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 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (58)

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'.

MDM2 12q15 HDMX, hdm2, ACTFS -MDM2 and Osteosarcoma
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 mutation in Osteosarcoma
CDKN2A 9p21.3 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A and Osteosarcoma
CDK4 12q14.1 CMM3, PSK-J3 -CDK4 Amplification in Osteosarcoma
CASP3 4q35.1 CPP32, SCA-1, CPP32B -CASP3 and Osteosarcoma
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 -RB1 and Osteosarcoma
VEGFA 6p21.1 VPF, VEGF, MVCD1 Prognostic
-VEGFA and Osteosarcoma
CD44 11p13 IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp1, CDW44, CSPG8, HCELL, HUTCH-I, ECMR-III Prognostic
-CD44 and Osteosarcoma
MMP2 16q12.2 CLG4, MONA, CLG4A, MMP-2, TBE-1, MMP-II -MMP2 and Osteosarcoma
RECQL4 8q24.3 RECQ4 Germline
-RECQL4 - Rothmund-Thomson Syndrome and increased risk of Osteosarcoma
BAX 19q13.33 BCL2L4 -BAX and Osteosarcoma
KIT 4q12 PBT, SCFR, C-Kit, CD117 -KIT and Osteosarcoma
FOS 14q24.3 p55, AP-1, C-FOS -FOS and Osteosarcoma
S100A4 1q21.3 42A, 18A2, CAPL, FSP1, MTS1, P9KA, PEL98 Prognostic
-S100A4 expression in Osteosarcoma
SRC 20q11.23 ASV, SRC1, THC6, c-SRC, p60-Src -SRC and Osteosarcoma
STAT3 17q21.2 APRF, HIES, ADMIO, ADMIO1 -STAT3 and Osteosarcoma
TNFRSF11B 8q24.12 OPG, TR1, OCIF, PDB5 -TNFRSF11B and Osteosarcoma
TNFRSF11A 18q21.33 FEO, OFE, ODFR, OSTS, PDB2, RANK, CD265, OPTB7, TRANCER, LOH18CR1 -TNFRSF11A and Osteosarcoma
CCK 3p22.1 -CCK and Osteosarcoma
BMP2 20p12.3 BDA2, BMP2A, SSFSC -BMP2 and Osteosarcoma
BCL2 18q21.33 Bcl-2, PPP1R50 -BCL2 and Osteosarcoma
ABCG2 4q22.1 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, CD338, GOUT1, MXR-1, CDw338, UAQTL1, EST157481 -ABCG2 and Osteosarcoma
ERBB2 17q12 NEU, NGL, HER2, TKR1, CD340, HER-2, MLN 19, HER-2/neu Prognostic
-ERBB2 and Osteosarcoma
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 -MYCN Amplification in Osteosarcoma
SPARC 5q33.1 ON, OI17, BM-40 -SPARC and Osteosarcoma
PLK1 16p12.2 PLK, STPK13 -PLK1 and Osteosarcoma
CCN1 1p22.3 GIG1, CYR61, IGFBP10 -CYR61 and Osteosarcoma
PMP22 17p12 DSS, CIDP, GAS3, HNPP, CMT1A, CMT1E, GAS-3, Sp110, HMSNIA -PMP22 and Osteosarcoma
BAD 11q13.1 BBC2, BCL2L8 -BAD and Osteosarcoma
E2F2 1p36.12 E2F-2 -E2F2 and Osteosarcoma
HES1 3q29 HHL, HRY, HES-1, bHLHb39 -HES1 and Osteosarcoma
TNFSF11 13q14.11 ODF, OPGL, sOdf, CD254, OPTB2, RANKL, TNLG6B, TRANCE, hRANKL2 -TNFSF11 and Osteosarcoma
CCNE1 19q12 CCNE, pCCNE1 -CCNE1 and Osteosarcoma
TSPAN31 12q13.3 SAS -TSPAN31 and Osteosarcoma
CHEK2 22q12.1 CDS1, CHK2, LFS2, RAD53, hCds1, HuCds1, PP1425 -CHEK2 mutations in Osteosarcoma
MMP13 11q22.2 CLG3, MDST, MANDP1, MMP-13 -MMP13 and Osteosarcoma
TERF2 16q22.1 TRF2, TRBF2 -TERF2 and Osteosarcoma
WNT10B 12q13.12 SHFM6, STHAG8, WNT-12 -WNT10B and Osteosarcoma
IBSP 4q22.1 BSP, BNSP, SP-II, BSP-II -IBSP and Osteosarcoma
HMGB1 13q12.3 HMG1, HMG3, HMG-1, SBP-1 -HMGB1 and Osteosarcoma
BCL2L2 14q11.2 BCLW, BCL-W, PPP1R51, BCL2-L-2 -BCL2L2 and Osteosarcoma
CTSL 9q21.33 MEP, CATL, CTSL1 -CTSL1 and Osteosarcoma
BIRC7 20q13.33 KIAP, LIVIN, MLIAP, RNF50, ML-IAP -BIRC7 and Osteosarcoma
PLA2G16 11q12.3-q13.1 AdPLA, HRSL3, HRASLS3, HREV107, HREV107-1, HREV107-3, H-REV107-1 -PLA2G16 and Osteosarcoma
RMI1 9q21.32 BLAP75, FAAP75, C9orf76 -RMI1 and Osteosarcoma
ERRFI1 1p36.23 MIG6, RALT, MIG-6, GENE-33 -ERRFI1 and Osteosarcoma
MIR122 18q21.31 MIR122A, MIRN122, mir-122, MIRN122A, miRNA122, miRNA122A, hsa-mir-122 -MIRN122 microRNA, human and Osteosarcoma
IER3 6p21.3 DIF2, IEX1, PRG1, DIF-2, GLY96, IEX-1, IEX-1L -IER3 and Osteosarcoma
CDKN2D 19p13.2 p19, INK4D, p19-INK4D -CDKN2D and Osteosarcoma
CCNB2 15q22.2 HsT17299 -CCNB2 and Osteosarcoma
EXT1 8q24.11 EXT, LGS, TTV, LGCR, TRPS2 Germline
-Secondary Osteosarcoma following Osteochondroma
PTH1R 3p22-p21.1 PFE, PTHR, PTHR1 -PTH1R and Osteosarcoma
PRIM1 12q13 p49 Amplification?
-PRIM1 Amplification in Osteosarcoma
CCNG1 5q34 CCNG -CCNG1 and Osteosarcoma
L1CAM Xq28 S10, HSAS, MASA, MIC5, SPG1, CAML1, CD171, HSAS1, N-CAML1, NCAM-L1, N-CAM-L1 -L1CAM and Osteosarcoma
KDM4C 9p24.1 GASC1, JHDM3C, JMJD2C, TDRD14C -KDM4C and Osteosarcoma
GAS7 17p13.1 -GAS7 and Osteosarcoma
MCM4 8q11.21 NKCD, CDC21, CDC54, NKGCD, hCdc21, P1-CDC21 -MCM4 and Osteosarcoma

