Osteosarcoma

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (44)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
MDM2 12q14.3-q15 HDMX, hdm2, ACTFS -MDM2 and Osteosarcoma
219
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 mutation in Osteosarcoma
111
CDKN2A 9p21 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A and Osteosarcoma
85
CDK4 12q14 CMM3, PSK-J3 -CDK4 Amplification in Osteosarcoma
68
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 -RB1 and Osteosarcoma
67
VEGFA 6p12 VPF, VEGF, MVCD1 Prognostic
-VEGFA and Osteosarcoma
49
CD44 11p13 IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp1, CDW44, CSPG8, HCELL, HUTCH-I, ECMR-III Prognostic
-CD44 and Osteosarcoma
47
TNFRSF11B 8q24 OPG, TR1, OCIF -TNFRSF11B and Osteosarcoma
43
CASP3 4q34 CPP32, SCA-1, CPP32B -CASP3 and Osteosarcoma
41
RECQL4 8q24.3 RECQ4 Germline
-RECQL4 - Rothmund-Thomson Syndrome and increased risk of Osteosarcoma
41
FOS 14q24.3 p55, AP-1, C-FOS -FOS and Osteosarcoma
30
BAX 19q13.3-q13.4 BCL2L4 -BAX and Osteosarcoma
30
MMP2 16q12.2 CLG4, MONA, CLG4A, MMP-2, TBE-1, MMP-II -MMP2 and Osteosarcoma
29
KIT 4q12 PBT, SCFR, C-Kit, CD117 -KIT and Osteosarcoma
26
S100A4 1q21 42A, 18A2, CAPL, FSP1, MTS1, P9KA, PEL98 Prognostic
-S100A4 expression in Osteosarcoma
18
TNFRSF11A 18q22.1 FEO, OFE, ODFR, OSTS, PDB2, RANK, CD265, OPTB7, TRANCER, LOH18CR1 -TNFRSF11A and Osteosarcoma
18
SRC 20q12-q13 ASV, SRC1, c-SRC, p60-Src -SRC and Osteosarcoma
18
STAT3 17q21.31 APRF, HIES, ADMIO -STAT3 and Osteosarcoma
16
BMP2 20p12 BDA2, BMP2A -BMP2 and Osteosarcoma
15
ERBB2 17q12 NEU, NGL, HER2, TKR1, CD340, HER-2, MLN 19, HER-2/neu Prognostic
-ERBB2 and Osteosarcoma
14
SPARC 5q31.3-q32 ON -SPARC and Osteosarcoma
11
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 -MYCN Amplification in Osteosarcoma
10
PLK1 16p12.2 PLK, STPK13 -PLK1 and Osteosarcoma
10
PMP22 17p12 DSS, HNPP, CMT1A, CMT1E, GAS-3, Sp110, HMSNIA -PMP22 and Osteosarcoma
9
ABCG2 4q22 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, CD338, GOUT1, CDw338, UAQTL1, EST157481 -ABCG2 and Osteosarcoma
9
BCL2 18q21.3 Bcl-2, PPP1R50 -BCL2 and Osteosarcoma
8
CYR61 1p22.3 CCN1, GIG1, IGFBP10 -CYR61 and Osteosarcoma
8
BAD 11q13.1 BBC2, BCL2L8 -BAD and Osteosarcoma
7
TSPAN31 12q13.3 SAS -TSPAN31 and Osteosarcoma
6
E2F2 1p36 E2F-2 -E2F2 and Osteosarcoma
5
CHEK2 22q12.1 CDS1, CHK2, LFS2, RAD53, hCds1, HuCds1, PP1425 -CHEK2 mutations in Osteosarcoma
5
CCNE1 19q12 CCNE -CCNE1 and Osteosarcoma
4
HMGB1 13q12 HMG1, HMG3, SBP-1 -HMGB1 and Osteosarcoma
4
IBSP 4q21.1 BSP, BNSP, SP-II, BSP-II -IBSP and Osteosarcoma
4
WNT10B 12q13 SHFM6, WNT-12 -WNT10B and Osteosarcoma
3
CTSL 9q21.33 MEP, CATL, CTSL1 -CTSL1 and Osteosarcoma
3
CDKN2D 19p13 p19, INK4D, p19-INK4D -CDKN2D and Osteosarcoma
2
PTH1R 3p22-p21.1 PFE, PTHR, PTHR1 -PTH1R and Osteosarcoma
2
EXT1 8q24.11 EXT, LGS, TTV, LGCR, TRPS2 Germline
-Secondary Osteosarcoma following Osteochondroma
2
CCNB2 15q22.2 HsT17299 -CCNB2 and Osteosarcoma
2
RMI1 9q21.32 BLAP75, FAAP75, C9orf76 -RMI1 and Osteosarcoma
2
IER3 6p21.3 DIF2, IEX1, PRG1, DIF-2, GLY96, IEX-1, IEX-1L -IER3 and Osteosarcoma
2
PRIM1 12q13 p49 Amplification?
-PRIM1 Amplification in Osteosarcoma
1
GAS7 17p13.1 MLL/GAS7 -GAS7 and Osteosarcoma
1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

18q LOH in Osteosarcoma and Paget's Disease of Bone

Paget disease is a common metabolic bone disease characterized by rapid bone remodeling and abnormal bone formation. It occurs mostly in people aged over 40 yrs. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occurring after age 60 years. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of chromosome 18q. Nellissery et al (1998) analysed tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas and also osteosarcomas from patients with Paget disease, and found both groups included LOH in this region. Johnson-Pais et al (2003) localised this "LOH18CR locus" to the distal end of chromosome 18q21.33.

