Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

Lin, Yu-Hsuan; Jewell, Brittany E.; Gingold, Julian A.; Lu, Linchao; Zhao, Ruiying; Wang, Lisa L.; Lee, Dung‐Fang

doi:10.1016/j.molmed.2017.06.004

Cited by 131 publications

(122 citation statements)

References 163 publications

(245 reference statements)

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“…2 The metaphysis of the long tubular bone is the principle site of OS, although other bones can be affected. 3 Patients with OS are usually treated with surgical resection in combination with adjuvant chemotherapy, transplantation, and radiotherapy. 4 With the development of early diagnostic methods and therapeutic techniques, clinical outcomes of patients with OS have noticeably improved.…”

Section: Introductionmentioning

confidence: 99%

<p>Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression</p>

Yin

Liu

Zhao

et al. 2020

OTT

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Purpose: ASB16 antisense RNA 1 (ASB16-AS1) is a cancer-associated long non-coding RNA that contributes to tumorigenesis and tumor development. Nevertheless, to the best of our knowledge, whether and how ASB16-AS1 is implicated in osteosarcoma (OS) malignancy remains unclear and therefore warrants exploration. Our current study focused on making in-depth investigation of ASB16-AS1 in OS. In the present study, the expression pattern of ASB16-AS1 in OS tissues and cell lines was analyzed. In addition, we examined the clinical value of ASB16-AS1 for OS patients. Furthermore, we explored the impacts of ASB16-AS1 on the malignant phenotype of OS cells in vitro and in vivo as well as the underlying mechanism. Methods: ASB16-AS1, microRNA-760 (miR-760) and hepatoma-derived growth factor (HDGF) expressions were measured using reverse transcription-quantitative PCR. Cell proliferation and apoptosis were evaluated using CCK-8 and flow cytometry analyses, respectively, and cell migration and invasion were determined via cell migration and invasion assays. Results: ASB16-AS1 expression was significantly elevated in OS tissues and cell lines, and increased ASB16-AS1 expression was related to patients' tumor size, TNM stage, and distant metastasis. The overall survival rate of OS patients presenting high ASB16-AS1 expression was shorter than that of patients presenting low ASB16-AS1 expression. Reduced ASB16-AS1 expression inhibited OS cell proliferation, migration, and invasion; promoted cell apoptosis; and impaired tumor growth in vivo. Mechanistically, ASB16-AS1 served as a sponge for miR-760 and positively modulated the expression of its target HDGF. Finally, inhibiting miR-760 and restoring HDGF expression abolished the impacts of ASB16-AS1 knockdown on the malignant characteristics of OS cells. Conclusion: ASB16-AS1 is a novel oncogenic lncRNA in OS cells. ASB16-AS1 increased HDGF expression by sponging miR-760, thereby conferring cancer-promoting roles in OS. ASB16-AS1 is a potential early diagnostic and therapeutic target in OS.

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Section: Introductionmentioning

confidence: 99%

<p>Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression</p>

Yin

Liu

Zhao

et al. 2020

OTT

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“…It accounts for about 60% of all primary bone tumors and about 2% of all childhood cancers (1,2). Despite significant advances in OS treatment modalities, the 5-y overall survival rate has remained stable over the last 20 y at 60-70% for patients with primary OS and less than 30% for patients with metastasis (3,4). This stagnation of clinical outcomes underlines the urgent necessity for novel model systems to study the mechanism of OS in a patient-specific context and to identify molecular targets for the development of new therapeutic strategies.…”

mentioning

confidence: 99%

Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism

Kim

Yoo

Zhou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li–Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of SFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a β-catenin–independent manner. Conversely, inhibition of SFRP2, FOXM1, or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of SFRP2 in the development of p53 mutation-associated OS and that inhibition of SFRP2 is a potential therapeutic strategy.

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“…Osteosarcomagenesis is initiated in bone epiphyseal growth plates with rapid turnover during childhood and adolescence and has also been observed in high incidence in patients affected by Paget's disease, a pathological entity characterized by excessive osteoid formation and breakdown. These findings suggest that molecular disturbances in osteoblast proliferation and differentiation are involved in osteosarcoma pathogenesis through dysregulation of major signal transduction pathways and osteogenic transcriptional factors [4,[42][43][44][45][46][47]. Several major signal transduction pathways, mainly Wnt/β-catenin, bone morphogenetic protein (BMP), Hedgehog, HIF1α, Notch, PI3K/Akt, JNK and NF-κB pathways are implicated in osteosarcoma development and metastatic progression [48][49][50].…”

Section: Lncrnas and Signal Transduction Pathways In Osteosarcomamentioning

confidence: 99%

“…Some of these lncRNAs have also been reported to play a crucial role in osteosarcoma pathogenesis and metastatic process as well as in chemotherapy drug resistance. Thus, they are considered candidate molecules as prognostic or preventive biomarkers and/or novel therapeutic targets [42][43][44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNAs in Osteosarcoma: Mechanisms and Potential Clinical Implications

Valavanis¹,

Stanc²

2019

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

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Long noncoding RNAs (lncRNAs) are noncoding transcripts consisting of a diverse class of long RNAs of more than 200 nucleotides in length. Recent studies have shown that lncRNAs are involved in cell signal transduction pathways, cell cycle and cell death regulation, chromatin remodeling, and gene expression regulation at the transcriptional and posttranscriptional levels. They are also involved in the metastatic process of different types of tumors, such as urothelial carcinoma, colon carcinoma, breast carcinoma, lung carcinoma, and hepatocellular carcinoma. In addition, lncRNAs demonstrate precise expression patterns in specific tissues and cells and therefore play important roles in cell differentiation and tissue development. In this chapter, we review the molecular mechanisms of lncRNA cell functions and their involvement in the pathogenesis, progression, and metastasis of osteosarcoma, a rare bone tumor of childhood and adolescence. We also review emerging clinical implications of lncRNA use as potential prognostic biomarkers and therapeutic targets, as well as their putative involvement in drug resistance, in osteosarcoma progression, and in therapeutic interventions.

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Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

Cited by 131 publications

References 163 publications

<p>Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression</p>

<p>Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression</p>

Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism

Long Noncoding RNAs in Osteosarcoma: Mechanisms and Potential Clinical Implications

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