MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma through a Sox9-Mediated Positive Feedback Loop.

Abstract:

:Despite the fact that osteosarcoma is one of the most common primary bone malignancies with poor prognosis, the mechanism behind the pathogenesis of osteosarcoma is only partially known. Here we characterized differentially expressed genes by extensive analysis of several publicly available gene expression profile datasets and identified musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) as a key transcriptional regulator in osteosarcoma progression. MAFB was highly expressed in tumor tissues and required for proliferation and tumorigenicity of osteosarcoma cells. MAFB expression was elevated in osteosarcoma stem cells to maintain their self-renewal potential in vitro and in vivo through upregulation of stem cell regulator Sox9 at the transcriptional level. Sox9 in turn activated MAFB expression via direct recognition of its sequence binding enrichment motif on the MAFB locus, thereby forming a positive feedback regulatory loop. Sox9-mediated feedback activation of MAFB was pivotal to tumorsphere-forming and tumor-initiating capacities of osteosarcoma stem cells. Moreover, expression of MAFB and Sox9 was highly correlated in osteosarcoma and associated with disease progression. Combined detection of both MAFB and Sox9 represented a promising prognostic biomarker that stratified a subset of patients with osteosarcoma with shortest overall survival. Taken together, these findings reveal a MAFB-Sox9 reciprocal regulatory axis driving cancer stemness and malignancy in osteosarcoma and identify novel molecular targets that might be therapeutically applicable in clinical settings. SIGNIFICANCE: Transcription factors MAFB and Sox9 form a positive feedback loop to maintain cell stemness and tumor growth in vitro and in vivo, revealing a potential target pathway for therapeutic intervention in osteosarcoma.

journal_name

Cancer Res

journal_title

Cancer research

authors

Chen Y,Wang T,Huang M,Liu Q,Hu C,Wang B,Han D,Chen C,Zhang J,Li Z,Liu C,Lei W,Chang Y,Wu M,Xiang D,Chen Y,Wang R,Huang W,Lei Z,Chu X

doi

10.1158/0008-5472.CAN-19-1764

subject

Has Abstract

pub_date

2020-06-15 00:00:00

pages

2472-2483

issue

12

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-19-1764

journal_volume

80

pub_type

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