Johnson-Pais TL, Nellissery MJ, Ammerman DG, et al.
Determination of a minimal region of loss of heterozygosity on chromosome 18q21.33 in osteosarcoma.
Int J Cancer. 2003; 105(2):285-8 [PubMed] Related Publications
Previous analysis of tumor-specific constitutional LOH had identified a putative tumor-suppressor gene (LOH18CR) active in osteosarcoma tumorigenesis, which mapped to a subregion of chromosome 18q linked to both familial Paget's disease and FEO. Using 9 new polymorphic loci within the previous minimal region of LOH, we have reduced the minimal region of LOH in osteosarcoma tumors to localize the LOH18CR locus to the distal end of chromosome 18q21.33. This new region is approximately 500 kb and contains at least 7 known genes; however, it excludes 2 previous candidate genes: TNFRSF11A (RANK) and BCL2.

Nellissery MJ, Padalecki SS, Brkanac Z, et al.
Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone.
Am J Hum Genet. 1998; 63(3):817-24 [PubMed] Free Access to Full Article Related Publications
Paget disease of bone, or "osteitis deformans," is a bone disorder characterized by rapid bone remodeling resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3%-5% of subjects aged >40 years. Recent evidence suggests that predisposition to Paget disease may have a genetic component. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of chromosome 18q near the polymorphic locus D18S42. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occurring after age 60 years. Our analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identified a putative tumor-suppressor locus that maps to chromosome 18q. We have localized this tumor-suppressor locus between D18S60 and D18S42, a region tightly linked to familial Paget disease. Analysis of osteosarcomas from patients with Paget disease revealed that these tumors also undergo LOH in this region. These findings suggest that the association between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on chromosome 18.

Dseases that predispose to osteosarcoma

Disease Gene(s) Location Notes
Bloom Syndrome BLM (RECQL3) 15q26.1 An inherited autosomal recessive disease characterized by short stature, sun-sensitive skin changes, and other health problems. People with Bloom syndrome have an increased risk of cancer. They can develop a wide range of types of cancer, usually at a younger age compared to the wider population, and affected individuals can develop more than one type of cancer.
Diamond-Blackfan Anaemia RPS19
RPL5
RPL11
RPL35A
RPS7
RPS10
RPS17
RPS24
RPS26
19q13.2
1p22.1
1p36.1-
3q29
2p25
6p21.31
15q
10q22
12q13
An inherited autosomal dominant disorder of the bone marrow. People with Diamond-Blackfan anemia have an increased risk of developing myelodysplastic syndrome, acute myeloid leukaemia and osteosarcoma.
Li-Fraumeni Syndrome TP53 17p13.1 A rare inherited autosomal dominant disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The most frequent types of cancer associated with Li-Fraumeni syndrome are breast cancer, osteosarcoma, and soft tissue sarcomas. People affected also have increase risk of brain tumuors, leukaemias, adrenocortical carcinoma and other types of cancer.
Paget Disease SQSTM1
TNFRSF11A
TNFRSF11B
5q35
18q22.1
8q24
A disease causing excessive breakdown of bone with abnormal bone formation and remodeling. It is thought to be caused by a combination of genetic and environmental factors. People with Paget Disease have a small, but increased risk of developing osteosarcoma.
Retinoblastoma RB1 13q14.2 A type of eye cancer starting in the retina that usually develops in early childhood, usualy involving changes to the RB1 gene. An estimated 40% of cases are germinal retinoblastoma - meaning that the RB1 mutations occur in all of the body's cells, including reproductive cells. People with germinal retinoblastoma have an increased risk of developing pinealoma, osteosarcoma, and melanoma.
Rothmund-Thomson Syndrome RECQL4 8q24.3 An inherited autosomal recessive condition characterised by poikiloderma (skin redness, thiness and clustering of blood vessels), sparse hair, slow growth, abnormalities of the teeth and nails, and gastrointestinal problems in infancy. People with Rothmund-Thomson Syndrome have an increased chance of developing osteosarcoma and different forms of skin cancer.
Werner Syndrome WRN (RECQL2) 8p12 A rare autosomal recessive disorder characterized by premature aging and short stature -usually lacking a growth spurt during puberty. Symptoms include ealy graying and loss of hair, a hoarse voice, and thin, hardened skin. People with Werner Syndrome have an increased risk of osteosarcoma, thyroid cancer, melanoma, meningioma, soft tissue sarcomas, leukemia and other cancers.

Kansara M, Thomas DM
Molecular pathogenesis of osteosarcoma.
DNA Cell Biol. 2007; 26(1):1-18 [PubMed] Related Publications
Osteosarcoma is a devastating but rare disease, whose study has illuminated both the basic biology and clinical management of cancer over the past 30 years. These contributions have included insight into the roles of key cancer genes such as the retinoblastoma tumor suppressor gene and TP53, the identification of familial cancer syndromes implicating DNA helicases, and dramatic improvements in survival by the use of adjuvant chemotherapy. This review provides a synoptic overview of our current understanding of the molecular causes of osteosarcoma, and suggests future directions for study.

