scholarly journals A murine mesenchymal stem cell model for initiating events in osteosarcomagenesis points to CDK4/CDK6 inhibition as a therapeutic target

2021 ◽  
Author(s):  
Natasja Franceschini ◽  
Raffaele Gaeta ◽  
Paul Krimpenfort ◽  
Inge Briaire-de Bruijn ◽  
Alwine B. Kruisselbrink ◽  
...  
Keyword(s):  
Cell Model ◽  
Primary Tumour ◽  
Three Dimensional ◽  
Genetic Alterations ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Rb Pathway ◽  
Human Osteosarcoma Cell ◽  
Stem Cell Model ◽  
Tissue Microarray Analysis

AbstractOsteosarcoma is a high-grade bone-forming neoplasm, with a complex genome. Tumours frequently show chromothripsis, many deletions, translocations and copy number alterations. Alterations in the p53 or Rb pathway are the most common genetic alterations identified in osteosarcoma. Using spontaneously transformed murine mesenchymal stem cells (MSCs) which formed sarcoma after subcutaneous injection into mice, it was previously demonstrated that p53 is most often involved in the transformation towards sarcomas with complex genomics, including osteosarcoma. In the current study, not only loss of p53 but also loss of p16Ink4a is shown to be a driver of osteosarcomagenesis: murine MSCs with deficient p15Ink4b, p16Ink4a, or p19Arf transform earlier compared to wild-type murine MSCs. Furthermore, in a panel of nine spontaneously transformed murine MSCs, alterations in p15Ink4b, p16Ink4a, or p19Arf were observed in eight out of nine cases. Alterations in the Rb/p16 pathway could indicate that osteosarcoma cells are vulnerable to CDK4/CDK6 inhibitor treatment. Indeed, using two-dimensional (n = 7) and three-dimensional (n = 3) cultures of human osteosarcoma cell lines, it was shown that osteosarcoma cells with defective p16INK4A are sensitive to the CDK4/CDK6 inhibitor palbociclib after 72-hour treatment. A tissue microarray analysis of 109 primary tumour biopsies revealed a subset of patients (20–23%) with intact Rb, but defective p16 or overexpression of CDK4 and/or CDK6. These patients might benefit from CDK4/CDK6 inhibition, therefore our results are promising and might be translated to the clinic.

scholarly journals Antiproliferative Properties of Oleuropein in Human Osteosarcoma Cells

2016 ◽  
Vol 11 (4) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Jose M. Moran ◽  
Olga Leal-Hernandez ◽  
Maria L. Canal-Macías ◽  
Raul Roncero-Martin ◽  
Rafael Guerrero-Bonmatty ◽  
...  
Keyword(s):  
Cell Lines ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Osteosarcoma Cells ◽  
Probit Regression ◽  
Cytotoxic Effects ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Mg63 Cells ◽  
Human Osteosarcoma Cell

In this study, we evaluated the antiproliferative activity on two human osteosarcoma cell lines (MG-63 and Saos2) of oleuropein, an olive oil compound traditionally found in the Mediterranean diet. Oleuropein exhibited obvious cytotoxic effects on human osteosarcoma cells in a concentration- and time-dependent manner. Statistical analysis of IC50 by the Probit regression method suggested that oleuropein had similar toxic effects on both cell lines tested (IC50 range from 247.4–475.0 μM for MG63 cells and from 798.7–359.9 μM for Saos2 cells).

scholarly journals Micro-RNA 122 and micro-RNA 96 affected human osteosarcoma biological behavior and associated with prognosis of patients with osteosarcoma

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Bin Liu ◽  
Shuqiang Yao ◽  
Jiping Zhou
Keyword(s):  
Independent Predictor ◽  
Micro Rna ◽  
Biological Behavior ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Rt Pcr ◽  
Normal Tissues ◽  
Human Osteosarcoma ◽  
Tumor Tissues ◽  
Human Osteosarcoma Cell