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
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
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

Khwaja R, Mantilla E, Fink K, Pan E
Adult Primary Peripheral PNET/Ewing's Sarcoma of the Cervical and Thoracic Spine.
Anticancer Res. 2019; 39(8):4463-4465 [PubMed] Related Publications
This case report describes a patient with a rare occurrence of primary spinal intramedullary Ewing's sarcoma (ES) in the cervical and thoracic spine. The older age of disease occurrence, uncommon location in the cervical and thoracic spine, and EWSR1 gene fusion as the basis of diagnosis are unique features of this case. There is no clear protocol for treatment of primary extraskeletal ES of the spine, with controversy between evidence for pursuing surgery versus a combination of radiation and chemotherapy. Our patient was treated with temozolomide chemotherapy for recurrent metastatic disease of primary ES of the spine.

Higuchi T, Sugisawa N, Miyake K, et al.
Sorafenib and Palbociclib Combination Regresses a Cisplatinum-resistant Osteosarcoma in a PDOX Mouse Model.
Anticancer Res. 2019; 39(8):4079-4084 [PubMed] Related Publications
BACKGROUND/AIM: Recurrent osteosarcoma is a recalcitrant disease; therefore, an improved strategy is urgently needed to provide therapy. In order to develop a novel strategy for this disease, our lab has developed a patient-derived orthotopic xenograft (PDOX) mouse model for osteosarcoma. The combination of sorafenib (SFN) and palbociclib (PAL) was shown to be effective of hepatocellular carcinoma. However, whether this combination is efficacious on osteosarcoma has not been reported. The aim of this study was to determine the efficacy of the SFN and PAL combination on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model.
MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into five treatment groups: untreated-control, CDDP, SFN, PAL and the combination of SFN and PAL.
RESULTS: Of these agents, the SFN-PAL combination significantly regressed tumor growth, and enhanced tumor necrosis with degenerative changes in the osteosarcoma PDOX.
CONCLUSION: The SFN-PAL combination is an effective treatment strategy for osteosarcoma and therefore holds promise for clinical efficacy.

Jerez S, Araya H, Hevia D, et al.
Extracellular vesicles from osteosarcoma cell lines contain miRNAs associated with cell adhesion and apoptosis.
Gene. 2019; 710:246-257 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
Osteosarcoma is the most common primary bone tumor during childhood and adolescence. Several reports have presented data on serum biomarkers for osteosarcoma, but few reports have analyzed circulating microRNAs (miRNAs). In this study, we used next generation miRNA sequencing to examine miRNAs isolated from microvesicle-depleted extracellular vesicles (EVs) derived from six different human osteosarcoma or osteoblastic cell lines with different degrees of metastatic potential (i.e., SAOS2, MG63, HOS, 143B, U2OS and hFOB1.19). EVs from each cell line contain on average ~300 miRNAs, and ~70 of these miRNAs are present at very high levels (i.e., >1000 reads per million). The most prominent miRNAs are miR-21-5p, miR-143-3p, miR-148a-3p and 181a-5p, which are enriched between 3 and 100 fold and relatively abundant in EVs derived from metastatic SAOS2 cells compared to non-metastatic MG63 cells. Gene ontology analysis of predicted targets reveals that miRNAs present in EVs may regulate the metastatic potential of osteosarcoma cell lines by potentially inhibiting a network of genes (e.g., MAPK1, NRAS, FRS2, PRCKE, BCL2 and QKI) involved in apoptosis and/or cell adhesion. Our data indicate that osteosarcoma cell lines may selectively package miRNAs as molecular cargo of EVs that could function as paracrine agents to modulate the tumor micro-environment.