Lu L, Jin W, Liu H, Wang LL
RECQ DNA helicases and osteosarcoma.
Adv Exp Med Biol. 2014; 804:129-45 [PubMed] Related Publications
The RECQ family of DNA helicases is a conserved group of enzymes that are important for maintaining genomic integrity. In humans, there are five RECQ helicase genes, and mutations in three of them-BLM, WRN, and RECQL4-are associated with the genetic disorders Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome (RTS), respectively. Importantly all three diseases are cancer predisposition syndromes. Patients with RTS are highly and uniquely susceptible to developing osteosarcoma; thus, RTS provides a good model to study the pathogenesis of osteosarcoma. The "tumor suppressor" role of RECQL4 and the other RECQ helicases is an area of active investigation. This chapter reviews what is currently known about the cellular functions of RECQL4 and how these may relate to tumorigenesis, as well as ongoing efforts to understand RECQL4's functions in vivo using animal models. Understanding the RECQ pathways may provide insight into avenues for novel cancer therapies in the future.

Latest Publications

Mirabello L, Yeager M, Mai PL, et al.
Germline TP53 variants and susceptibility to osteosarcoma.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.

Niu G, Li B, Sun J, Sun L
miR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met.
Cell Prolif. 2015; 48(3):348-55 [PubMed] Related Publications
OBJECTIVES: Osteosarcoma is the most common primary bone malignancy of children and young adults. Increasing evidence has shown that microRNAs (miRNAs) are associated with cancer development, but, little is known concerning the role of miR-454 in osteosarcoma.
MATERIALS AND METHODS: qRT-PCR was performed to detect expression of miR-454 in osteosarcoma cell lines and tissues. To understand its role in osteosarcoma, we reintroduced expression of miR-454 in the MG-63 cell line by transfection with miR-454 mimics or inhibitors. CCK-8 assay and an invasion assay were used to detect the functional role of miR-454. Luciferase assay and western blot analysis were performed to detect the target gene of miR-454.
RESULTS: miR-454 was found to be down-regulated in osteosarcoma tissues and cell lines. Its over-expression inhibited tumour growth and invasion and its down-regulation promoted cell proliferation and invasion. Subsequent investigation revealed that c-Met was a direct and functional target of miR-454 in osteosarcoma. Overexpression of miR-454 impaired c-Met-induced cell proliferation and invasion. Finally, miR-454 was found to be inversely correlated to c-Met expression in human osteosarcoma tissues.
CONCLUSIONS: Reduced-expression of miR-454 in osteosarcoma cells promoted tumour growth by targeting c-Met, thus miR-454 may be a potential therapy target for this tumour.

He JY, Xi WH, Zhu LB, et al.
Knockdown of Aurora-B alters osteosarcoma cell malignant phenotype via decreasing phosphorylation of VCP and NF-κB signaling.
Tumour Biol. 2015; 36(5):3895-902 [PubMed] Related Publications
The aim of this study is to investigate the effects of inhibiting Aurora-B on osteosarcoma (OS) cell malignant phenotype, phosphorylation of valosin-containing protein (VCP), and the activity of NF-κB signaling in vitro. The expressions of Aurora-B and p-VCP proteins were detected by immunohistochemistry in 24 OS tissues, and the relationship between Aurora-B and p-VCP was investigated. The results showed that there was a positive correlation between Aurora-B and p-VCP proteins. The expression of Aurora-B in human OS cell lines U2-OS and HOS cells was inhibited by specific short hairpin RNA (shRNA) lentivirus (AURKB-shRNA lentivirus, Lv-shAURKB) which targeted Aurora-B. The results showed that the phosphorylation of VCP, the activity of NF-κB signaling pathway and the malignant phenotype of OS cells were all suppressed by knockdown of Aurora-B. It indicated that the inhibition of Aurora-B alters OS cells malignant phenotype by downregulating phosphorylation of VCP and activating of the NF-κB signaling pathway in vitro.

Wojewoda M, Walczak J, Duszyński J, Szczepanowska J
Selenite activates the ATM kinase-dependent DNA repair pathway in human osteosarcoma cells with mitochondrial dysfunction.
Biochem Pharmacol. 2015; 95(3):170-6 [PubMed] Related Publications
Mitochondrial dysfunction and reactive oxygen species (ROS) induced oxidative damage are implicated in the pathogenesis of several human diseases. Based on our previous findings that ROS level was higher in human osteosarcoma cybrids--Neuropathy, Ataxia and Retinitis Pigmentosa (NARP) and was reduced by selenite treatment, this study was designed to elucidate the effects of selenite administration on oxidative and nitrosative damage to lipids, proteins and DNA. Oxidative and nitrosative damage to lipids and proteins was not increased in NARP cybrids or mitochondrial DNA-lacking Rho0 cells (displaying mitochondrial dysfunction) when compared with control WT cells. However, we found the enhanced formation of DNA double-strand breaks based on the level of histone γH2AX (phosphorylated at Ser 139), which is known to be phosphorylated by ATM (Ataxia Telangiectasia Mutated) kinase in response to DNA damage. Selenite increased the activity of ATM kinase in NARP cybrids and Rho0 cells without concomitant increase in levels of histone γH2AX. Activation of the ATM kinase-dependent DNA repair pathway triggered by selenite could not be associated with enhanced DNA damage but might rather result from selenite-induced activation of ATM-dependent DNA repair mechanisms which could account for protective effects of this agent.

Lee DF, Su J, Kim HS, et al.
Modeling familial cancer with induced pluripotent stem cells.
Cell. 2015; 161(2):240-54 [PubMed] Article available free on PMC after 09/04/2016 Related Publications
In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.

