首页|Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3KIAKT pathway and promotes osteosarcoma progression

Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3KIAKT pathway and promotes osteosarcoma progression

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Osteosarcoma is the most common primary malignancy of bones and primarily oc-curs in adolescents and young adults.However,a second smaller peak of osteosarcoma inci-dence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tu-mor progression by metabolic reprogramming.Recent research has shown that methylmalo-nic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis acceler-ated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhib-itors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.

Cellular senescenceElderly patientsMAFB-NOTCH3axisMethylmalonic acidOsteosarcomaPI3K-AKTpathway

Zhenhao Zhang、Doudou Jing、Baijun Xuan、Zhicai Zhang、Wei Wu、Zengwu Shao

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Department of Orthopedics,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei 430022,China

Department of Orthopedics,The Second Hospital of Shanxi Medical University,Taiyuan,Shanxi 030001,China

Department of Cardiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei 430022,China

国家自然科学基金

82072979

2024

10.1016/j.gendis.2023.02.028

基因与疾病(英文)

基因与疾病(英文)

ISSN：
年,卷(期)：2024.11(2)
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