Chen ZD, Ye WB, Zeng WR, et al.
[Downregulation of Herg1 suppresses osteosarcoma proliferation and invasion by targeting Hippo signaling pathway].
Zhonghua Zhong Liu Za Zhi. 2019; 41(5):338-345 [PubMed] Related Publications

Meng Y, Liu YL, Li K, Fu T
Prognostic value of long non-coding RNA breast cancer anti-estrogen resistance 4 in human cancers: A meta-analysis.
Medicine (Baltimore). 2019; 98(21):e15793 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
BACKGROUND: Since long non-coding RNA breast cancer anti-estrogen resistance 4 (lncRNA BCAR4) is dysregulated in various types of cancers, we conducted a meta-analysis to determine its prognostic value in cancer.
METHODS: PubMed, EMBASE database, and CENTRAL were systematically searched.Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were collected to estimate the prognostic value. Odds ratios (ORs) and their 95% CIs were used to assess the association between lncRNA BCAR4 expression and clinicopathological features, including tumor size, differentiation, lymph node metastasis, distant metastasis, and tumor stage.
RESULTS: Ten studies with 890 patients were included in this meta-analysis. The pooled results indicated that high lncRNA BCAR4 expression was associated with poor overall survival (OS) (HR 2.80, 95% CI: 2.08-3.78; P < .001). Overexpression of lncRNA BCAR4 was related to lymph node metastasis (OR 3.68, 95% CI: 2.25-6.00; P < .001), high tumor stage (OR 3.19, 95% CI: 1.98-5.13; P < .001), and distant metastasis (OR 3.83, 95% CI: 2.15-6.82; P < .001), but not to tumor size.
CONCLUSIONS: Therefore, lncRNA BCAR4 overexpression is associated with poor OS and advanced clinicopathological features, and lncRNA BCAR4 may be a novel prognostic biomarker in cancer patients. However, further high-quality studies are needed to confirm these findings.

Shen WC, Lai YC, Li LH, et al.
Methylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis.
Nat Commun. 2019; 10(1):2226 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells.

Li X, Ding D, Yao J, et al.
Chromatin remodeling factor BAZ1A regulates cellular senescence in both cancer and normal cells.
Life Sci. 2019; 229:225-232 [PubMed] Related Publications
AIMS: Cellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. BAZ1A, a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of BAZ1A in regulating senescence in cancer and normal cells.
MATERIALS AND METHODS: Knockdown of BAZ1A was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by CCK-8 assay, SA-β-Gal staining and EdU incorporation assay, etc. KEY FINDINGS: Knockdown (KD) of BAZ1A induced series of senescence-associated phenotypes in both cancer and normal cells. BAZ1A-KD caused the upregulated expression of SMAD3, which in turn activated the transcription of p21 coding gene CDKN1A and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS).
SIGNIFICANCE: Our results revealed chromatin remodeling modulator BAZ1A acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.

Liu Y, Luo G, He D
Clinical importance of S100A9 in osteosarcoma development and as a diagnostic marker and therapeutic target.
Bioengineered. 2019; 10(1):133-141 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
OBJECTIVE: S100A9 is a calcium- and zinc-binding molecule of S100 family. The aim of the study was to evaluate the role of S100A9 in osteosarcoma (OS) and its value as a diagnostic and therapeutic target in OS.
METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and microdissection-based mRNA analysis were used to detect S100A9 mRNA and protein expression in OS and normal bone tissues and its potential as a diagnostic marker in OS. In vitro experiments with RNA interference were performed to evaluate the functional role of S100A9 and its potential as a therapeutic target in OS.
RESULTS: S100A9 mRNA levels were significantly higher in OS tissues than that of in normal bone tissues. Receiver operating characteristic curves showed that S100A9 could be a useful diagnostic marker in OS. In vitro data showed that inhibition of S100A9 decreased the proliferation and invasiveness of OS cells, and these findings were supported by microarray data.
CONCLUSIONS: Assessment of S100A9 mRNA expression is a promising tool for the diagnosis of OS, and S100A9 may be a promising therapeutic target in OS.

Chen JK, Peng SF, Lai KC, et al.
Fistein Suppresses Human Osteosarcoma U-2 OS Cell Migration and Invasion
In Vivo. 2019 May-Jun; 33(3):801-810 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
BACKGROUND/AIM: Evidence has indicated that fisetin induces cytotoxic effects in human cancer cell lines, including the inhibition of cell migration and invasion, however, the exact molecular mechanism of action of fisetin in human osteosarcoma cells remains unclear.
MATERIALS AND METHODS: The anti-metastatic mechanisms of fisetin in human osteosarcoma U-2 OS cells were investigated in vitro.
RESULTS: Fisetin reduced the viability of cells at different concentrations (2.5, 5 and 10 μM) as measured by flow cytometric assay. Fisetin suppressed cell mobility, migration and invasion of U-2 OS cells, as shown by wound healing assay and transwell filter chambers, respectively. The gelatin zymography assay showed that fisetin inhibited MMP-2 activity in U-2 OS cells. Results from western blotting indicated that fisetin reduced the levels of pEGFR, SOS-1, GRB2, Ras, PKC, p-ERK1/2, p-JNK, p-p-38, VEGF, FAK, RhoA, PI3K, p-AKT, NF-ĸB, uPA, MMP-7, MMP-9, and MMP-13, but increased GSK3β and E-cadherin in U-2 OS cells after 48 h of treatment.
CONCLUSION: Fisetin can be used in the future, as a target for the treatment of metastasis of human osteosarcoma cells.

