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Ectopic Tbx2 expression results in polyploidy and cisplatin resistance
1Division of Cell Biology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Province, South Africa.
Abstract:
T-box factors play critical roles in embryonic development and have been implicated in cell cycle regulation and cancer. For example, Tbx2 can suppress senescence through a mechanism involving the repression of the cyclin-dependent kinase inhibitors, p19(ARF) and p21(WAF1/CIP1/SDII), and the Tbx2 gene is deregulated in melanoma, breast and pancreatic cancers. In this study, several transformed human lung fibroblast cell lines were shown to downregulate Tbx2. To further investigate the role of Tbx2 in oncogenesis we therefore stably reexpressed Tbx2 in one such cell line. Compared to their parental cells, the resulting Tbx2-expressing cells are larger, with binucleate and lobular nuclei containing double the number of chromosomes. Moreover, these cells had an increase in frequency of several features of genomic instability such as chromosome missegregation, chromosomal rearrangements and polyploidy. While grossly abnormal, these cells still divide and give rise to cells that are resistant to the chemotherapeutic drug cisplatin. Furthermore, this is shown to be neither species nor cell type dependent, as ectopically expressing Tbx2 in a murine melanoma cell line also induce mitotic defects and polyploidy. These results have important implications for our understanding of the role of Tbx2 in tumorigenesis because polyploidy frequently precedes aneuploidy, which is associated with high malignancy and poor prognosis.
Insights
Reintroducing T-box 2 (Tbx2) into lung cancer cells caused genomic instability, including polyploidy and resistance to chemotherapy. These findings highlight Tbx2's role in oncogenesis and poor patient prognosis.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- T-box factors, including Tbx2, are crucial in development and implicated in cancer.
- Tbx2 represses cell cycle inhibitors and is deregulated in various cancers, such as melanoma and breast cancer.
- Transformed human lung fibroblast cell lines were observed to downregulate Tbx2.
Purpose of the Study:
- To investigate the role of Tbx2 in oncogenesis by reexpressing it in a Tbx2-downregulated cell line.
- To determine the effects of Tbx2 reexpression on cellular morphology, genomic stability, and drug resistance.
Main Methods:
- Stable reexpression of Tbx2 in transformed human lung fibroblasts.
- Analysis of cell size, nuclear morphology, chromosome number, and genomic instability markers.
- Assessment of resistance to cisplatin chemotherapy.
- Ectopic Tbx2 expression in a murine melanoma cell line to confirm species and cell type independence.
Main Results:
- Tbx2-expressing cells exhibited larger size, binucleate and lobular nuclei, and doubled chromosome numbers compared to parental cells.
- Increased frequencies of chromosome missegregation, rearrangements, and polyploidy were observed in Tbx2-expressing cells.
- These abnormal cells divided and developed resistance to cisplatin.
- Similar mitotic defects and polyploidy were induced by Tbx2 in a murine melanoma cell line.
Conclusions:
- Tbx2 reexpression induces significant genomic instability, including polyploidy, in cancer cell lines.
- Polyploidy induced by Tbx2 is linked to chemoresistance and may precede aneuploidy, a marker of malignancy.
- These findings underscore Tbx2's role in tumorigenesis and its association with poor prognosis.
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