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Thyroid cell transformation requires the expression of the HMGA1 proteins
Maria Teresa Berlingieri1, Giovanna M Pierantoni, Vincenzo Giancotti
1Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli, Via Pansini 5, 80131 Naples, Italy.
Abstract:
Elevated expression of HMGA1 and HMGA2 proteins is correlated with a highly malignant phenotype in several human tumors. We previously demonstrated that the block of HMGA2 protein synthesis prevented rat thyroid cell transformation by murine retroviruses. Suppression of HMGA2 synthesis was associated with lack of induction of HMGA1 proteins suggesting that both HMGA1 and HMGA2 play a role in the process of neoplastic transformation. To determine the role of the HMGA1 gene in thyroid cell transformation, we blocked HMGA1 protein synthesis by an antisense methodology. Here we report that transfection of an HMGA1 cDNA antisense construct into a normal rat thyroid cell line (FRTL-5 Cl2), followed by infection with Kirsten murine sarcoma virus (KiMSV), generated a transformed cell line that expresses high levels of the v-ras-Ki oncogene and that does not require thyroid-stimulating hormones for growth. However, this cell line does not show the malignant phenotype, i.e., it neither grows in soft agar nor induces tumors after injection in athymic mice. Moreover, the lack of the neoplastic phenotype in the virus-infected thyroid cells carrying the HMGA1 antisense construct correlates with the absence of induction of AP-1 transcriptional activity.
Insights
High mobility group A1 (HMGA1) and HMGA2 proteins are linked to cancer malignancy. Blocking HMGA1 synthesis in rat thyroid cells prevented full neoplastic transformation, suggesting HMGA1 is crucial for tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- High mobility group A (HMGA) proteins, specifically HMGA1 and HMGA2, are implicated in the malignant progression of various human cancers.
- Previous research indicated that inhibiting HMGA2 synthesis hindered rat thyroid cell transformation induced by murine retroviruses, suggesting a role for both HMGA1 and HMGA2 in neoplastic transformation.
Purpose of the Study:
- This study aimed to elucidate the specific role of the HMGA1 gene in thyroid cell transformation.
- The researchers sought to determine if blocking HMGA1 protein synthesis would impact the transformation and malignant potential of rat thyroid cells.
Main Methods:
- A normal rat thyroid cell line (FRTL-5 Cl2) was transfected with an HMGA1 cDNA antisense construct to inhibit HMGA1 protein synthesis.
- The modified cells were subsequently infected with Kirsten murine sarcoma virus (KiMSV).
- The transformed cell line's characteristics, including oncogene expression, growth factor independence, and tumorigenicity, were evaluated. AP-1 transcriptional activity was also assessed.
Main Results:
- Transfection with the HMGA1 antisense construct followed by KiMSV infection resulted in a transformed rat thyroid cell line expressing high levels of the v-ras-Ki oncogene.
- This transformed cell line exhibited independence from thyroid-stimulating hormones for growth.
- Crucially, the cells did not display a fully malignant phenotype, failing to grow in soft agar or form tumors in athymic mice. This lack of malignancy correlated with the absence of AP-1 transcriptional activity induction.
Conclusions:
- While HMGA1 is involved in the initial transformation of thyroid cells and oncogene expression, its complete suppression prevents the acquisition of a fully malignant phenotype.
- The findings suggest that HMGA1 plays a critical, but perhaps not solely sufficient, role in the neoplastic transformation of thyroid cells.
- The absence of AP-1 transcriptional activity in HMGA1-suppressed cells points to its potential involvement in the downstream pathways leading to malignancy.