Wang Y, Huang H, Li Y
Knocking down miR-384 promotes growth and metastasis of osteosarcoma MG63 cells by targeting SLBP.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1458-1465 [PubMed] Related Publications
Osteosarcoma is a common malignant bone tumour in adolescents and old people, with highly invasive and metastatic features and poor prognosis. This study aimed to explore the role of miR-384 in osteosarcoma MG63 cells by targeting SLBP. Cell viability, migration and invasion, apoptosis, as well as apoptosis-related factors were evaluated by CCK-8 assay, Transwell assay, flow cytometer and Western blotting, respectively. Dual-luciferase reporter assay was used to determine the target of miR-384. SLBP level was analyzed using qRT-PCR and Western blotting. Important factors of MEK/ERK and PI3K/AKT signalling pathways were analyzed using Western blotting. We found that miR-384 was down-regulated in osteosarcoma tissue samples and cell lines (MG63, U2OS and OS732). miR-384 overexpression inhibited viability, migration and invasion, but promoted apoptosis of MG63 cells; whereas, miR-384 silence exhibited the contrary effects on MG63 cells. SLBP was a target of miR-384. Knockdown of SLBP reversed the promoting effect of miR-384 silence on cells, indicating that miR-384 silence promoted growth and metastasis of MG63 cells by up-regulating SLBP. In conclusion, knocking down miR-384 promoted the growth and metastasis of osteosarcoma MG63 cells by up-regulating SLBP. To conclude, miR-384-SLBP may be a potential therapeutic target for osteosarcoma therapy.

Rossi F, Tortora C, Punzo F, et al.
The Endocannabinoid/Endovanilloid System in Bone: From Osteoporosis to Osteosarcoma.
Int J Mol Sci. 2019; 20(8) [PubMed] Article available free on PMC after 06/05/2020 Related Publications
Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system's receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management.

Qi NN, Tian S, Li X, et al.
Up-regulation of microRNA-496 suppresses proliferation, invasion, migration and in vivo tumorigenicity of human osteosarcoma cells by targeting eIF4E.
Biochimie. 2019; 163:1-11 [PubMed] Related Publications
Osteosarcoma is an aggressive bone tumor characterized by a high level of genetic instability and recurring DNA deletions and amplifications. This study aims to investigate how microRNA-496 (miR-496) affects proliferation, invasion, and migration of human osteosarcoma (OS) cells and in vivo tumorigenicity by targeting eukaryotic translation initiation factor 4E (eIF4E). Microarray-based gene expression profiling involving OS was used in order to identify differentially expressed genes. After that, the interaction between miR-496 expression and OS patients' survival rate was determined. The expression pattern of miR-496 and eIF4E was determined in OS tissues and cells, and their potential relationship was further analyzed by using the dual luciferase reporter gene assay. With the purpose of identifying the functional role miR-496 in OS, cell proliferation, migration, and invasion were measured in cells treated with miR-496 mimic or inhibitor. A nude mouse model was constructed in order to investigate the regulatory effects of miR-496 on tumor growth in vivo by regulating eIF4E. OS cells exhibited a down-regulated expression of miR-496 and an up-regulated expression of eIF4E. miR-496 expression was positively correlated to OS patients' survival rate. Bioinformatics analysis suggested eIF4E would be a direct target of miR-496, and the expression of eIF4E was inhibited by overexpression of miR-496. miR-496 elevation was found to exert suppressive effects on OS cell proliferation, migration and invasion in vitro and tumor growth in vivo, with the effects being reversed using miR-496 depletion. Altogether, the above findings support a conclusion that miR-496 could work as a tumor suppressor in OS through down-regulation of eIF4E. This study may provide a novel target for treatment of OS.

Wang Y, Yu W, Zhu J, et al.
Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma.
J Exp Clin Cancer Res. 2019; 38(1):168 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited.
METHODS: In this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166
RESULTS: CD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity.
CONCLUSIONS: Together, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.

Chen G, Yu W, Li Z, et al.
Potential Regulatory Effects of miR-182-3p in Osteosarcoma via Targeting EBF2.
Biomed Res Int. 2019; 2019:4897905 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
Osteosarcoma (OS) is one of the most common primary malignant bone tumors in adolescents with a high mortality rate. MicroRNA (miRNA) is a kind of noncoding RNAs and has been proved to participate in many physiological processes. Many miRNAs have been reported to act as function regulators in OS. In our study, the miRNA and gene expression profiles of OS were downloaded from GEO Datasets and the differential expression analysis was performed using GEO2R. 58 up- and 126 downregulated miRNAs were found. In the three OS gene profiles, 125 up- and 27 downregulated genes were found to be differentially expressed in at least two profiles. The miRNA-mRNA networks were constructed to predict the potential target genes of 10 most up- and downregulated miRNA. Venn analysis was used to detect the coexpressed differentially expressed genes (DEGs). EBF2, one of the upregulated DEGs, was also a potential target gene of miR-182-3p. Knockdown and overexpression of miR-182-3p resulted in overexpression and downexpression of EBF2 separately. Luciferase reporter gene experiment further verified the binding site of miR-182-3p and EBF2. CCK8 assay showed that miR-182-3p knockdown can further enhance the proliferation activity of OS cells, while overexpressing miR-182-3p can inhibit the proliferation activity of OS cells. Our research indicated that downexpression of miR-182-3p in OS cells results in overexpression of EBF2 and promotes the progression of OS.