Abstract Osteosarcoma (OS) is the most common bone malignancy in both children and adolescents. In the present study, we aimed to explore the association of miRNA-122 and miRNA-96 expression with the clinical characteristics and prognosis of patients with osteosarcoma. The expression of miRNA-122 and miRNA-96 in human osteosarcoma cell lines and tissues were detected in the present study. Reverse transcriptase-PCR (RT-PCR) was used to determine the expression levels of miRNA-122 and miRNA-96 in 68 human OS samples. We found that MiRNA-122 and miRNA-96 were widely up-regulated in osteosarcoma, gastric cancer and pancreatic cancer. In HOS, Saos-2 and U2OS osteosarcoma cells, miRNA-122 and miRNA-96 were up-regulated significantly, while down-regulated in MG-63 cells. After further investigation, we found that miRNA-122 and miRNA-96 concentrations were significantly higher in the tumor tissues than those in the normal tissues (P<0.01). Moreover, the cell proliferation of LV-miRNA-122-RNAi and LV-miRNA-96-RNAi transfected SaOS2 was significantly decreased compared with the LV- miRNA-122-RNAi-CN and LV- miRNA-96-RNAi group. After adjusting for competing risk factors, we found combined high miRNA-122 and miRNA-96 expression was identified as independent predictor of overall survival.

scholarly journals C. elegans germ cells divide and differentiate along a folded epithelium

2018 ◽  
Author(s):  
Hannah S. Seidel ◽  
Tilmira A. Smith ◽  
Jessica K. Evans ◽  
Jarred Q. Stamper ◽  
Thomas G. Mast ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Germ Cells ◽  
Cell Model ◽  
Three Dimensional ◽  
3D Models ◽  
Germline Stem Cells ◽  
C Elegans ◽  
Stem Cell Regulation ◽  
Stem Cell Model

AbstractKnowing how stem cells and their progeny are positioned within their tissues is essential for understanding their regulation. One paradigm for stem cell regulation is the C. elegans germline, which is maintained by a pool of germline stem cells in the distal gonad, in a region known as the ‘progenitor zone’. The C. elegans germline is widely used as a stem cell model, but the cellular architecture of the progenitor zone has been unclear. Here we characterize this architecture by creating virtual 3D models of the progenitor zone in both sexes. We show that the progenitor zone in adult hermaphrodites is essentially a folded epithelium. The progenitor zone in males is not folded. Analysis of germ cell division shows that daughter cells are born side-by-side along the surface of the epithelium. Analysis of a key regulator driving differentiation, GLD-1, shows that germ cells in hermaphrodites differentiate along the path of the folded epithelium, with previously described “steps” in GLD-1 expression corresponding to germline folds. Our study provides a three-dimensional view of how C. elegans germ cells progress from stem cell to overt differentiation, with critical implications for regulators driving this transition.

scholarly journals MicroRNA-133a Inhibits Osteosarcoma Cells Proliferation and Invasion via Targeting IGF-1R

2016 ◽  
Vol 38 (2) ◽  
pp. 598-608 ◽  
Author(s):  
Guangnan Chen ◽  
Tingting Fang ◽  
Zhongming Huang ◽  
Yiying Qi ◽  
Shaohua Du ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Osteoblastic Cell ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Invasion And Metastasis ◽  
Osteoblastic Cell Line ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell

Background/Aims: MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Downregulated microRNAs and their roles in cancer development have attracted much attention. A growing body of evidence showed that microRNA-133a (miR-133a) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of osteosarcoma. Methods: MiR-133a expression in human osteosarcoma cell lines and human normal osteoblastic cell line hFOB was investigated by real-time PCR (RT-PCR). The role of miR-133a in human osteosarcoma growth and invasion was assessed in cell lines in vitro and in vivo. Then, luciferase reporter assay validated IGF-1R as a downstream and functional target of miR-133a, and functional studies revealed that the anti-tumor effect of miR-133a was probably due to targeting and repressing of IGF-1R expression. Results: MiR-133a was lower expressed in human osteosarcoma cell lines than human normal osteoblastic cell line hFOB and its effect on inhibiting proliferation, invasion and metastasis is mediated by its direct interaction with the IGF-1R. Furthermore, the tumour-suppressive function of miR-133a probably contributed to inhibiting the activation AKT and ERK signaling pathway. Conclusion: MiR-133a suppresses osteosarcoma progression and metastasis by targeting IGF-1R in human osteosarcoma cells, providing a novel candidate prognostic factor and a potential anti-metastasis therapeutic target in osteosarcoma.

scholarly journals Elevated expression of serine/threonine phosphatase type 5 correlates with malignant proliferation in human osteosarcoma.

