MAPK7 and MAP2K4 as prognostic markers in osteosarcoma

Tesser-Gamba, Francine; Petrilli, Antônio Sérgio; Alves, Maria Teresa de Seixas; Filho, Reynaldo Jesus Garcia; Juliano, Yára; Toledo, Sílvia Regina Caminada de

doi:10.1016/j.humpath.2011.08.003

Cited by 25 publications

(28 citation statements)

References 31 publications

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“…3b and Supplementary Table 4 ) 40–42 . The remaining top regulators were MAPK7 ( P = 7.64 × 10 −5 ) and WT1 ( P = 8.50 × 10 −5 ), both implicated in osteosarcoma as prognostic markers of poor outcome 43,44 . These data demonstrate that CIS-associated genes are enriched in cancer signaling pathways and cellular processes, and a significant number are regulated by miRNAs and genes implicated in human osteosarcoma.…”

Section: Resultsmentioning

confidence: 99%

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

et al. 2015

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Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.

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Section: Resultsmentioning

confidence: 99%

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

et al. 2015

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“…Evidence supporting the oncogenic role of STMN1 in OS can be inferred from experiments demonstrating high levels of expression in OS tumors (21, 25), the cytogenetic location to 1p36, a known cancer-related region in OS (11, 12), and the role in growth regulation (34, 38). Attenuation of STMN1 suppresses growth of STMN1 expressing OS cells (33, 36), indicating elevated levels of STMN1 play an important role in disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Gene deletions and rearrangements are frequently observed in the 1p36 region in a variety of human cancers including neuroblastoma, glioma, leukemia and breast cancer (10). In OS, 1p36 is a region of chromosomal gains with the amplified expression of several genes (11, 12). miR-34a was identified as an inhibitor of cancer cell growth in a wide range of solid and hematological malignancies (13, 14), including OS tumors (15, 16).…”

Section: Introductionmentioning

confidence: 99%

The Microtubule Network and Cell Death Are Regulated by an miR-34a/Stathmin 1/βIII-Tubulin Axis

Vetter

Kolb

Mills

et al. 2017

Molecular Cancer Research

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MicroRNA-34a (miR-34a) is a master regulator of signaling networks that maintain normal physiology and disease and is currently in development as a miRNA-based therapy for cancer. Prior studies have reported low miR-34a expression in osteosarcoma (OS); however, the molecular mechanisms underlying miR-34a activity in OS are not well defined. Therefore, this study evaluated the role of miR-34a in regulating signal transduction pathways that influence cell death in OS. Levels of miR-34a were attenuated in human OS cells and xenografts of the Pediatric Preclinical Testing Consortium (PPTC). Bioinformatics predictions identified stathmin 1 (STMN1) as a potential miR-34a target. Biotin pulldown assay and luciferase reporter analysis confirmed miR-34a target interactions within the STMN1 mRNA 3′UTR. Overexpression of miR-34a in OS cells suppressed STMN1 expression and reduced cell growth in vitro. Restoration of miR-34a led to microtubule destabilization and increased βIII-tubulin expression, with corresponding G1/G2 phase cell cycle arrest and apoptosis. Knockdown of the Sp1 transcription factor, by siRNA silencing, also upregulated βIII-tubulin expression in OS cells, suggesting miR-34a indirectly affects Sp1. Validating the coordinating role of miR-34a in microtubule destabilization, when miR-34a was combined with either microtubule inhibitors or chemotherapy, STMN1 phosphorylation was suppressed and there was greater cytotoxicity in OS cells. These results demonstrate that miR-34a directly represses STMN1 gene and protein expression and upregulates βIII-tubulin, leading to disruption of the microtubule network and cell death. Implications The miR-34a/STMN1/βIII-tubulin axis maintains the microtubule cytoskeleton in osteosarcoma, and combining miR-34a with microtubule inhibitors can be investigated as a novel therapeutic strategy.

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“…However, patients with metastasis at the time of diagnosis, which represents 10-20% of patients with osteosarcoma, have a 5-year survival rate of <30%. Despite the dramatic increase in our understanding of sarcoma biology and treatment, the survival rate has not increased over the past two decades, with the main cause of patient death being pulmonary metastasis [77,78].…”

Section: Osteosarcomamentioning

confidence: 99%

“…However, only recently was ERK5 considered a potential therapeutic target. ERK5 overexpression correlated with tumour progression, resistance to treatment, and worse overall patient survival [78], suggesting that ERK5 has an important role in tumour development. However, in two additional studies, ERK5 silencing failed to decrease tumour cell proliferation as would be initially expected [77].…”

Section: Osteosarcomamentioning

confidence: 99%

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

Simões

Rodrigues

Borralho

2016

Drug Discovery Today

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MAPK7 and MAP2K4 as prognostic markers in osteosarcoma

Cited by 25 publications

References 31 publications

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

The Microtubule Network and Cell Death Are Regulated by an miR-34a/Stathmin 1/βIII-Tubulin Axis

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

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