Janus-Faced role of microRNA let-7d in osteosarcoma 3AB-OS cancer stem cells

Risultato della ricerca: Other

Abstract

Osteosarcoma (OS) is the most common malignancy of bone in children and adolescent. It is a highly invasive and metastatic bone-malignancy because of which, despite therapeutic advances, 30%-50% of patients still die of pulmonary metastasis. As a consequence, there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of the patients. Advances in OS treatment are inconceivable without better understanding of molecular mechanism of osteosarmagenesis and, especially, metastatic processes. Growing evidence suggests that cancer stem cells (CSCs), which have self-renewing and malignant potential, are at the root of tumor growth and relapse. Thus, a challenge for innovative therapy is their identification and eradication. Here, we have used the 3AB-OS CSCs, a cell line previously produced in our laboratory from the OS-MG63 cells, which was genetically, molecularly and functionally characterized. This study was focused on the role of let-7d miRNA-previously found by us to be downregulated in 3AB-OS-CSCs- in managing their stemness properties. We have found that let-7d-overesperession reduces cell proliferation by both decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also reduces sarcosphere and colony-forming ability and the expression of Oct3/4, Sox2, Nanog, Lin28B and HMGA2, key regulators of cancer cell stemness. Moreover, let-7d induces mesenchymal-to-epithelium-transition, as shown by both N-Cadherin-E-cadherin-switch and vimentin decrease. Surprisingly, this swich was accompanied by enhanced migratory/invasive capacities and by increases in MMP9, CXCR4 and VersicanV1. Let-7d also reduced the resistance to serum starvation and chemotherapy. A decrease in caspase-3 with an increase in Bcl-2 was also observed. Overall, this study shows that let-7d displaying both suppressor and oncogenic functions behaves as a Janus-Faced miRNA. Thus, we suggest that, before prospecting new therapeutic strategies by let-7d modulation, it is urgent to better understand its functions.
Lingua originaleEnglish
Numero di pagine3
Stato di pubblicazionePublished - 2015

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Neoplastic Stem Cells
Osteosarcoma
MicroRNAs
Cadherins
Neoplasms
Cyclin-Dependent Kinase Inhibitor p27
Bone and Bones
Investigational Therapies
Vimentin
Therapeutics
Starvation
Caspase 3
Cell Cycle
Down-Regulation
Epithelium
Cell Proliferation
Neoplasm Metastasis
Recurrence
Drug Therapy
Cell Line

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title = "Janus-Faced role of microRNA let-7d in osteosarcoma 3AB-OS cancer stem cells",
abstract = "Osteosarcoma (OS) is the most common malignancy of bone in children and adolescent. It is a highly invasive and metastatic bone-malignancy because of which, despite therapeutic advances, 30{\%}-50{\%} of patients still die of pulmonary metastasis. As a consequence, there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of the patients. Advances in OS treatment are inconceivable without better understanding of molecular mechanism of osteosarmagenesis and, especially, metastatic processes. Growing evidence suggests that cancer stem cells (CSCs), which have self-renewing and malignant potential, are at the root of tumor growth and relapse. Thus, a challenge for innovative therapy is their identification and eradication. Here, we have used the 3AB-OS CSCs, a cell line previously produced in our laboratory from the OS-MG63 cells, which was genetically, molecularly and functionally characterized. This study was focused on the role of let-7d miRNA-previously found by us to be downregulated in 3AB-OS-CSCs- in managing their stemness properties. We have found that let-7d-overesperession reduces cell proliferation by both decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also reduces sarcosphere and colony-forming ability and the expression of Oct3/4, Sox2, Nanog, Lin28B and HMGA2, key regulators of cancer cell stemness. Moreover, let-7d induces mesenchymal-to-epithelium-transition, as shown by both N-Cadherin-E-cadherin-switch and vimentin decrease. Surprisingly, this swich was accompanied by enhanced migratory/invasive capacities and by increases in MMP9, CXCR4 and VersicanV1. Let-7d also reduced the resistance to serum starvation and chemotherapy. A decrease in caspase-3 with an increase in Bcl-2 was also observed. Overall, this study shows that let-7d displaying both suppressor and oncogenic functions behaves as a Janus-Faced miRNA. Thus, we suggest that, before prospecting new therapeutic strategies by let-7d modulation, it is urgent to better understand its functions.",
keywords = "Cancer stem cells, microRNA, osteosarcoma",
author = "Daniela Carlisi and {De Blasio}, Anna and {Di Fiore}, Riccardo and Giovanni Tesoriere and Renza Vento and {Drago Ferrante}, Rosa",
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TY - CONF