Jian Y, Tian X, Li B, et al.
Letter regarding Li JS et al. entitled "ERCC polymorphisms and prognosis of patients with osteosarcoma".
Tumour Biol. 2015; 36(5):3195-6 [PubMed] Related Publications
With great interest, we read the article "ERCC polymorphisms and prognosis of patients with osteosarcoma" (by Li JS et al.), which has reached important conclusions about the relationship between ERCC polymorphisms and osteosarcoma prognosis. Through quantitative analysis, the meta-analysis showed that ERCC2 Lys751Gln (ORGG vs. AA = 0.40 (95%CI = 0.1-0.86), P heterogeneity = 0.502; I (2) = 0 %) and ERCC5 His46His (ORCC vs. TT = 0.37 (95%CI = 0.15-0.93), P heterogeneity = 0.569; I (2) = 0 %) polymorphisms might influence the prognosis of patients with osteosarcoma [1]. The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise.

Yu H, Sun H, Bai Y, et al.
MEF2D overexpression contributes to the progression of osteosarcoma.
Gene. 2015; 563(2):130-5 [PubMed] Related Publications
The underlying molecular pathogenesis of osteosarcoma remains poorly understood. The transcription factor MEF2D promotes the survival of various types of cells and functions as an oncogene in liver cancer. However, its potential contribution to osteosarcoma has not been explored. In this study, we investigated MEF2D expression and function in osteosarcoma, finding that MEF2D elevation in osteosarcoma clinical specimens was associated with patients' poor prognosis. MEF2D suppression was shown to decrease the proliferation of osteosarcoma cells, while forced expression of MEF2D was able to promote the proliferation of normal bone fibroblast. Notably, MEF2D silencing abolished osteosarcoma tumorigenicity in an animal model. Mechanistic investigations revealed that MEF2D silencing triggered G2-M arrest in osteosarcoma cells by suppressing RPRM and CDKN1A. miR-144 was found to suppress the expression of MEF2D in osteosarcoma cells. Collectively, our results demonstrated that MEF2D is a candidate oncogene for osteosarcoma and a potential molecular target for cancer therapy.

Sonnemann J, Grauel D, Blümel L, et al.
RETRA exerts anticancer activity in Ewing's sarcoma cells independent of their TP53 status.
Eur J Cancer. 2015; 51(7):841-51 [PubMed] Related Publications
Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES.

Tang Z, Li C, Chen Z
[Inhibitory effect of baicalein on the proliferation and invasion of osteosarcoma cells and mechanism].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2015; 31(3):342-5 [PubMed] Related Publications
OBJECTIVE: To explore the effect of baicalein on the proliferation and invasion of osteosarcoma cells and its related mechanism.
METHODS: Osteosarcoma MG-63 cells that were cultured in vitro were respectively treated with 20 μL culture medium (control group), dehydrated alcohol (0 μmol/L baicalein group), 100 and 200 μmol/L baicalein solution for 48 hours. Cell proliferation was analyzed by MTT assay. The cell invasion ability was detected using Transwell(TM) invasion assay. The expression of ezrin mRNA was examined by real-time quantitative PCR. The expressions of ezrin protein and p-ezrin protein were measured using Western blotting. Apoptosis index (AI) was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL).
RESULTS: The inhibitory rates of cell proliferation significantly increased in 100 and 200 μmol/L baicalein groups as compared with 0 μmol/L baicalein group. Moreover, that was higher in 200 μmol/L baicalein group than in 100 μmol/L baicalein group. In comparison with control and 0 μmol/L baicalein groups, the mean cell numbers of permeated membrane and levels of ezrin mRNA, ezrin protein and p-ezrin protein gradually decreased, but AI was gradually elevated with the increase of baicalein concentrations, whereas there was no significant difference in these indicators between 0 μmol/L baicalein group and control group.
CONCLUSION: Baicalein can inhibit the proliferation and invasion of osteosarcoma MG-63 cells. The mechanism may be associated with the inhibited expression and activity of ezrin protein and the promoted tumor cell apoptosis.

Tsuru A, Setoguchi T, Matsunoshita Y, et al.
Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression.
Br J Cancer. 2015; 112(7):1232-40 [PubMed] Article available free on PMC after 31/03/2016 Related Publications
BACKGROUND: Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma.
METHODS: Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1.
RESULTS: HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression.
CONCLUSIONS: Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.

Selvanathan SP, Graham GT, Erkizan HV, et al.
Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.
Proc Natl Acad Sci U S A. 2015; 112(11):E1307-16 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based on proteins that modulate splice site selection. EWS-FLI1 is an Ewing sarcoma (ES) oncoprotein with an interactome that we demonstrate to have multiple partners in spliceosomal complexes. We evaluate the effect of EWS-FLI1 on posttranscriptional gene regulation using both exon array and RNA-seq. Genes that potentially regulate oncogenesis, including CLK1, CASP3, PPFIBP1, and TERT, validate as alternatively spliced by EWS-FLI1. In a CLIP-seq experiment, we find that EWS-FLI1 RNA-binding motifs most frequently occur adjacent to intron-exon boundaries. EWS-FLI1 also alters splicing by directly binding to known splicing factors including DDX5, hnRNP K, and PRPF6. Reduction of EWS-FLI1 produces an isoform of γ-TERT that has increased telomerase activity compared with wild-type (WT) TERT. The small molecule YK-4-279 is an inhibitor of EWS-FLI1 oncogenic function that disrupts specific protein interactions, including helicases DDX5 and RNA helicase A (RHA) that alters RNA-splicing ratios. As such, YK-4-279 validates the splicing mechanism of EWS-FLI1, showing alternatively spliced gene patterns that significantly overlap with EWS-FLI1 reduction and WT human mesenchymal stem cells (hMSC). Exon array analysis of 75 ES patient samples shows similar isoform expression patterns to cell line models expressing EWS-FLI1, supporting the clinical relevance of our findings. These experiments establish systemic alternative splicing as an oncogenic process modulated by EWS-FLI1. EWS-FLI1 modulation of mRNA splicing may provide insight into the contribution of splicing toward oncogenesis, and, reciprocally, EWS-FLI1 interactions with splicing proteins may inform the splicing code.

