p18INK4C and BRCA1 inhibit follicular cell proliferation and dedifferentiation in thyroid cancer
p18INK4C and BRCA1 inhibit follicular cell proliferation and dedifferentiation in thyroid cancer
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DOI：
10.1080/15384101.2023.2225938
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发表时间：
2023-06-23
期刊：
影响因子：
4.3
通讯作者：
Pei，Xin-Hai
中科院分区：
文献类型：
--
作者：
Bai，Feng;Liu，Xiong;Pei，Xin-Hai
Only 3% of thyroid cancers are medullary thyroid carcinomas (MTCs), the rest are follicular epithelial cell derived non-MTCs (NMTCs). A dysfunctional INK4-CDK4-RB pathway is detected in most of NMTCs. DNA repair defects and genome instability are associated with NMTC dedifferentiation and aggressiveness. Whether inactivation of the INK4-CDK4-RB pathway induces NMTCs and how differentiation of NMTC cells is controlled remain elusive. In this study, we generatedp18Ink4candBrca1singly and doubly deficient mice as well asp16Ink4aandBrca1singly and doubly deficient mice. By using these mice and human thyroid carcinoma cell lines, we discovered that loss ofp18Ink4c, notp16Ink4a, in mice stimulated follicular cell proliferation and induced NMTCs. Depletion ofBrca1alone or bothp16Ink4aandBrca1did not induce thyroid tumor. Depletion ofBrca1inp18Ink4cnull mice results in poorly differentiated and aggressive NMTCs with epithelial-mesenchymal transition (EMT) features and enhanced DNA damage. Knockdown ofBRCA1in thyroid carcinoma cells activated EMT and promoted tumorigenesis whereas overexpression ofBRCA1inhibited EMT.BRCA1and EMT marker expression were inversely related in human thyroid cancers. Our finding, for the first time, demonstrates that inactivation of INK4-CDK4-RB pathway induces NMTCs and thatBrca1deficiency promotes dedifferentiation of NMTC cells. These results suggest that BRCA1 and p18INK4C collaboratively suppress thyroid tumorigenesis and progression and CDK4 inhibitors will be effective for treatment ofINK4-inactivated or cyclin D-overexpressed thyroid carcinomas.
