Abstract
The nuclear lamina is essential for the maintenance of nuclear shape and mechanics. Mutations in lamin genes have been identified in a heterogeneous spectrum of human diseases known as “laminopathies” associated with nuclear envelope defects and deregulation of cellular functions. Interestingly, osteosarcoma is the only neoplasm described in the literature in association with laminopathies. This study aims characterized the expression of A-type and B-type lamins and emerin in osteosarcoma, revealing a higher percentage of dysmorphic nuclei in osteosarcoma cells in comparison to normal osteoblasts and all the hallmarks of laminopathic features. Both lamins and emerin were differentially expressed in osteosarcoma cell lines in comparison to normal osteoblasts and correlated with tumor aggressiveness. We analysed lamin A/C expression in a tissue-microarray including osteosarcoma samples with different prognosis, finding a positive correlation between lamin A/C expression and the overall survival of osteosarcoma patients. An inefficient MKL1 nuclear shuttling and actin depolymerization, as well as a reduced expression of pRb and a decreased YAP nuclear content were observed in A-type lamin deficient 143B cells. In conclusion, we described for the first time laminopathic nuclear phenotypes in osteosarcoma cells, providing evidence for an altered lamins and emerin expression and a deregulated nucleoskeleton architecture of this tumor.
Highlights
The nuclear lamins are type V intermediate filament proteins that polymerize to form a highly-organized meshwork between the inner nuclear membrane (INM) and the chromatin
Comparing morphological nucleoskeletal changes and the immunoexpression data among osteoblasts and osteosarcoma cell lines (Figures 1 and 7), we found a clear association between higher lamin B1 expression levels and nuclear dysmorphisms in osteoblastic cell lines; SaOS2 cells, showing the higher variability of alterations, i.e., donut-shaped or fragmented nuclei, or nuclear envelope (NE) with blebs, septa and folds, exhibited high values of lamin B1 immunoexpression (Figure 7A,C)
In order to functionally characterize the alteration of nuclear envelope proteins in osteosarcoma cells, we addressed the expression of protein Retinoblastoma in relationship to A-type lamin content, starting observation thatthat mouse fibroblasts deficient for A-type lamin showed startingfrom fromthethe observation mouse fibroblasts deficient for A-type lamin reduced showed levels of pRb
Summary
The nuclear lamins are type V intermediate filament proteins that polymerize to form a highly-organized meshwork between the inner nuclear membrane (INM) and the chromatin. A-type lamins bind to B-type lamins and to several structural proteins, including the integral INM protein emerin, nesprins, lamina-associated polypeptide 2 isoform α (LAP2α), NUP153, SUN-domain-containing proteins, and nuclear actin forming a structural network essential for nuclear integrity and nucleo-cytoskeletal coupling [10,11]. Both A- and B-type lamins are localized in the nucleus lamina, and A-type lamins are expressed in the rest of the nucleoplasm as they are non-farnesylated proteins after maturation steps [12,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