Zhang Y, Duan G, Feng S
MicroRNA-301a modulates doxorubicin resistance in osteosarcoma cells by targeting AMP-activated protein kinase alpha 1.
Biochem Biophys Res Commun. 2015; 459(3):367-73 [PubMed] Related Publications
MicroRNAs have been implicated in drug resistance of osteosarcoma (OS). MicroRNA-301a (miR-301a) is up-regulated and functions as an oncogene in various cancers. However, little is known about the role of miR-301a in drug resistance of OS cells. In this study, we found that doxorubicin induced time-dependent expression of miR-301a in OS cells. Meantime, doxorubicin promoted HMGCR expression and inhibited AMPKα1 expression, which was further facilitated by miR-301a overexpression. Luciferase reporter assay identified AMPKα1 as direct target gene of miR-301a. Notably, miR-301a reduced doxorubicin-induced cell apoptosis whereas anti-miR-301a enhanced apoptosis in OS cells, suggesting that up-regulation of miR-301a contributed to chemoresistance of OS cells. Consistently, our data showed that miR-301a and HMGCR were up-regulated in chemotherapy-resistant OS compared to those in control OS. Our findings suggested that miR-301a might be a potential biomarker for chemotherapy-resistant OS and a promising therapeutic target for overcoming drug resistance of OS.

Righi A, Gambarotti M, Longo S, et al.
Small cell osteosarcoma: clinicopathologic, immunohistochemical, and molecular analysis of 36 cases.
Am J Surg Pathol. 2015; 39(5):691-9 [PubMed] Related Publications
Small round cell osteosarcoma is a very rare type of osteosarcoma, histologically mimicking other small round cell malignancies of bone, most notably Ewing sarcoma. To distinguish small cell osteosarcoma from other primary small cell malignancies of bone, we evaluated the immunohistochemical (IHC) expression of CD99 and SATB2, a marker of osteoblastic differentiation. Second, we analyzed EWSR1 and FUS gene aberrations using fluorescence in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR) techniques to assess whether small cell osteosarcoma and Ewing sarcoma share the same genetic alteration analysis. Thirty-six cases of primitive small cell osteosarcoma of bone were included in this study. All the cases of small cell osteosarcoma showed strong nuclear expression of SATB2 associated with negativity for CD99 antibody or weak, cytoplasmic staining in few neoplastic cells. Reverse transcription-polymerase chain reaction was negative for EWS-FLI1 type 1-2, EWS-ERG type 1, and CIC-DUX4 in the 10 available cases of small cell osteosarcoma analyzed. Fluorescence in situ hybridization analysis was feasible with a readable signal in 13 cases of small cell osteosarcoma, and none of these cases showed any EWSR1 and FUS gene rearrangements. In conclusion, it appears extremely useful to combine IHC analysis of SATB2 and CD99 with molecular analysis of Ewing sarcoma-associated genetic aberrations, to differentiate small cell osteosarcoma from other small round cell malignancies of bone. The strong IHC expression of SATB2 associated with CD99 immunonegativity and the absence of EWSR1 and FUS gene rearrangements in small cell osteosarcoma argues against the existence of a morphologic/genetic continuum with Ewing sarcoma.

Schwentner R, Papamarkou T, Kauer MO, et al.
EWS-FLI1 employs an E2F switch to drive target gene expression.
Nucleic Acids Res. 2015; 43(5):2780-9 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters.

Righi A, Gambarotti M, Benini S, et al.
MDM2 and CDK4 expression in periosteal osteosarcoma.
Hum Pathol. 2015; 46(4):549-53 [PubMed] Related Publications
Periosteal osteosarcoma is defined by the World Health Organization as an intermediate-grade, malignant, cartilaginous, and bone-forming neoplasm arising on the surface of bone. Unlike other subtypes of osteosarcoma, no data have been published about mouse double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) expression. For this reason, we evaluated the molecular and immunohistochemical features of MDM2 and CDK4 in 27 cases relative to 20 patients with a diagnosis of periosteal osteosarcoma, surgically treated at the Rizzoli Institute between 1981 and 2014. When possible, these results were compared with the MDM2 amplification status as determined by fluorescence in situ hybridization (FISH). All but 1 case (26/27, 96.3%) were negative for MDM2 protein using immunohistochemistry both in primary and in recurrent periosteal osteosarcoma, whereas gene amplification of MDM2 was not detected in any tumor analyzed (10 cases). The positive immunohistochemical case shows a weak/moderate focal nuclear expression of MDM2 antibody in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid production in a primary periosteal osteosarcoma. CDK4 immunohistochemical expression was negative in all 27 cases. This retrospective analysis has demonstrated that MDM2 and CDK4 are very rarely expressed in primary and recurrent periosteal osteosarcomas and therefore do not appear to be molecules central to the control of cancer development, growth, and progression in periosteal osteosarcoma. Therefore, when compared with low-grade central and parosteal osteosarcomas, MDM2 and CDK4 markers cannot be used diagnostically to differentiate this subtype of osteosarcoma.

Liu F, Zhang Q
Questions about XY Wen et al. entitled "Matrix metalloproteinase 2 expression and survival of patients with osteosarcoma: a meta-analysis".
Tumour Biol. 2015; 36(2):557-8 [PubMed] Related Publications
XY Wen et al. published an article entitled "Matrix metalloproteinase 2 expression and survival of patients with osteosarcoma: a meta-analysis" in Tumor Biology last year. The investigators demonstrated that high MMP2 expression was associated with poor prognosis in osteosarcoma. After reading these articles, we have some questions about the data extraction and processing in the meta-analysis.

