Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

Lauriola, Angela; Martello, Andrea; Fantini, Sebastian; Marverti, Gaetano; Zanocco-Marani, Tommaso; Davalli, Pierpaola; Guardavaccaro, Daniele; Mai, Sabine; Caporali, Andrea; D’Arca, Domenico

doi:10.3390/cancers12040993

Cited by 9 publications

(17 citation statements)

References 41 publications

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“…Mitotic abnormalities in normal cells frequently lead to missegregation of chromosomes, which produces genomic instability that triggers the development and progression of tumors ( 105 ). TNF-α and TGF-β have dual roles in causing genomic instability and mutations, as shown in Table 5 .…”

Section: Interaction Between Tnf-α and Tgf-βmentioning

confidence: 99%

Duality of Interactions Between TGF-β and TNF-α During Tumor Formation

Liu

Zhang

et al. 2022

Front. Immunol.

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The tumor microenvironment is essential for the formation and development of tumors. Cytokines in the microenvironment may affect the growth, metastasis and prognosis of tumors, and play different roles in different stages of tumors, of which transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α) are critical. The two have synergistic and antagonistic effect on tumor regulation. The inhibition of TGF-β can promote the formation rate of tumor, while TGF-β can promote the malignancy of tumor. TNF-α was initially determined to be a natural immune serum mediator that can induce tumor hemorrhagic necrosis, it has a wide range of biological activities and can be used clinically as a target to immune diseases as well as tumors. However, there are few reports on the interaction between the two in the tumor microenvironment. This paper combs the biological effect of the two in different aspects of different tumors. We summarized the changes and clinical medication rules of the two in different tissue cells, hoping to provide a new idea for the clinical application of the two cytokines.

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Section: Interaction Between Tnf-α and Tgf-βmentioning

confidence: 99%

Duality of Interactions Between TGF-β and TNF-α During Tumor Formation

Liu

Zhang

et al. 2022

Front. Immunol.

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“…Moreover, considering that modified nuclear architecture is a marker of malignant transformation [ 32 ], we investigated whether TpMs depletion changes the genome organization of the cells through the alteration of the nuclear architecture organization, as defined by the spatial arrangement of chromosomes and other nuclear components. Altogether, we demonstrate that the telomere alterations generated in TpMs-depleted HCT116 cells are consistent with chromosome aberrations that generate chromosomal instability [ 9 ]. Our observations represent a connection between the tumor suppression ability of TpMs with its function in maintaining chromosomal segregation.…”

Section: Introductionmentioning

confidence: 74%

“…The gene encoding TpMs localizes to the chromosome 12q24.1; it was identified as Ts12q and a putative tumor suppressor at 12q [ 2 ]. Our previous investigations demonstrated that TpMs silencing causes abnormal activity of the spindle assembly checkpoint (SAC) in several cell lines [ 9 ]. SAC represents a cell cycle checkpoint during mitosis and meiosis, which allows the proper segregation of chromosomes by preventing the separation of the duplicated chromosomes during the anaphase until each chromosome is properly attached to the spindle.…”

Section: Introductionmentioning

confidence: 99%

“…These aberrations are typical hallmarks of chromosome mis-segregation, premature sister–chromatid separation and chromosomal end-to-end fusions, which are all distinctive features of chromosomal instability (CIN). CIN is characterized by the gain or loss of chromosomes, as well as by the rearrangement of the genetic material during the cell division, finally generating ongoing and dynamic genomic instability [ 9 ]. CIN is considered a major driving force in human malignant transformation, leading cancer cells of different tissues in different organs to acquire functional capabilities that allow them to survive, proliferate and disseminate [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Telomere Dysfunction Is Associated with Altered DNA Organization in Trichoplein/Tchp/Mitostatin (TpMs) Depleted Cells

et al. 2022

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Recently, we highlighted a novel role for the protein Trichoplein/TCHP/Mitostatin (TpMs), both as mitotic checkpoint regulator and guardian of chromosomal stability. TpMs-depleted cells show numerical and structural chromosome alterations that lead to genomic instability. This condition is a major driving force in malignant transformation as it allows for the cells acquiring new functional capabilities to proliferate and disseminate. Here, the effect of TpMs depletion was investigated in different TpMs-depleted cell lines by means of 3D imaging and 3D Structured illumination Microscopy. We show that TpMs depletion causes alterations in the 3D architecture of telomeres in colon cancer HCT116 cells. These findings are consistent with chromosome alterations that lead to genomic instability. Furthermore, TpMs depletion changes the spatial arrangement of chromosomes and other nuclear components. Modified nuclear architecture and organization potentially induce variations that precede the onset of genomic instability and are considered as markers of malignant transformation. Our present observations connect the tumor suppression ability of TpMs with its novel functions in maintaining the proper chromosomal segregation as well as the proper telomere and nuclear architecture. Further investigations will investigate the connection between alterations in telomeres and nuclear architecture with the progression of human tumors with the aim of developing personalized therapeutic interventions.

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“…TCHP is also involved in the spindle assembly checkpoint during cell division. TCHP knockdown leads to chromosome misalignment, DNA damage, and genomic instability, which may be an important cause of cancer development (Lauriola et al, 2020). In addition, TCHP knockdown leads to elevated expression of p16 in vascular endothelial cells, allowing the cells to reach a senescent state (Martello et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Cell cycle arrest induced by trichoplein depletion is independent of cilia assembly

Huang

Kong

Tang

et al. 2022

Journal Cellular Physiology

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Cilia assembly and centriole duplication are closely coordinated with cell cycle progression, and inhibition of cilia disassembly impedes cell cycle progression. The centrosomal protein trichoplein (TCHP) has been shown to promote cell cycle progression in the G 1 -S phase by disassembling cilia. In this study, we showed that deletion of TCHP not only prevented the progression to the S phase but also resulted in cell cycle exit and entrance into G 0 phase. Surprisingly, we found that loss of TCHP-induced G 0 arrest could not be reversed by blocking the assembly of cilia.In cells without IFT20 or CEP164, two genes encoding key factors for ciliogenesis, depletion of TCHP still led to G 0 arrest. Mechanistically, we also found that TCHP depletion-induced cell cycle arrest was not mediated through a centrosome surveillance mechanism, but inhibition of Rb or concomitant inhibition of both Rb and p53 signaling pathways was required to reverse the cell cycle phenotype. In conclusion, our study provides new insights into the function of TCHP in cell cycle progression.

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Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

Cited by 9 publications

References 41 publications

Duality of Interactions Between TGF-β and TNF-α During Tumor Formation

Duality of Interactions Between TGF-β and TNF-α During Tumor Formation

Telomere Dysfunction Is Associated with Altered DNA Organization in Trichoplein/Tchp/Mitostatin (TpMs) Depleted Cells

Cell cycle arrest induced by trichoplein depletion is independent of cilia assembly

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