Bhuvaneshwar K, Harris M, Gusev Y, et al.
Genome sequencing analysis of blood cells identifies germline haplotypes strongly associated with drug resistance in osteosarcoma patients.
BMC Cancer. 2019; 19(1):357 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients.
METHODS: We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter (DMET) genes associated with tumor necrosis and survival.
RESULTS: We found intronic and intergenic hotspot regions from 26 genes common to both the TARGET and INOVA datasets significantly associated with relapse outcome. Among significant results were mutations in genes belonging to AKR enzyme family, cell-cell adhesion biological process and the PI3K pathways; as well as variants in SLC22 family associated with both tumor necrosis and overall survival. The SNPs from our results were confirmed using Sanger sequencing. Our results included known as well as novel SNPs and haplotypes in genes associated with drug resistance.
CONCLUSION: We show that combining next generation sequencing data from multiple datasets and defined clinical data can better identify relevant pathway associations and clinically actionable variants, as well as provide insights into drug response mechanisms.

Zhao D, Wang S, Chu X, Han D
LncRNA HIF2PUT inhibited osteosarcoma stem cells proliferation, migration and invasion by regulating HIF2 expression.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1342-1348 [PubMed] Related Publications
PURPOSE: The function of lncRNAs in cancer stem cells (CSCs) remains to be elucidated. The present study aimed to investigate the regulating role of a novel lncRNA, hypoxia-inducible factor-2α (HIF-2α) promoter upstream transcript (HIF2PUT), in osteosarcoma stem cells.
METHODS: The expression of lncRNA HIF2PUT and HIF-2α in osteosarcoma stem cell lines and tissues was monitored by real-time PCR and western blot. The proliferation ability was examined by MTT assay when HIF2PUT overexpression or knockdown. The self-renewing capabilities of the cells were assessed by spheroid formation assay. The migration and invasion of cells were monitored by wound-healing assay and transwell cell assay, respectively. The correlation of HIF2PUT and HIF-2α expression was determined in osteosarcoma cancer tissues.
RESULTS: LncRNA HIF2PUT and HIF-2α were downregulated in osteosarcoma cell lines. HIF2PUT exhibited a significant decline in proliferation capacity. Wound healing and transwell assays showed that lncRNA overexpression inhibited osteosarcoma stem cell migration and invasion. HIF2PUT inhibited sphere formation in osteosarcoma stem cells. Increased HIF2PUT expression inhibited the enrichment of CD133 in osteosarcoma stem cells. There was a strong positive correlation between relative HIF2PUT level and relative HIF-2α level in the 30 paired osteosarcoma cancer tissues.
CONCLUSIONS: Overexpression of lncRNA HIF2PUT significantly attenuated the proliferation, migration and invasion of osteosarcoma stem cells. Furthermore, we demonstrated that lncRNA overexpression inhibited the sphere-formation of osteosarcoma stem cells by downregulating HIF-2α. These findings suggest that lncRNA HIF2PUT may act as a tumour suppressor in osteosarcoma. LncRNA HIF2PUT/HIF-2α may be a novel therapeutic target in the treatment of osteosarcoma.

He C, Sun Z, Hoffman RM, et al.
P-Glycoprotein Overexpression Is Associated With Cisplatin Resistance in Human Osteosarcoma.
Anticancer Res. 2019; 39(4):1711-1718 [PubMed] Related Publications
BACKGROUND/AIM: Osteosarcoma (OS) is a diagnosed primary cancer of the bone. Despite the great advances that have been made during the past decades in OS therapy, drug resistance and tumor recurrence are still major problems. It is urgent to find novel strategies to overcome drug resistance in order to prolong the survival time of OS patients.
MATERIALS AND METHODS: Cell viability was investigated by the cell count kit-8 (CCK-8) and colony formation assays. P-Glycoprotein (P-gp) expression was analyzed by RT-qPCR and western blot. A xenograft mouse model was used to identify the synergistic efficacy of a P-gp inhibitor with cisplatin. Student's t-test was used to determine statistically significant differences.
RESULTS: P-gp expression levels were associated with cisplatin efficacy in OS patients. OS cells with higher P-gp expression were more resistant to cisplatin. Knockdown or inhibition of P-gp sensitized OS cells to cisplatin.
CONCLUSION: Down-regulating the expression of P-gp in OS maybe a promising strategy to overcome cisplatin resistance.

Yuan Y, Wang Y, Liu Z, et al.
MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma by targeting epidermal growth factor receptor and proliferating cell nuclear antigen.
Int J Oncol. 2019; 54(6):2019-2029 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
Osteosarcoma (OS) is the most commonly diagnosed bone tumor in young people with poor prognosis. At present, the mechanisms underlying tumorigenesis in OS are not well understood. The methionine adnosyltransferase 2B (MAT2B) gene encodes the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies demonstrated that it is highly expressed in a number of human malignancies; however, is undefined in OS. In the present study, MAT2B expression was investigated in tumor samples and cell lines. In vivo and in vitro, lentivirus‑mediated small hairpin RNA was constructed to target the MAT2B gene and examine the role of MAT2B in OS proliferation. Microarray analysis was performed to examine the possible downstream molecular target of MAT2B in OS. MAT2B was markedly increased in OS specimens compared with the normal bone tissues, and it was additionally abundantly expressed in OS cell lines. Inhibition of MAT2B expression caused a marked decrease in proliferation and significant increase in apoptosis. In vivo, MAT2B silencing significantly inhibited OS cell growth. Microarray analysis suggested that epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) may function as downstream targets of MAT2B in OS, as confirmed by reverse transcription‑quantitative polymerase chain reaction assays and western blotting. Collectively, these results suggested that MAT2B serves a critical role in the proliferation of OS by regulating EGFR and PCNA and that it may be a potential therapeutic target and prognostic factor of OS.