Bilbao-Aldaiturriaga N, Gutierrez-Camino A, Martin-Guerrero I, et al.
Polymorphisms in miRNA processing genes and their role in osteosarcoma risk.
Pediatr Blood Cancer. 2015; 62(5):766-9 [PubMed] Related Publications
BACKGROUND: The possible associations between genetic variants and osteosarcoma risk have been analyzed without conclusive results. Those studies were focused mainly on genes of biologically plausible pathways. However, recently, another pathway has acquired relevance in cellular transformation and tumorigenesis, the microRNA (miRNA) processing pathway. Dysregulation of the expression levels of genes in this pathway has been described in cancer. Consequently, single nucleotide polymorphisms (SNPs) in genes that codify for proteins involved in the miRNA processing pathway may affect miRNAs, and therefore their target genes, which might be associated with cancer development and progression. The aim of this study was to evaluate whether SNPs in miRNA processing genes confer predisposition to osteosarcoma.
PROCEDURE: We analyzed 72 SNPs in 21 miRNA processing genes in a total of 99 osteosarcoma patients and 387 controls.
RESULTS: A total of three SNPs were associated with osteosarcoma susceptibility. Interestingly, these SNPs were located in miRNA processing genes (CNOT1, CNOT4 and SND1) which are part of the RISC complex. Among them, the association of rs11866002 in CNOT1 was nearly significant after Bonferroni correction.
CONCLUSIONS: This study suggests that SNPs in RISC complex genes may be involved in osteosarcoma susceptibility, especially rs11866002 in CNOT1.

Huang YW, Chang SJ, I-Chen Harn H, et al.
Mechanosensitive store-operated calcium entry regulates the formation of cell polarity.
J Cell Physiol. 2015; 230(9):2086-97 [PubMed] Related Publications
Ca(2+) -mediated formation of cell polarity is essential for directional migration which plays an important role in physiological and pathological processes in organisms. To examine the critical role of store-operated Ca(2+) entry, which is the major form of extracellular Ca(2+) influx in non-excitable cells, in the formation of cell polarity, we employed human bone osteosarcoma U2OS cells, which exhibit distinct morphological polarity during directional migration. Our analyses showed that Ca(2+) was concentrated at the rear end of cells and that extracellular Ca(2+) influx was important for cell polarization. Inhibition of store-operated Ca(2+) entry using specific inhibitors disrupted the formation of cell polarity in a dose-dependent manner. Moreover, the channelosomal components caveolin-1, TRPC1, and Orai1 were concentrated at the rear end of polarized cells. Knockdown of TRPC1 or a TRPC inhibitor, but not knockdown of Orai1, reduced cell polarization. Furthermore, disruption of lipid rafts or overexpression of caveolin-1 contributed to the downregulation of cell polarity. On the other hand, we also found that cell polarity, store-operated Ca(2+) entry activity, and cell stiffness were markedly decreased by low substrate rigidity, which may be caused by the disorganization of actin filaments and microtubules that occurs while regulating the activity of the mechanosensitive TRPC1 channel.

Ilić MP, Kiralj A, Markov B, et al.
Li-Fraumeni syndrome: a case report.
Vojnosanit Pregl. 2014; 71(12):1159-62 [PubMed] Related Publications
INTRODUCTION: Li-Fraumeni syndrome (LFS) is a very rare familial disease with the predisposition to the development of malignant tumors, such as osteosarcoma, breast cancer, brain neoplasm, leukemia, and adrenal tumors. Inheritance is autosomal dominant and is caused by heterozygous mutations in the p53 gene. The diagnosis is based on clinical criteria: a person under the age of 45 years suffering from sarcoma, the closest relative younger than 45 years diagnosed with cancer and a relative of the first or second degree, which is up to 45 years, was diagnosed with cancer and was diagnosed with sarcoma at any age.
CASE REPORT: The presented family with three members diagnosed with malignant disease typical for LFS suggests the need to carefully follow those diagnosed with LFS related tumor. A 24-year-old man diagnosed and treated for osteosarcoma of the maxilla died in the first year. His younger brother was submitted to surgery due to osteosarcoma of the mandible three years later, and a year later in his 24 year he had no signs of locoregional recurrence. Their mother was operated in 1996 for glioblastoma multiform brain cancer and ductal carcinoma, and died two years later at the age of 33.
CONCLUSION: The presented family highlights the need for careful examination, inspection and notification of the risks of family members diagnosed with LFS related tumors.

Svoboda LK, Harris A, Bailey NJ, et al.
Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs.
Epigenetics. 2014; 9(12):1613-25 [PubMed] Related Publications
The polycomb proteins BMI-1 and EZH2 are highly overexpressed by Ewing sarcoma (ES), a tumor of stem cell origin that is driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. In the current study we analyzed expression of transcription programs that are controlled by polycomb proteins during embryonic development to determine if they are abnormal in ES. Our results show that polycomb target gene expression in ES deviates from normal tissues and stem cells and that, as expected, most targets are relatively repressed. However, we also discovered a paradoxical up regulation of numerous polycomb targets and these were highly enriched for homeobox (HOX) genes. Comparison of HOX profiles between malignant and non-malignant tissues revealed a distinctive HOX profile in ES, which was characterized by overexpression of posterior HOXD genes. In addition, ectopic expression of EWS-FLI1 during stem cell differentiation led to aberrant up regulation of posterior HOXD genes. Mechanistically, this up regulation was associated with altered epigenetic regulation. Specifically, ES and EWS-FLI1+ stem cells displayed a relative loss of polycomb-dependent H3K27me3 and gain of trithorax-dependent H3K4me3 at the promoters of posterior HOXD genes and also at the HOXD11.12 polycomb response element. In addition, a striking correlation was evident between HOXD13 and other genes whose regulation is coordinately regulated during embryonic development by distal enhancer elements. Together, these studies demonstrate that epigenetic regulation of polycomb target genes, in particular HOXD genes, is altered in ES and that these changes are mediated downstream of EWS-FLI1.

