Integrated Genome-Wide Methylation and Expression Analyses Reveal Key Regulators in Osteosarcoma

Osteosarcoma (OS) is one of the most common types of primary bone tumors in early adolescence with unsatisfied prognosis. Aberrant DNA methylation had been demonstrated to be related to tumorigenesis and progression of multiple cancers and could serve as the potential biomarkers for the prognosis of human cancers. In conclusion, this study identified 18 downregulated hypomethylation genes and 52 upregulated hypomethylation genes in OS by integrating the analysis the GSE97529 and GSE42572 datasets. Bioinformatics analysis revealed that OS-specific methylated genes were involved in regulating multiple biological processes, including chemical synaptic transmission, transcription, response to drug, and regulating immune response. KEGG pathway analysis showed that OS-specific methylated genes were associated with the regulation of Hippo, cAMP calcium, MAPK, and Wnt signaling pathways. By analyzing R2 datasets, this study showed that the dysregulation of these OS-specific methylated genes was associated with the metastasis-free survival time in patients with OS, including CBLN4, ANKMY1, BZW1, KRTCAP3, GZMB, KRTDAP, LY9, PFKFB2, PTPN22, and CLDN7. This study provided a better understanding of the molecular mechanisms underlying the progression and OS and novel biomarkers for the prognosis of OS.

[1]  S. Strauss,et al.  Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma , 2012, Cancer.

[2]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[3]  K. Bhatia,et al.  Aberrant methylation of multiple tumor suppressor genes in acute myeloid leukemia , 2004, American journal of hematology.

[4]  Wei Liu,et al.  MicroRNA‐490‐3p regulates cell proliferation and apoptosis by targeting HMGA2 in osteosarcoma , 2015, FEBS letters.

[5]  A. Yalçin,et al.  PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells , 2020, Molecular and Cellular Biochemistry.

[6]  A. Angulo,et al.  Viral CD229 (Ly9) homologs as new manipulators of host immunity , 2019, Journal of leukocyte biology.

[7]  Hong Liu,et al.  The dual functions of YAP-1 to promote and inhibit cell growth in human malignancy , 2013, Cancer and Metastasis Reviews.

[8]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[9]  P. Picci,et al.  Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin , 1990, Cancer.

[10]  G. Cao,et al.  Long non-coding RNA XIST predicts poor prognosis and promotes malignant phenotypes in osteosarcoma , 2018, Oncology letters.

[11]  L. Kowalski,et al.  PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas , 2019, International journal of molecular sciences.

[12]  F. Verrecchia,et al.  Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers? , 2020, Cancers.

[13]  M. Panchatcharam,et al.  UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation , 2017, Oncotarget.

[14]  K. Antman,et al.  Sarcomas of soft tissue and bone , 1991, Cancer.

[15]  N. Chang,et al.  WW Domain-Containing Proteins YAP and TAZ in the Hippo Pathway as Key Regulators in Stemness Maintenance, Tissue Homeostasis, and Tumorigenesis , 2019, Front. Oncol..

[16]  Giulia Basile,et al.  Intragenic DNA methylation prevents spurious transcription initiation , 2017, Nature.

[17]  T. Slaga,et al.  GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy , 2017, Autophagy.

[18]  I. Lewis,et al.  Osteosarcoma treatment - where do we stand? A state of the art review. , 2014, Cancer treatment reviews.

[19]  E. Simpson,et al.  Understanding osteosarcomas , 2018, JAAPA : official journal of the American Academy of Physician Assistants.

[20]  C. You,et al.  Long non-coding RNA UCA1/miR-182/PFKFB2 axis modulates glioblastoma-associated stromal cells-mediated glycolysis and invasion of glioma cells. , 2018, Biochemical and biophysical research communications.

[21]  C. Boland,et al.  Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma , 2008, Hepatology.

[22]  Srijit Das,et al.  The Emerging Role of the Hippo Pathway in Lung Cancers: Clinical Implications. , 2017, Current drug targets.

[23]  P. Qiu,et al.  Correlation Patterns Between DNA Methylation and Gene Expression in The Cancer Genome Atlas , 2019, Cancer informatics.

[24]  P. Dong,et al.  miR-613 inhibits Warburg effect in gastric cancer by targeting PFKFB2. , 2019, Biochemical and biophysical research communications.

[25]  Jia Huang,et al.  Correlation study of DNA methylation of WNT6 gene with osteosarcoma in children , 2017, Oncology letters.

[26]  E. Kleinerman,et al.  Epigenetic Regulation of Apoptosis and Cell Cycle in Osteosarcoma , 2010, Sarcoma.

[27]  Q. Cheng,et al.  LncRNA XIST serves as a ceRNA to regulate the expression of ASF1A, BRWD1M, and PFKFB2 in kidney transplant acute kidney injury via sponging hsa-miR-212-3p and hsa-miR-122-5p , 2020, Cell cycle.

[28]  A. Cleton-Jansen,et al.  Mesenchymal stromal cells of osteosarcoma patients do not show evidence of neoplastic changes during long-term culture , 2015, Clinical Sarcoma Research.

[29]  A. Petrilli,et al.  Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma , 2013, OncoTargets and therapy.

[30]  Wan-chun Wang,et al.  Epigenetic changes in osteosarcoma. , 2011, Bulletin du cancer.

[31]  B. Wang,et al.  DNA Methylation Mediated Downregulation of miR-449c Controls Osteosarcoma Cell Cycle Progression by Directly Targeting Oncogene c-Myc , 2017, International journal of biological sciences.

[32]  X. Zi,et al.  The Wnt signaling pathway: implications for therapy in osteosarcoma , 2011, Expert review of anticancer therapy.

[33]  T. Iwakuma,et al.  Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression , 2016, Nature Communications.

[34]  DNA Methylation-Based Classifier for Accurate Molecular Diagnosis of Bone Sarcomas. , 2017, JCO precision oncology.

[35]  Da-qing Liu,et al.  BZW1, a novel proliferation regulator that promotes growth of salivary muocepodermoid carcinoma. , 2009, Cancer letters.