1970 ◽  
Vol 64 (1) ◽  
Author(s):  
Kun Han ◽  
Zhihua Gan ◽  
Shuchen Lin ◽  
Haiyan Hu ◽  
Zan Shen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Functional Role ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Facs Analysis ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell ◽  
Elevated Expression ◽  
Common Primary Malignant Bone

Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. However, the involvement of serine/threonine phosphatase type 5 (PP5) in osteosarcoma remains unclear. The aim of this study was to evaluate the functional role of PP5 in osteosarcoma cells. Firstly, we found that PP5 is widely expressed in several human osteosarcoma cell lines. Then we used lentivirus-delivered siRNA to silence PP5 expression in Saos-2 and U2OS cell lines. Knockdown of endogenous PP5 expression by shRNA-expressing lentivirus significantly decreased the viability and proliferation of the osteosarcoma cells. Moreover, FACS analysis showed that knockdown of PP5 expression induced a significant arrest in the G0/G1 phase of the cell cycle, which was associated with the inhibition of cell proliferation. Therefore, knockdown of PP5 is likely to provide a novel alternative to targeted therapy of osteosarcoma and deserves further investigation.

scholarly journals Effect of the Tumor Suppressor miR-320a on Viability and Functionality of Human Osteosarcoma Cell Lines Compared to Primary Osteoblasts

2020 ◽  
Vol 10 (8) ◽  
pp. 2852
Author(s):  
Laura De-Ugarte ◽  
Susanna Balcells ◽  
Robert Guerri-Fernandez ◽  
Daniel Grinberg ◽  
Adolfo Diez-Perez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tumor Suppressor ◽  
Cell Viability ◽  
Cell Lines ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Matrix Mineralization ◽  
Cellular Effects ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell

The miR-320a regulates a number of genes involved in various physiological processes. In particular, it has been reported as a tumor suppressor in several types of human cancers and involved in osteoporotic fracture and osteoblast function. Hence, the role of miR-320a has been evaluated in tumor cells and in primary cells in a separated context, but its effect has never been explored in a comparative manner. The present study aims to evaluate the cellular effects of miR-320a on human osteosarcoma cell lines (MG-63 and U2OS) compared to that on primary human osteoblasts (hOBs). miR-320a was either overexpressed or inhibited in all cell lines, and cell proliferation and viability were analyzed. Additionally, the effects of miR-320a on matrix mineralization, alkaline phosphatase activity, and oxidative stress were also evaluated in order to assess osteoblast functionality. In osteosarcoma cells, miR-320a overexpression reduced cell viability and proliferation, while in hOB cell viability was not affected and proliferation even was increased. The overexpression of miR-320a in both osteosarcoma cells and hOBs reduced the mineralization capacity. Finally, an increased oxidative stress was detected in all cells after miR-320a overexpression mainly in osteosarcoma. In conclusion, the overexpression of miR-320a increased stress oxidation levels, which could be involved in the reduced osteoblast performance, even though the cell viability was only affected in osteosarcoma cells.

scholarly journals β-Phenethyl Isothiocyanate Induces Cell Death in Human Osteosarcoma through Altering Iron Metabolism, Disturbing the Redox Balance, and Activating the MAPK Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-23
Author(s):  
Huanhuan Lv ◽  
Chenxiao Zhen ◽  
Junyu Liu ◽  
Peng Shang
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Iron Metabolism ◽  
Ros Generation ◽  
Osteosarcoma Cell ◽  
Phenethyl Isothiocyanate ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Human Osteosarcoma Cell

Osteosarcoma is the most common primary malignancy of the skeleton in children and adults. The outcomes of people with osteosarcomas are unsatisfied. β-Phenethyl isothiocyanate (PEITC) exhibits chemoprevention and chemotherapeutic activities against many human cancers. The molecular mechanism underlying its action on osteosarcoma is still unknown. This study was aimed at investigating the effect of PEITC on human osteosarcoma both in vitro and in vivo. The results showed that PEITC reduced cell viability, inhibited proliferation, and caused G2/M cell cycle arrest in four human osteosarcoma cell lines (MNNG/HOS, U-2 OS, MG-63, and 143B). Then, we found that PEITC altered iron metabolism related to the processes of iron import, storage, and export, which resulted in increased labile iron. Expectedly, PEITC caused oxidative stress as a consequence of GSH depletion-inducing ROS generation and lipid peroxidation. Multiple cell death modalities, including ferroptosis, apoptosis, and autophagy, were triggered in human osteosarcoma cells. Three MAPKs (ERK, p38, and JNK) were all activated after PEITC treatment; however, they presented different responses among the four human osteosarcoma cell lines. ROS generation was proved to be the major cause of PEITC-induced decreased proliferative potential, altered iron metabolism, cell death, and activated MAPKs in human osteosarcoma cells. In addition, PEITC also significantly delayed tumor growth in a xenograft osteosarcoma mouse model with a 30 mg/kg administration dose. In conclusion, this study reveals that PEITC simultaneously triggers ferroptosis, apoptosis, and autophagy in human osteosarcoma cells by inducing oxidative stress.

