdifferentiation. This study is the first to demonstrate that glycosylation of tubulin-β2 and tubulin-β3 in microtubules enhances sensitivity to TGF-β1 stimulation in human microvascular endothelial cells. We observed that the microtubules enriched in glycosylated tubulin-β2 and tubulin-β3 were necessary for caveolae-dependent TGF-β receptor internalization. Post-translational modulation is critical for the generation of myofibroblasts through endothelial-mesenchymal transition during fibrosis development. We suggest that microtubule glycosylation may become the target of new effective therapies for patients with recognized fibrotic diseases., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Increasing evidence indicates that the tumor microenvironment is a critical factor supporting cancer progression, chemoresistance and metastasis. Recently, cancer-associated fibroblasts (CAFs) have been recognized as a crucial tumor stromal component promoting cancer growth and invasiveness via modulation of the extracellular matrix (ECM) structure, tumor metabolism and immune reprogramming. One of the main sources of CAFs are endothelial cells undergoing the endothelial-mesenchymal transition (EndMT). EndMT is mainly promoted by the Transforming Growth Factor-β (TGF-β) family secreted by tumor cells, though the role of particular members in EndMT regulation remains poorly understood. Our findings demonstrate that TGF-β2 induces mesenchymal transdifferentiation of human microvascular endothelial cells (HMEC-1 cells) to CAF-like cells in association with elongated cell morphology, modulation of stress fiber organization, higher α-SMA protein levels and activation of RhoA and Rac-1 pathways. Such regulation is similar to that observed in cells maintained using conditioned medium from invasive colorectal cancer cell line culture. Furthermore, TGF-β2 stimulation resulted in myocardin-related transcription factor (MRTF) activation and upregulation. Our results demonstrate for the first time that such interaction is sufficient for integrin-linked kinase (ILK) overexpression. ILK upregulation also enhanced MRTF activation via RhoA and Rac-1-MMP9 via inside-out integrin activation. Herein, we propose a new ILK-MMP9-MRTF axis that appears to be critical for EndMT differentiation of endothelial to CAF-like cells. Thus, it might be an attractive target for cancer treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Numerous G-protein coupled receptors have been reported to enhance cancer cell survival and resistance to clinically used chemotherapeutics. Recently, hydroxycarboxylic acid receptor 1 (HCAR1) was shown to drive lactate-dependent enhancement of cell survival and metastasis in pancreatic and breast cancers. Furthermore, our previous study confirmed the involvement of HCAR1 in lactate-related enhancement of DNA repair in cervical cancer cells. In the present study, we examined the possible mechanisms of HCAR1-mediated enhancement of DNA repair capacity. We observed that the HCAR1 agonist dihydroxybenzoic acid (DHBA) up-regulated BRCA1 (breast cancer type 1 susceptibility protein) and NBS1 (Nijmegen breakage syndrome 1) expression in HeLa cells. Moreover, HCAR1 silencing decreased mRNA and protein levels of BRCA1 by 30% and 20%, respectively. Immunocytochemical analyses of BRCA1, nibrin and DNA-PKcs indicated an increased accumulation of these proteins in cell nuclei after DHBA stimulation. Subsequently, these changes in the DNA repair protein levels translated into an enhanced DNA repair rate after doxorubicin treatment, as shown by γ-H2AX and comet assay experiments. In contrast, the down-regulation of HCAR1 decreased the efficiency of DNA repair. Finally, we observed the abrogation of DHBA-driven BRCA1 protein up-regulation and enhanced DNA repair following the preincubation of cells with the PKC inhibitor Gö6983. Taken together, our data indicate that lactate receptor/HCAR1 expression in cervical carcinoma cells may contribute to the modulation of cellular DNA repair mechanisms., (Copyright © 2017 Elsevier B.V. All rights reserved.)