Tesi etd-02022024-123206
Link copiato negli appunti
Tipo di tesi
Dottorato
Autore
DE LUCA, DAVIDE
URN
etd-02022024-123206
Titolo
MICAL2 maintains nuclear and genomic integrity through the Sonic hedgehog signaling pathway
Settore scientifico disciplinare
BIO/11
Corso di studi
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
Commissione
relatore Prof.ssa ANGELONI, DEBORA
Parole chiave
- cancer
- cytoskeleton
- lamins
- mechanotransduction
- metastasis
- MICAL2
- nuclear envelope
Data inizio appello
09/12/2024;
Disponibilità
parziale
Riassunto analitico
Metastasis is responsible for over 90% of cancer-related deaths, with cancer cell migration and secondary tumor formation driven by mechanotransduction, the process by which physical forces, transduced in cells into biochemical signals, influence cellular behaviour. Central in mechanotransduction is the Hippo pathway, which, through its effectors YAP and TAZ, regulates cell proliferation and invasiveness. The cytoskeleton, especially filamentous actin (F-ACTIN), plays a crucial role in transmitting mechanical signals. MICAL2 monoxygenase, involved in cytoskeletal dynamics through modification of F-ACTIN redox status and polymerization, has been linked to epithelial-to-mesenchymal transition (EMT) in cancer; this study aims to explore MICAL2 involvement in nuclear envelope (NE) maintenance, genomic stability and cell mechanotransduction, still poorly understood.
In MICAL2-depleted (MIC2-KD) cells, alterations in nuclear morphology were observed, with significant increases in micronuclei and compromised NE integrity, qualitatively corroborated by transmission electron microscopy which revealed structural defects in the NE. The response to mechanical stress, such as ultrasound waves exposure, showed a dose-dependent increase in micronuclei in reference cells, but no significant change in MIC2-KD cells, suggesting impaired mechanical stress response. Additionally, MIC2-KD cells displayed altered expression of NE proteins, including LAMIN A/C, LAMIN B1 and LAMIN B2, indicating potential post-transcriptional regulation. These cells also exhibited lower expression of NESPRIN2, a component of the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, which connects the cytoskeleton to the NE, implying a defective force transmission mechanism. Further analyses revealed that MICAL2 depletion increased susceptibility to DNA damage, as indicated by enhanced RAD51 activation following X-rays exposure. The Hippo pathway was also affected, with a significant reduction in YAP1 protein expression and downstream gene activity in MIC2-KD cells. Additionally, the Sonic Hedgehog (Shh) signaling pathway, associated with EMT, was downregulated in MIC2-KD cells, suggesting a broader role for MICAL2 in cell signaling.
In conclusion, this study suggests that MICAL2 is essential for maintaining nuclear integrity and mechanotransduction, likely through its involvement in the LINC complex. These findings introduce a novel role for MICAL2 in mechanosensing and cancer progression, positioning MICAL2 as a potential therapeutic target in metastasis process.
In MICAL2-depleted (MIC2-KD) cells, alterations in nuclear morphology were observed, with significant increases in micronuclei and compromised NE integrity, qualitatively corroborated by transmission electron microscopy which revealed structural defects in the NE. The response to mechanical stress, such as ultrasound waves exposure, showed a dose-dependent increase in micronuclei in reference cells, but no significant change in MIC2-KD cells, suggesting impaired mechanical stress response. Additionally, MIC2-KD cells displayed altered expression of NE proteins, including LAMIN A/C, LAMIN B1 and LAMIN B2, indicating potential post-transcriptional regulation. These cells also exhibited lower expression of NESPRIN2, a component of the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, which connects the cytoskeleton to the NE, implying a defective force transmission mechanism. Further analyses revealed that MICAL2 depletion increased susceptibility to DNA damage, as indicated by enhanced RAD51 activation following X-rays exposure. The Hippo pathway was also affected, with a significant reduction in YAP1 protein expression and downstream gene activity in MIC2-KD cells. Additionally, the Sonic Hedgehog (Shh) signaling pathway, associated with EMT, was downregulated in MIC2-KD cells, suggesting a broader role for MICAL2 in cell signaling.
In conclusion, this study suggests that MICAL2 is essential for maintaining nuclear integrity and mechanotransduction, likely through its involvement in the LINC complex. These findings introduce a novel role for MICAL2 in mechanosensing and cancer progression, positioning MICAL2 as a potential therapeutic target in metastasis process.
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