Snail-Family Proteins: Role in Carcinogenesis and Prospects for Antitumor Therapy

Yastrebova, Margarita A.; Khamidullina, Alvina I.; Tatarskiy, Victor V.; Scherbakov, Alexander M.

doi:10.32607/actanaturae.11062

Cited by 11 publications

(9 citation statements)

References 130 publications

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“…In fact, Snail itself has been described as sometimes having a cytoplasmatic rather than nuclear localization [ 65 ], and this could be attributed to the different posttranslational modifications of Snail that can either induce its import into the nucleus or export into the cytoplasm [ 66 ]. Although cytoplasmatic Snail does not induce EMT [ 65 ], it may have other functions as it has been shown that Snail can directly act on other proteins, such as p53, by blocking their DNA-binding domain and inhibiting their function [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Differences in Immunohistochemical and Ultrastructural Features between Podocytes and Parietal Epithelial Cells (PECs) Are Observed in Developing, Healthy Postnatal, and Pathologically Changed Human Kidneys

Ogorevc

Kosović

Filipović

et al. 2022

IJMS

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During human kidney development, cells of the proximal nephron gradually differentiate into podocytes and parietal epithelial cells (PECs). Podocytes are terminally differentiated cells that play a key role in both normal and pathological kidney function. Therefore, the potential of podocytes to regenerate or be replaced by other cell populations (PECs) is of great interest for the possible treatment of kidney diseases. In the present study, we analyzed the proliferation and differentiation capabilities of podocytes and PECs, changes in the expression pattern of nestin, and several early proteins including WNT4, Notch2, and Snail, as well as Ki-67, in tissues of developing, postnatal, and pathologically changed human kidneys by using immunohistochemistry and electron microscopy. Developing PECs showed a higher proliferation rate than podocytes, whereas nestin expression characterized only podocytes and pathologically changed kidneys. In the developing kidneys, WNT4 and Notch2 expression increased moderately in podocytes and strongly in PECs, whereas Snail increased only in PECs in the later fetal period. During human kidney development, WNT4, Notch2, and Snail are involved in early nephrogenesis control. In kidneys affected by congenital nephrotic syndrome of the Finnish type (CNF) and focal segmental glomerulosclerosis (FSGS), WNT4 decreased in both cell populations, whereas Notch2 decreased in FSGS. In contrast, Snail increased both in CNF and FSGS, whereas Notch2 increased only in CNF. Electron microscopy revealed cytoplasmic processes spanning the urinary space between the podocytes and PECs in developing and healthy postnatal kidneys, whereas the CNF and FSGS kidneys were characterized by numerous cellular bridges containing cells with strong expression of nestin and all analyzed proteins. Our results indicate that the mechanisms of gene control in nephrogenesis are reactivated under pathological conditions. These mechanisms could have a role in restoring glomerular integrity by potentially inducing the regeneration of podocytes from PECs.

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Section: Discussionmentioning

confidence: 99%

Differences in Immunohistochemical and Ultrastructural Features between Podocytes and Parietal Epithelial Cells (PECs) Are Observed in Developing, Healthy Postnatal, and Pathologically Changed Human Kidneys

Ogorevc

Kosović

Filipović

et al. 2022

IJMS

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“…Since several studies have described the roles of TGFβ1-activated SMADs in EMT induction (28), our further analyses were focused on TGFβ1/SMAD signalling target genes including the transcription factors SNAIL and SLUG which in turn induced the expression of mesenchymal genes (such as Vimentin and α-SMA) (29,30) and the repression of epithelial marker genes (such as E-cadherin and CK8/18). Western Blot analyses showed that CRC_sEVs elicited in hepatocytes the effects due to the activation of TGF-β1/SMAD signalling pathway with different time courses for the different analysed target genes.…”