Meng G, Li Y, Lv Y, et al.
Preliminary screening of differentially expressed genes involved in methyl-CpG-binding protein 2 gene-mediated proliferation in human osteosarcoma cells.
Tumour Biol. 2015; 36(4):3009-15 [PubMed] Related Publications
Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.

Dufresne A, Cassier P, Heudel P, et al.
[Molecular biology of sarcoma and therapeutic choices].
Bull Cancer. 2015; 102(1):6-16 [PubMed] Related Publications
Soft tissue sarcomas (STS) are a set of very heterogeneous tumors with numerous histological categories. The development of the molecular biology allowed identifying recurring molecular anomalies in certain subgroups of sarcomas, being able to represent diagnostic, prognosis and therapeutic tools. The molecular classification of STS includes until today 5 main groups of abnormalities: sarcomas with "simple genomic profile" showing reciprocal (1) chromosomal translocations, (2) activating mutation, (3) inhibitive mutation or (4) simple amplification; (5) sarcomas with "complex genomic profile" can include several tens of molecular abnormalities. The development of new-targeted therapies is based on the identification of a target, specific of a tumors subgroup and involved in carcinogenesis mechanisms and/or tumoral growth. Then, the aim of clinical research is to establish the proof of the concept through clinical trials, demonstrating the benefit brought to the patient and ending in the marketing of the drug. This proof of the concept was clearly established for imatinib, sunitinib and regorafenib in gastrointestinal stromal tumors, for imatinib in dermatofibrosarcoma protuberans and pigmented vilo-nodular synovitis, for denosumab in giant cell tumors of the bone, ending in the authorization to use these new therapies in these indications. It is in progress and promising for anti-IGF-1R in Ewing sarcomas, for crizotinib in myofibroblastic inflammatory tumors, for mTOR inhibitor in PEComas... The role of molecular abnormalities identified in the mechanisms of tumoral progress for sarcomas and their potential therapeutic impact will be detailed.

Barbato S, Sgarbi G, Gorini G, et al.
The inhibitor protein (IF1) of the F1F0-ATPase modulates human osteosarcoma cell bioenergetics.
J Biol Chem. 2015; 290(10):6338-48 [PubMed] Article available free on PMC after 06/03/2016 Related Publications
The bioenergetics of IF1 transiently silenced cancer cells has been extensively investigated, but the role of IF1 (the natural inhibitor protein of F1F0-ATPase) in cancer cell metabolism is still uncertain. To shed light on this issue, we established a method to prepare stably IF1-silenced human osteosarcoma clones and explored the bioenergetics of IF1 null cancer cells. We showed that IF1-silenced cells proliferate normally, consume glucose, and release lactate as controls do, and contain a normal steady-state ATP level. However, IF1-silenced cells displayed an enhanced steady-state mitochondrial membrane potential and consistently showed a reduced ADP-stimulated respiration rate. In the parental cells (i.e. control cells containing IF1) the inhibitor protein was found to be associated with the dimeric form of the ATP synthase complex, therefore we propose that the interaction of IF1 with the complex either directly, by increasing the catalytic activity of the enzyme, or indirectly, by improving the structure of mitochondrial cristae, can increase the oxidative phosphorylation rate in osteosarcoma cells grown under normoxic conditions.

Flynn RL, Cox KE, Jeitany M, et al.
Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.
Science. 2015; 347(6219):273-7 [PubMed] Article available free on PMC after 16/01/2016 Related Publications
Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin-remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.

Fang D, Yang H, Lin J, et al.
17β-estradiol regulates cell proliferation, colony formation, migration, invasion and promotes apoptosis by upregulating miR-9 and thus degrades MALAT-1 in osteosarcoma cell MG-63 in an estrogen receptor-independent manner.
Biochem Biophys Res Commun. 2015; 457(4):500-6 [PubMed] Related Publications
In bone, different concentration of estrogen leads to various of physiological processes in osteoblast, such as the proliferation, migration, and apoptosis in an estrogen receptor-dependent manner. But little was known about the estrogen effects on osteosarcoma (OS). In this study, OS cell MG-63 was treated with low (1 nM) or high (100 nM) dose of 17β-Estradiol (E2) with the presence or absence of estrogen receptor α (ERα), for evaluating the E2 effects on proliferation, migration, invasion, colony formation and apoptosis. Consistent with a previous study, high dose of E2 treatment dramatically downregulated expressing level of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT-1). The observation of upregulation of miR-9 after a high dose of E2 treatment indicated the cause of MALAT-1 reduction. Downregulation of MALAT-1 promoted the combination of SFPQ/PTBP2 complex. It was also observed that the proliferation, migration, invasion, colony formation and apoptosis of OS cells were remarkably affected by high dose of E2 treatment, but not by low dose, in an ERα independent manner. Furthermore, the abolishment of the effects on these physiological processes caused by ectopic expression of miR-9 ASOs suggested the necessity of miR-9 in MALAT-1 regulation. Here we found that the high dose of E2 treatment upregulated miR-9 thus posttranscriptionally regulated MALAT-1 RNA level in OS cells, and then the downregulation of MALAT-1 inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) processes in the E2-dose dependent and ER-independent ways.