Ma C, Nie XG, Wang YL, et al.
CBX3 predicts an unfavorable prognosis and promotes tumorigenesis in osteosarcoma.
Mol Med Rep. 2019; 19(5):4205-4212 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
CBX3, namely chromobox protein homolog 3, a member of the heterochomatin protein 1 (HP1) family, has been shown to be associated with the tumorigenesis of various types of cancer. The aim of the present study was to assess the biological role and the clinicopathological importance of CBX3 in osteosarcoma. The Oncomine database was utilized to determine the CBX3 expression in sarcoma patients. A retrospective cohort study was conducted to evaluate the prognostic value of CBX3 expression. In addition, correlations between the clinicopathological features of the osteosarcoma patients and CBX3 expression were assessed and involved recurrence, distant metastasis, lymph node metastasis, response to chemotherapy, pathological differentiation, clinical stage, anatomic location, tumor size and age. To investigate the function of CBX3 in osteosarcoma, a small interfering RNA for CBX3 was designed and this was used for the transfection of osteosarcoma MG63 cells. Then, the effects of CBX3 on proliferation, cell cycle distribution and apoptosis of osteosarcoma cells were investigated via CCK‑8 assay and cell cycle assay and cell apoptosis analysis, respectively. Based on our findings, upregulation of CBX3 expression was noted both in osteosarcoma and also other sarcoma types, which included pleomorphic liposarcoma, myxofibrosarcoma, myxoid/round cell liposarcoma and dedifferentiated liposarcoma. In addition, based on the retrospective cohort study, CBX3 expression was associated with the disease‑free survival (DFS) and overall survival (OS) of the osteosarcoma patients and a large tumor size, high distant metastasis rate and high clinical stage rate. In addition, the proliferation ability was blocked by the knockdown of CBX3 through the application of CBX3 siRNA, and CBX3 knockdown also led to increased apoptosis and cell cycle arrest at G0 and G1 phases in osteosarcoma cells. CBX3 is highly expressed in human osteosarcoma tissues. Meanwhile, high CBX3 is a predictor of the poor prognosis of osteosarcoma patients. To conclude, the growth of osteosarcoma can be promoted by CBX3, which may be used as an independent potential prognostic biomarker for patients suffering from osteosarcoma.

Wu Y, Xie Z, Chen J, et al.
Circular RNA circTADA2A promotes osteosarcoma progression and metastasis by sponging miR-203a-3p and regulating CREB3 expression.
Mol Cancer. 2019; 18(1):73 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
BACKGROUND: As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. However, little is known about the role of circTADA2A, also named hsa_circ_0043278, in osteosarcoma (OS).
METHODS: CircTADA2A was selected from a previously reported circRNA microarray comparing OS cell lines and normal bone cells. QRT-PCR was used to detect the expression of circTADA2A in OS tissue and cell lines. Luciferase reporter, RNA immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were performed to confirm the binding of circTADA2A with miR-203a-3p. OS cells were stably transfected with lentiviruses, and Transwell migration, Matrigel invasion, colony formation, proliferation, apoptosis, Western blotting, and in vivo tumorigenesis and metastasis assays were employed to evaluate the roles of circTADA2A, miR-203a-3p and CREB3.
RESULTS: Our findings demonstrated that circTADA2A was highly expressed in both OS tissue and cell lines, and circTADA2A inhibition attenuated the migration, invasion and proliferation of OS cells in vitro as well as tumorigenesis and metastasis in vivo. A mechanistic study revealed that circTADA2A could readily sponge miR-203a-3p to upregulate the expression of CREB3, which was identified as a driver gene in OS. Furthermore, miR-203a-3p inhibition or CREB3 overexpression could reverse the circTADA2A silencing-induced impairment of malignant tumor behavior.
CONCLUSIONS: CircTADA2A functions as a tumor promoter in OS to increase malignant tumor behavior through the miR-203a-3p/CREB3 axis, which could be a novel target for OS therapy.

Moghimi M, Sobhan MR, Jarahzadeh MH, et al.
Association of GSTM1, GSTT1, GSTM3, and GSTP1 Genes Polymorphisms with Susceptibility to Osteosarcoma: a Case- Control Study and Meta-Analysis
Asian Pac J Cancer Prev. 2019; 20(3):675-682 [PubMed] Related Publications
Background: Some studies have investigated the association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with susceptibility to osteosarcoma; however, these studies results are inconsistent and inconclusive. In order to drive a more precise estimation, the present case-control study and meta-analysis was performed to investigate association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with osteosarcoma. Methods: Eligible articles were identified by a search of several electronic databases for the period up to May 5, 2018. Odds ratios were pooled using either fixed-effects or random effects models. Results: Finally, a total of 24 case-control studies with 2,405 osteosarcoma cases and 3,293 controls were included in the present meta-analysis. Overall, significantly increased osteosarcoma risk was found when all studies were pooled into the meta-analysis of GSTT1 (Null vs. Present: OR= 1.247 95% CI 1.020-1.524, P= 0.031) and GSTP1 polymorphism (B vs. A: OR= 8.899 95% CI 2.722-29.094, P≤0.001). In the stratified, significantly increased osteosarcoma risk was observed for GSTT1 polymorphism among Asians (Null vs. Present: OR= 1.300 95% CI 1.034-1.635, P= 0.025), but not among Caucasians. Conclusions: This meta-analysis demonstrated that GSTP1 and GSTT1 null genotype are associated with the risk of osteosarcoma. Future large welldesigned epidemiological studies are warranted to validate our results.

