Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma

Otani, Shohei; Date, Yuki; Ueno, Tomoya; Ito, Tomoko; Kajikawa, Satoru; Omori, Keisuke; Taniuchi, Ichiro; Umeda, Masahiro; Komori, Toshihisa; Toguchida, Junya; Ito, Kosei

doi:10.1038/s41388-021-02120-w

Cited by 19 publications

(42 citation statements)

References 53 publications

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“…p53 mutations have also been associated with pathological grade and survival and have been reported as a potential prognostic biomarker for OS. 25 , 26 In the current study, p53 expression was positively correlated with that of NY-ESO-1 and MAGE-A4, suggesting their potential as prognostic biomarkers for OS. Ki-67 is also a well-known marker for assessing cell proliferation and invasion, 27-29 and has been reported as a marker for diagnosis of malignancy, proliferation, response to chemotherapy, and prognosis in OS.…”

Section: Discussionsupporting

confidence: 59%

Clinicopathological assessment of cancer/testis antigens NY‑ESO‑1 and MAGE‑A4 in osteosarcoma

et al. 2022

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The cancer/testis antigens (CTAs), New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen gene (MAGE)-A4 are normally restricted to male germ cells but are aberrantly expressed in several cancers. Considering the limited information regarding their significance in osteosarcoma (OS), the purpose of this study was to determine the clinical significance of NY-ESO-1 and MAGE-A4 expression in OS. Nine patients with OS treated at Kindai University Hospital were included in the study. The median age was 27 years, and median follow-up period was 40 months. The specimens obtained at the time of biopsy were used to perform immunostaining for NY-ESO, MAGE-A4, p53, and Ki-67. The positive cell rates and positive case rates of NY-ESO, MAGE-A4, p53, and Ki-67 were calculated. The correlation between the positive cell rate of immunohistochemical markers was also calculated. The correlation between the positive cell rate of NY-ESO-1 or MAGE-A4 and tumor size or maximum standardized uptake (SUV-max) was also determined. The positive cell rates of NY-ESO-1 or MAGE-A4 in continuous disease-free (CDF) cases were also compared with those in alive with disease (AWD) or dead of disease (DOD) cases. The average positive cell rates of NY-ESO, MAGEA4, p53, and Ki-67 were 71.7%, 85.1%, 16.2%, and 14.7%, and their positive case rates were 33.3%, 100%, 44.4%, and 100%, respectively. The positivity rates of NY-ESO-1 and p53 were strongly correlated, whereas those of NY-ESO-1 and Ki-67 were moderately correlated. The MAGE-A4 and p53 positivity rates and the MAGE-A4 and Ki-67 positive cell rates were both strongly correlated. The NY-ESO-1 and MAGE-A4 positivity rates were moderately correlated. The positive correlation between the NY-ESO-1 positive cell rate and tumor size was medium, and that between the MAGE-A4 positivity rate and SUV-max was very strong. There was no significant difference in the positive cell rates of NY-ESO-1 or MAGE-A4 between CDF cases and AWD or DOD cases. Overall, our results suggest that NY-ESO-1 and MAGE-A4 may be involved in the aggressiveness of OS.

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Section: Discussionsupporting

confidence: 59%

Clinicopathological assessment of cancer/testis antigens NY‑ESO‑1 and MAGE‑A4 in osteosarcoma

et al. 2022

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“…The ability of Runx3 to act as an oncogene was revealed by a study of OS [ 32 ]. The p53 gene is the most important tumor suppressor gene in the majority of human cancers, and its inactivation and alterations have been widely implicated in tumor development and malignant transformation [ 33 , 34 , 35 , 36 ].…”

Section: Oncogenic Runx In the Absence Of P53mentioning

confidence: 99%

“…OS development is highly dependent on the functional status of p53. TP53 inactivation is often observed in sporadic OS [ 32 , 37 , 38 ], and patients with Li-Fraumeni syndrome possessing germline mutations in TP53 have a high incidence of OS [ 39 , 40 ]. In mice, systemic p53 deletion is known to cause OS [ 41 ], and restrictive deletion of p53 in osteoprogenitor and mesenchymal stromal cells results in an almost 100% incidence of OS in Osterix ( Osx )/ Sp7 -Cre; p53 fl/fl mice (herein, OS mice), a widely used animal model of human OS [ 42 , 43 , 44 ].…”

Section: Oncogenic Runx In the Absence Of P53mentioning

confidence: 99%

“…By using OS mice, the root of the tumorigenic process that occurs after p53 inactivation was shown to be Runx3-induced Myc overexpression via mR1 , a Runx consensus site in the Myc promoter [ 32 ]. Specifically, both RUNX3/Runx3 and MYC/Myc were upregulated in p53 -deficient human and mouse OS [ 32 ]; heterozygous deletion of Runx3 ( OS ; Runx3 fl/+ mice) or Myc ( OS ; Myc fl/+ mice) in OS mice prolonged their lifespan and suppressed the development of OS ( Figure 1 A,B). Moreover, in the absence of p53, Runx3 enhanced Myc expression through mR1 .…”

Section: Oncogenic Runx In the Absence Of P53mentioning

confidence: 99%

“…However, mutants of p53 (R156P and R273H found in human OS cells) that did not interact with RUNX3 were unable to suppress MYC overexpression. Furthermore, suppression of Myc expression by p53 did not occur in cells lacking Runx3, showing that suppression of Myc expression was Runx3-dependent, i.e., p53 directly inhibited Runx3, which has the capacity of upregulating Myc [ 32 ]. Although RUNX3 was found to cooperate with p53 to induce p21 WAF1/CIP1 in p53 -positive OS (U2OS) cells [ 45 ], RUNX3 induced Myc rather than p21 WAF1/CIP1 in p53 -negative OS (G292) cells [ 32 ] ( Figure 2 ).…”

Section: Oncogenic Runx In the Absence Of P53mentioning

confidence: 99%

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p53 Deficiency-Dependent Oncogenicity of Runx3

Ito

Otani

Date

2023

Cells

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The RUNX transcription factors are frequently dysregulated in human cancers, suggesting their potential as attractive targets for drug treatment. However, all three transcription factors have been described as both tumor suppressors and oncogenes, indicating the need to determine their molecular mechanisms of action. Although RUNX3 has long been considered a tumor suppressor in human cancers, several recent studies have shown that RUNX3 is upregulated during the development or progression of various malignant tumors, suggesting it may act as a “conditional” oncogene. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. This review describes the evidence for the activities of RUNX3 in human cancer and proposes an explanation for the duality of RUNX3 involving the status of p53. In this model, p53 deficiency causes RUNX3 to become oncogenic, leading to aberrant upregulation of MYC.

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Endosteal stem cells at the bone‐blood interface: A double‐edged sword for rapid bone formation

Matsushita,

Liu,

Chu

et al. 2023

BioEssays

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Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non‐endosteal perisinusoidal niche. Single‐cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor‐making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast‐chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell‐like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation.

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Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma

Cited by 19 publications

References 53 publications

Clinicopathological assessment of cancer/testis antigens NY‑ESO‑1 and MAGE‑A4 in osteosarcoma

Clinicopathological assessment of cancer/testis antigens NY‑ESO‑1 and MAGE‑A4 in osteosarcoma

p53 Deficiency-Dependent Oncogenicity of Runx3

Endosteal stem cells at the bone‐blood interface: A double‐edged sword for rapid bone formation

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