T1 - Janus-Faced role of microRNA let-7d in osteosarcoma 3AB-OS cancer stem cells

AU - Carlisi, Daniela

AU - De Blasio, Anna

AU - Di Fiore, Riccardo

AU - Tesoriere, Giovanni

AU - Vento, Renza

AU - Drago Ferrante, Rosa

PY - 2015

Y1 - 2015

N2 - Osteosarcoma (OS) is the most common malignancy of bone in children and adolescent. It is a highly invasive and metastatic bone-malignancy because of which, despite therapeutic advances, 30%-50% of patients still die of pulmonary metastasis. As a consequence, there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of the patients. Advances in OS treatment are inconceivable without better understanding of molecular mechanism of osteosarmagenesis and, especially, metastatic processes. Growing evidence suggests that cancer stem cells (CSCs), which have self-renewing and malignant potential, are at the root of tumor growth and relapse. Thus, a challenge for innovative therapy is their identification and eradication. Here, we have used the 3AB-OS CSCs, a cell line previously produced in our laboratory from the OS-MG63 cells, which was genetically, molecularly and functionally characterized. This study was focused on the role of let-7d miRNA-previously found by us to be downregulated in 3AB-OS-CSCs- in managing their stemness properties. We have found that let-7d-overesperession reduces cell proliferation by both decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also reduces sarcosphere and colony-forming ability and the expression of Oct3/4, Sox2, Nanog, Lin28B and HMGA2, key regulators of cancer cell stemness. Moreover, let-7d induces mesenchymal-to-epithelium-transition, as shown by both N-Cadherin-E-cadherin-switch and vimentin decrease. Surprisingly, this swich was accompanied by enhanced migratory/invasive capacities and by increases in MMP9, CXCR4 and VersicanV1. Let-7d also reduced the resistance to serum starvation and chemotherapy. A decrease in caspase-3 with an increase in Bcl-2 was also observed. Overall, this study shows that let-7d displaying both suppressor and oncogenic functions behaves as a Janus-Faced miRNA. Thus, we suggest that, before prospecting new therapeutic strategies by let-7d modulation, it is urgent to better understand its functions.

AB - Osteosarcoma (OS) is the most common malignancy of bone in children and adolescent. It is a highly invasive and metastatic bone-malignancy because of which, despite therapeutic advances, 30%-50% of patients still die of pulmonary metastasis. As a consequence, there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of the patients. Advances in OS treatment are inconceivable without better understanding of molecular mechanism of osteosarmagenesis and, especially, metastatic processes. Growing evidence suggests that cancer stem cells (CSCs), which have self-renewing and malignant potential, are at the root of tumor growth and relapse. Thus, a challenge for innovative therapy is their identification and eradication. Here, we have used the 3AB-OS CSCs, a cell line previously produced in our laboratory from the OS-MG63 cells, which was genetically, molecularly and functionally characterized. This study was focused on the role of let-7d miRNA-previously found by us to be downregulated in 3AB-OS-CSCs- in managing their stemness properties. We have found that let-7d-overesperession reduces cell proliferation by both decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also reduces sarcosphere and colony-forming ability and the expression of Oct3/4, Sox2, Nanog, Lin28B and HMGA2, key regulators of cancer cell stemness. Moreover, let-7d induces mesenchymal-to-epithelium-transition, as shown by both N-Cadherin-E-cadherin-switch and vimentin decrease. Surprisingly, this swich was accompanied by enhanced migratory/invasive capacities and by increases in MMP9, CXCR4 and VersicanV1. Let-7d also reduced the resistance to serum starvation and chemotherapy. A decrease in caspase-3 with an increase in Bcl-2 was also observed. Overall, this study shows that let-7d displaying both suppressor and oncogenic functions behaves as a Janus-Faced miRNA. Thus, we suggest that, before prospecting new therapeutic strategies by let-7d modulation, it is urgent to better understand its functions.

KW - Cancer stem cells

KW - microRNA

KW - osteosarcoma

UR - http://hdl.handle.net/10447/234939

UR - https://www.ibim.cnr.it/homebiotec

M3 - Other

ER -