Li XF, Zhao GQ, Li LY
Ginsenoside impedes proliferation and induces apoptosis of human osteosarcoma cells by down-regulating β-catenin.
Cancer Biomark. 2019; 24(4):395-404 [PubMed] Related Publications
BACKGROUND: Osteosarcoma (OS) is the most commonly occurred primary bone malignancy with high incident rates among children and adolescents. In pharmacologic treatment, the drug ginsenoside has been shown to exert anticancer effects on several malignant diseases. The purpose of this research was to investigate the effect of ginsenoside on the apoptosis and proliferation of human OS MG-63 and Saos-2 cells by regulating the expression of β-catenin.
METHODS: Human OS MG-63 and Saos-2 cells were assigned into control group, and four groups with treatment by varying concentrations (12.5 μg/mL, 25 μg/mL, 50 μg/mL and 100 μg/mL) of ginsenoside, respectively. Cell growth after treatment was observed through cell slides. The proliferation rate of MG-63 and Saos-2 cells in each group was detected by CCK-8. After cell transfection at 48 h, cell cycle and cell apoptosis were detected by FITC-Annexin V staining and flow cytometry. The protein and mRNA expressions of β-catenin, Cyclin D1, Bcl-2, Bax and cleaved caspase-3 were detected by RT-qPCR and western blot analysis.
RESULTS: With increased exposure and concentration of ginsenoside, the cell density, total cell numbers and the absorbance of MG-63 and Saos-2 cells gradually decreased. FITC-Annexin V and FITC-Annexin V/PI staining demonstrated that the cell proportion at S phase decreased, whereas the total apoptotic rate of MG-63 and Saos-2 cells was increased. Furthermore, RT-qPCR and western blot analysis highlighted a gradual decrease in protein and mRNA expressions of β-catenin, Bcl-2 and Cyclin D1, while an elevation in those of Bax and cleaved caspase-3.
CONCLUSION: The results of this study demonstrate that ginsenoside inhibits proliferation and promotes apoptosis of human OS MG-63 and Saos-2 cells by reducing the expressions of β-catenin, Bcl-2 and Cyclin D1 and increasing the expression of Bax and cleaved caspase-3.

He F, Fang L, Yin Q
miR-363 acts as a tumor suppressor in osteosarcoma cells by inhibiting PDZD2.
Oncol Rep. 2019; 41(5):2729-2738 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
PDZ domain containing 2 (PDZD2) is a multi-PDZ domain protein that promotes the proliferation of insulinoma cells, and is upregulated during prostate tumorigenesis. However, the function of PDZD2 in other cancers, including osteosarcoma (OS), remains unclear. Dysregulation of microRNAs (miRNAs) contributes to tumor initiation, proliferation and metastasis, via the regulation of their target genes. The present study investigated the functions of miR-363 and PDZD2 in MG-63 OS cells. The results revealed that MG-63 cells contained low levels of miR-363, and that overexpression of miR-363 in MG-63 cells significantly inhibited the vitality, proliferation, and colony formation ability of the cells, but promoted their apoptosis and G1/S arrest by regulating proliferating cell nuclear antigen (PCNA) and caspase-3 expression. Additionally, miR-363 impaired the migration and invasion of MG-63 cells by regulating the epithelial-mesenchymal transition (EMT) phenotype. Notably, a bioinformatics analysis and luciferase reporter assay indicated that PDZD2 was a direct target of miR-363. miR-363 overexpression reduced PDZD2 protein levels and knockdown of PDZD2 suppressed the colony formation, migration and invasion of MG-63 cells, but promoted their apoptosis by regulating expression of PCNA, caspase-3, and the EMT phenotype. In vivo studies further confirmed that miR-363 functioned as tumor suppressor, by inhibiting tumor growth, promoting cell apoptosis, and reducing PDZD2 and PCNA levels and the prevalence of the EMT phenotype in tumor tissues. The present data demonstrated that downregulation of the tumor suppressor miR-363 may be involved in the development of osteosarcoma via regulation of PDZD2.

Koelsche C, Kriegsmann M, Kommoss FKF, et al.
DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.
J Cancer Res Clin Oncol. 2019; 145(5):1273-1281 [PubMed] Related Publications
PURPOSE: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS.
METHODS: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas.
RESULTS: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively.
CONCLUSION: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.

Zapata I, Moraes LE, Fiala EM, et al.
Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common.
BMC Genomics. 2019; 20(1):226 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
BACKGROUND: Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. Here we reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications.
RESULTS: First, meta-analysis revealed association near FGF9, which has strong biological and therapeutic relevance. Secondly, risk-modeling by multiple logistic regression shows 22 of the 34 associated loci contribute to risk and eight have large effect sizes. We validated the Greyhound stepwise model in our own, independent, case-control cohort. Lastly, we updated the gene annotation from approximately 50 genes to 175, and prioritized those using cross-species genomics data. Mostly positional evidence suggests 13 genes are likely to be associated with mapped risk (including MTMR9, EWSR1 retrogene, TANGO2 and FGF9). Previous annotation included seven of those 13 and prioritized four by pathway enrichment. Ten of our 13 priority genes are in loci that contribute to risk modeling and thus can be studied epidemiologically and translationally in pet dogs. Other new candidates include MYCN, SVIL and MIR100HG.
CONCLUSIONS: Polygenic osteosarcoma-risk commonly rises to Mendelian-levels in some dog breeds. This justifies caninized animal models and targeted clinical trials in pet dogs (e.g., using CDK4/6 and FGFR1/2 inhibitors).