Comparison of Mechanosensitivity of Human Primary-Cultured Osteoblast Cells and Human Osteosarcoma Cell Line Under Hydrostatic Pressure

2012 ◽  
Author(s):  
Yasaman Ganji ◽  
Mehran Kasra
Keyword(s):  
Alkaline Phosphatase ◽  
Hydrostatic Pressure ◽  
Cell Line ◽  
Cell Model ◽  
Bone Cell ◽  
Osteosarcoma Cell ◽  
Human Osteosarcoma Cell Line ◽  
Osteoblast Cells ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell

Regarding to the advances in mechanical stimulation of cells, this study aims to address important issues in bone generation and therapy at cellular level as it relates to understanding of bone cell response to hydrostatic pressure as well as choosing a proper cell model in studies of bone cell response to mechanical stimulation. G292 human osteosarcoma cell line and human primary osteoblast cells were tested under cyclic hydrostatic pressure. Monolayer culture of cells were divided into three groups of control without loading, static with the pressure of 0.5 MPa, and dynamic with the pressure of 0.5 MPa and the frequency of 1 Hz. The cells were analyzed with measurement of alkaline phosphatase activity. Higher level of alkaline phosphatase activity in all groups of primary cell model compared with cell line model indicated more sensitivity of response of primary cells to this kind of loading.

scholarly journals Bioinspired-Metalloporphyrin Magnetic Nanocomposite as a Reusable Catalyst for Synthesis of Diastereomeric (−)-Isopulegol Epoxide: Anticancer Activity Against Human Osteosarcoma Cells (MG-63)

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 52 ◽  
Author(s):  
Lucas Dias ◽  
Ana Batista de Carvalho ◽  
Sara Pinto ◽  
Gilberto Aquino ◽  
Mário Calvete ◽  
...  
Keyword(s):  
Reusable Catalyst ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma Cell Line ◽  
Anticancer Effect ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Human Osteosarcoma Cell ◽  
Ic50 Values

In the present study, we developed a green epoxidation approach for the synthesis of the diastereomers of (−)-isopulegol benzyl ether epoxide using molecular oxygen as the oxidant and a hybrid manganese(III)-porphyrin magnetic reusable nanocomposite as the catalyst. High activity, selectivity, and stability were obtained, with up to four recycling cycles without the loss of activity and selectivity for epoxide. The anticancer effect of the newly synthesized isopulegol epoxide diastereomers was evaluated on a human osteosarcoma cell line (MG-63); both diastereomers showed similar in vitro potency. The measured IC50 values were significantly lower than those reported for other monoterpene analogues, rendering these epoxide isomers as promising anti-tumor agents against low prognosis osteosarcoma.

scholarly journals Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II

2016 ◽  
Vol 39 (2) ◽  
pp. 802-813 ◽  
Author(s):  
Bhuvana A. Setty ◽  
Yi Jin ◽  
Peter J. Houghton ◽  
Nicholas D. Yeager ◽  
Thomas G. Gross ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Osteosarcoma Cells ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Human Osteosarcoma Cell ◽  
Arginase Ii

Background/Aims: Despite significant advancements in the diagnosis and treatment of osteosarcoma, the overall survival has remained relatively unchanged for over two decades. Hypoxic conditions have been demonstrated in solid tumors and are associated with increased cell proliferation and angiogenesis. L-arginine metabolism by arginase produces L-ornithine, the precursor for polyamine and proline synthesis required for cellular proliferation. We hypothesized that hypoxia would increase cellular proliferation via arginase induction in human osteosarcoma cell lines. Methods: We utilized a variety of approaches to examine the role of arginase II in hypoxic (1% O2, 5% CO2) cellular proliferation. Results: Arginase II mRNA and protein levels were significantly increased in osteosarcoma cells exposed to hypoxia for 48 hours. There were twice as many viable cells following 48 hours of hypoxia than following 48 hours of normoxia (21% O2, 5% CO2). The addition of difluoromethylornithine (DFMO), a putative arginase inhibitor, prevented hypoxia-induced proliferation. Transfection of small interfering RNAs (siRNA) targeting arginase II resulted in knockdown of arginase II protein levels and prevented hypoxia-induced cellular proliferation. Conclusions: These data support our hypothesis that hypoxia increases proliferation of osteosarcoma cells in an arginase II-dependent manner. We speculate that arginase II may represent a therapeutic target in osteosarcoma.

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