Section: Crc_sevs Carrying Tgfβ1 Modulate the Expression Of Emt Marke...mentioning

confidence: 99%

Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes

Pucci¹,

Moschetti²,

Urzì³

et al. 2022

Preprint

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Background: The liver is the main metastatic site for patients with colorectal cancer (CRC) and represents the most frequent cause of death for patients affected by this cancer. In recent years, a number of studies have highlighted the crucial role played by small extracellular vesicles (sEVs) released by cancer cells in initiating pre-metastatic niche formation in the liver, specifically affecting the activities of non-parenchymal cells as Kupffer cells and hepatic stellate cells, while the role of the hepatocytes still remains unknown. Even if this cell component is the most conspicuous in the liver and it is responsible for several physiological activities of this complex organ, its role in liver metastasis is only partly described and related to tumour cell colonization, while no data is available about its enrolment during the pre-metastatic niche formation. Methods: sEVs were isolated from SW480 and SW620 CRC cells through differential centrifugation, quantified using the Nanosight technology and characterized by transmission electron microscope and western blot. The presence of TGFβ1 on the surface of CRC_sEVs was assessed by western blot, super-resolution fluorescence microscope, and ELISA. Functional and epithelial to mesenchymal transition (EMT) markers were analyzed through RT PCR, ELISA assay, western blot, and confocal analysis in human healthy hepatocytes (THLE-2 cells) treated with sEVs derived from CRC cells (CRC_sEVs) at different time points. Results: Our study shows for the first time that CRC_sEVs carrying the transforming growth factor‑β1 (TGFβ1) impair the morphological and functional properties of human healthy hepatocytes by triggering their TGFβ1/SMAD-dependent EMT. These abilities of CRC_sEVs were further confirmed by evaluating the effects elicited on hepatocytes by sEVs isolated from plasma and biopsies from CRC patients. Conclusions: Since it is known that EMT of hepatocytes leads to the formation of a fibrotic environment, a well-known driver of metastasis, these results suggest that CRC_sEV conditioned hepatocytes could have an active and until now neglected role during the liver metastasis formation.

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“…All snail protein members encode transcriptional repressors with a similar structural organisation. The C-terminal domain is exceptionally conserved, containing four- to five-type zinc fingers (C2H2) which oversee sequence-specific binding to the E-box element (5′-CAG GTG-3′) of the target genes ( 43 ). The N-terminal in humans contains the evolutionarily conserved SNAG domain, which is important for the binding of various transcriptional corepressor complexes to enforce repression of the target genes ( 44 ).…”

Section: Emt and Metastasismentioning

confidence: 99%

Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors

et al. 2021

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Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs via a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but also resistant to several cytotoxic agents during treatment, owing to their anatomically diffuse localisation in the body system. As the quest to find an effective method of addressing metastasis in cancer intervention heightens, understanding the molecular interplay involving the signalling pathways, downstream effectors, and their interactions with the EMT would be an important requisite while the challenges of metastasis continue to punctuate. Unfortunately, the molecular underpinnings that govern this process remain to be completely illuminated. However, it is becoming increasingly clear that EMT, which initiates every episode of metastasis, significantly requires some master regulators called EMT transcription factors (EMT-TFs). Thus, this review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation. In addition, it discusses the interaction of various signalling molecules and effector proteins with these factors. It also provides insight into promising therapeutic targets that may inhibit the metastatic process to overcome the limitation of “undruggable” cancer targets in therapeutic design and upturn the current spate of drug resistance. More so, it extends the discussion from the basic understanding of the EMT binary switch model, and ultimately unveiling the E/M cellular plasticity along a phenotypic spectrum via multiple trans-differentiations. It wraps up on how this knowledge update shapes the diagnostic and clinical approaches that may demand a potential shift in investigative paradigm using novel technologies such as single-cell analyses to improve overall patient survival.

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Snail-Family Proteins: Role in Carcinogenesis and Prospects for Antitumor Therapy

Cited by 11 publications

References 130 publications

Differences in Immunohistochemical and Ultrastructural Features between Podocytes and Parietal Epithelial Cells (PECs) Are Observed in Developing, Healthy Postnatal, and Pathologically Changed Human Kidneys

Differences in Immunohistochemical and Ultrastructural Features between Podocytes and Parietal Epithelial Cells (PECs) Are Observed in Developing, Healthy Postnatal, and Pathologically Changed Human Kidneys

Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes

Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors

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