Shukla N
Ewing sarcoma: a tough road to clinically relevant biomarkers.
Pediatr Blood Cancer. 2015; 62(5):741-2 [PubMed] Related Publications

Zheng S, Qiao G, Min D, et al.
Heterogeneous expression and biological function of ubiquitin carboxy-terminal hydrolase-L1 in osteosarcoma.
Cancer Lett. 2015; 359(1):36-46 [PubMed] Related Publications
Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a member of the UCH class of DUBs, has been reported as either an oncogene or a tumor suppressor. However, the molecular mechanism underlying the biological function of UCHL1 in osteosarcoma is still unclear. This study was aimed at elucidating the roles of UCHL1 in regulating the biological behavior of osteosarcoma cells. In this study, we found that UCHL1 was elevated in osteosarcoma compared with normal bone tissue. Moreover, UCHL1 expression level was correlated with tumor maximum diameter, high rate of lung metastases and short survival time. Then, we found that knockdown of UCHL1 in osteosarcoma cell MG63 inhibited cell proliferation and significantly increased cell population in the G1 phase. Several cyclins promoting G1/S phase transition were reduced after UCHL1 knockdown, including cell cycle regulator cyclin D1, cyclin E1 and CDK6. Moreover, inhibition of UCHL1 in MG63 cells dramatically induced cell apoptosis. We also found that down-regulation of UCHL1 in MG63 significantly inhibited cell invasion. Then, we found that there was a positive correlation between UCHL1 expression level and the Akt and ERK phosphorylation status. Finally, in vivo data showed that knockdown of UCHL1 inhibited osteosarcoma growth in nude mice. These results indicate that UCHL1 could work as an oncogene and may serve as a promising therapeutic strategy for osteosarcoma.

Wang L, Shao J, Zhang X, et al.
microRNA-377 suppresses the proliferation of human osteosarcoma MG-63 cells by targeting CDK6.
Tumour Biol. 2015; 36(5):3911-7 [PubMed] Related Publications
MicroRNAs (miRNAs) are essential to the progression of osteosarcoma. Previous research using osteosarcoma samples confirmed that miR-377 expression is less than that observed in normal human osteoblast expression. These data suggest a role for miR-377 in osteosarcoma that warrants investigation. To address this concept, we measured miR-377 expression in two cell models, and we also observed that miR-377 was less expressed in osteosarcoma MG-63 cells compared to the hFOB1.19 human fetal osteoblastic cell line. Moreover, miR-377 overexpression reduced cell proliferation and suppressed invasion of MG-63 cells but had no effect on MG-63 cell apoptosis. Because cyclin-dependent kinase 6 (CDK6) may be a potential target of miR-377 in osteosarcoma cells, we overexpressed CDK6 and observed that overexpression attenuated tumor suppressive effects of miR-377 on cell proliferation. Our data suggest that miR-377 can suppress proliferation in MG-63 cells in part by targeting CDK6.

Long XH, Zhou YF, Peng AF, et al.
Demethylation-mediated miR-129-5p up-regulation inhibits malignant phenotype of osteogenic osteosarcoma by targeting Homo sapiens valosin-containing protein (VCP).
Tumour Biol. 2015; 36(5):3799-806 [PubMed] Related Publications
Previous studies demonstrated that increased Homo sapiens valosin-containing protein (VCP) may be involved in osteosarcoma (OS) metastasis. However, the underlying mechanism of VCP over-expression in OS remains unknown. In the present study, we found a significantly negative correlation between miR-129-5p and VCP protein expression in OS tissues with pulmonary metastasis (Spearman's rho, rs = -0.948). Bioinformatical prediction, Luciferase reporter assay, Western blot, and RT-PCR assays performed on OS cells indicated that VCP is a target of miR-129-5p. In addition, three CPG islands in the region of miR-129-5p promoter were detected by bioinformatical prediction, and significantly higher expression of miR-129-5p and lower methylation level of miR-129-2 gene in OS cells treated with 5-Aza-2'-deoxycytidine (a potent DNA demethylating agent) than in those untreated cells were observed. Furthermore, lower migratory and invasive ability was found in cells with elevated miR-129-5p than in those with decreased miR-129-5p. These findings indicated that increased miR-129-5p may be mediated by demethylation and inhibit OS cell migration and invasion by targeting VCP in OS, and targeting miR-129-5p/VCP signaling pathway may serve as a therapeutic strategy for OS management, although further studies will be necessary.

Agostini M, Niklison-Chirou MV, Catani MV, et al.
TAp73 promotes anti-senescence-anabolism not proliferation.
Aging (Albany NY). 2014; 6(11):921-30 [PubMed] Article available free on PMC after 16/01/2016 Related Publications
TAp73, a member of the p53 family, has been traditionally considered a tumor suppressor gene, but a recent report has claimed that it can promote cellular proliferation. This assumption is based on biochemical evidence of activation of anabolic metabolism, with enhanced pentose phosphate shunt (PPP) and nucleotide biosynthesis. Here, while we confirm that TAp73 expression enhances anabolism, we also substantiate its role in inhibiting proliferation and promoting cell death. Hence, we would like to propose an alternative interpretation of the accumulating data linking p73 to cellular metabolism: we suggest that TAp73 promotes anabolism to counteract cellular senescence rather than to support proliferation.

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