TY - JOUR
T1 - Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant
AU - Deng, Qipan
AU - Hu, Hui
AU - Yu, Xinfang
AU - Liu, Shuanglin
AU - Wang, Lei
AU - Chen, Weiqun
AU - Zhang, Chi
AU - Zeng, Zhaoyang
AU - Cao, Ya
AU - Xu-Monette, Zijun Y.
AU - Li, Ling
AU - Zhang, Mingzhi
AU - Rosenfeld, Steven
AU - Bao, Shideng
AU - Hsi, Eric
AU - Young, Ken H.
AU - Lu, Zhongxin
AU - Li, Yong
N1 - Funding Information:
The authors are grateful to Dr. Cassandra Talerico, a salaried employee of the Cleveland Clinic, for editing the manuscript and providing critical comments and to Dr. James F Crish for retroviral generation and injection. Research on the p53 variant using mouse models is supported in part by NIH R01 grants (CA138688, CA229080, and CA219556) and a grant from Cancer Prevention & Research Institute of Texas (RR190043).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.
AB - A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.
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U2 - 10.1038/s41467-019-13002-x
DO - 10.1038/s41467-019-13002-x
M3 - Article
C2 - 31699989
AN - SCOPUS:85074713380
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5061
ER -