Wang JS, Wang YG, Zhong YS, et al.
Identification of co-expression modules and pathways correlated with osteosarcoma and its metastasis.
World J Surg Oncol. 2019; 17(1):46 [PubMed] Article available free on PMC after 06/05/2020 Related Publications
BACKGROUND: Osteosarcoma is the most common bone tumor that occurs in children.
METHODS: To identify co-expression modules and pathways correlated with osteosarcoma and its clinical characteristics, we performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data of osteosarcoma with 52 samples. Then we performed pathway enrichment analysis on genes from significant modules.
RESULTS: A total of 5471 genes were included in WGCNA, and 16 modules were identified. Module-trait analysis identified that a module involved in microtubule bundle formation, drug metabolism-cytochrome P450, and IL-17 signaling pathway was negatively correlated with osteosarcoma and positively correlated with metastasis; a module involved in DNA replication was positively correlated with osteosarcoma; a module involved in cell junction was positively correlated with metastasis; and a module involved in heparin binding negatively correlated with osteosarcoma. Moreover, expression levels in four of the top ten differentially expressed genes were validated in another independent dataset.
CONCLUSIONS: Our analysis might provide insight for molecular mechanisms of osteosarcoma.

Izadpanah S, Shabani P, Aghebati-Maleki A, et al.
Insights into the roles of miRNAs; miR-193 as one of small molecular silencer in osteosarcoma therapy.
Biomed Pharmacother. 2019; 111:873-881 [PubMed] Related Publications
Today, cancer is one of the most common causes of death. Osteosarcoma (OS) is a tumor in long bones and its prevalence is high in teenagers and young people. Among the methods that used to treat cancer, one can name chemotherapy, surgery, and radiotherapy. Since these methods have some disadvantages and they are not absolutely successful, the use of microRNAs (miRNAs) is very useful in diagnosis and treatment of OS. MiRNAs are small non-coding RNA molecules, containing 18-25 nucleotides, which are involved in the regulation of gene expression via binding to messenger RNA (mRNA). These RNAs are divided into two classes of suppressors and oncogenes. During OS, there is aberrant expression of several miRNAs. Among these miRNAs are downregulation of miR-193 that has been associated with cancer occurrence. The aim of the current manuscript is to have overview on the treatment approaches of OS with special focus on miR-193.

Wang Y, Li W, Chen X, et al.
MIR210HG predicts poor prognosis and functions as an oncogenic lncRNA in hepatocellular carcinoma.
Biomed Pharmacother. 2019; 111:1297-1301 [PubMed] Related Publications
MIR210HG is a novel long noncoding RNA (lncRNA) and has been found to be overexpresed in osteosarcoma and glioma. However, the level of MIR210HG and its clinical significance in hepatocellular carcinoma (HCC) are not well known. In results of our research, MIR210HG expression was increased in HCC tissue samples and cells compared with paired adjacent normal liver tissue samples and normal liver cell line respectively, and a good marker to discriminate HCC tissues from non-tumorous tissues. MIR210HG high-expression was correlated advanced clinical stage, big tumor size, present vascular invasion and unfavorable histological differentiation. The survival analysis from our cohort and TCGA cohort consistently suggested that HCC patients with MIR210HG high-expression had poorer prognosis than HCC patients with MIR210HG low-expression. Furthermore, univariate and multivariate Cox regression analyses showed that MIR210HG high-expression was an independent unfavorable prognostic factor for overall survival in HCC patients. The in vitro study showed that silencing of MIR210HG depressed HCC cell proliferation, migration and invasion. In conclusion, MIR210HG functions as an oncogenic lncRNA in HCC, and may be a potential biomarker for predicting clinical progression and prognosis.

Hattinger CM, Patrizio MP, Luppi S, et al.
Current understanding of pharmacogenetic implications of DNA damaging drugs used in osteosarcoma treatment.
Expert Opin Drug Metab Toxicol. 2019; 15(4):299-311 [PubMed] Related Publications
INTRODUCTION: DNA damaging drugs are widely used for the chemotherapeutic treatment of high-grade osteosarcoma (HGOS). In HGOS patients, several germline polymorphisms have been reported to impact on the development of adverse toxic events related to DNA damaging drugs treatment. Some of these polymorphisms, when present in tumor cells, may also influence treatment response and prognosis of HGOS patients. Area covered: In this review, the authors have focused on pharmacogenetic markers (mainly germline polymorphisms) described in patients with HGOS, which have proved or indicated to be related to the susceptibility to adverse toxic reactions and/or to influence response to DNA damaging drugs. The concordant and discordant results reported in different studies have also been discussed. Expert opinion: Response and toxicity predisposition to DNA damaging drugs are influenced by genes encoding proteins involved in their uptake, efflux, activation, inactivation, and in DNA repair, activity of which may vary according to specific gene variations. In HGOS, there is a substantial medical need for biomarkers predictive for individual response and toxicity predisposition to DNA-targeting drugs, which may be used to tailor therapy in order to decrease the occurrence of adverse side effects and increase treatment efficacy and safety.

Perkins AR, Macaulay RJB, Bui MM, et al.
A Frontal Dural-Based Lesion in a 63-Year Old Male.
Brain Pathol. 2019; 29(2):301-302 [PubMed] Related Publications

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