Oncogene-Induced Senescence Is a Crucial Antitumor Defense Mechanism of Human Endometrial Stromal Cells

被引:2
|
作者
Toropov, Artem L. [1 ]
Deryabin, Pavel I. [1 ]
Shatrova, Alla N. [2 ]
Borodkina, Aleksandra V. [1 ]
机构
[1] Russian Acad Sci, Inst Cytol, Mech Cellular Senescence Grp, Tikhoretsky Ave 4, St Petersburg 194064, Russia
[2] Russian Acad Sci, Inst Cytol, Lab Intracellular Membranes Dynam, Tikhoretsky Ave 4, St Petersburg 194064, Russia
关键词
endometrial stromal cells; senescence; oncogenes; cancer; HRAS(G12V); RAS-INDUCED SENESCENCE; DNA-DAMAGE; STEM-CELLS; TRANSFORMATION; ACCUMULATION; EXPRESSION; P53;
D O I
10.3390/ijms241814089
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Being the major cellular component of highly dynamic tissue, endometrial stromal cells (EnSCs) are exposed to cycles of proliferation upon hormonal stimulation, which might pose risks for the accumulation of mutations and malignization. However, endometrial stromal tumors are rare and uncommon. The present study uncovered defense mechanisms that might underlie the resistance of EnSCs against oncogenic transformation. All experiments were performed in vitro using the following methods: FACS, WB, RT-PCR, IF, molecular cloning, lentiviral transduction, and CRISPR/Cas9 genome editing. We revealed that the expression of the mutant HRASG12V leads to EnSC senescence. We experimentally confirmed the inability of HRASG12V-expressing EnSCs to bypass senescence and resume proliferation, even upon estrogen stimulation. At the molecular level, the induction of oncogene-induced senescence (OIS) was accompanied by activation of the MEK/ERK, PI3K/AKT, p53/p21WAF/CIP/Rb, and p38/p16INK4a/Rb pathways; however, inhibiting either pathway did not prevent cell cycle arrest. PTEN loss was established as an additional feature of HRASG12V-induced senescence in EnSCs. Using CRISPR-Cas9-mediated PTEN knockout, we identified PTEN loss-induced senescence as a reserve molecular mechanism to prevent the transformation of HRASG12V-expressing EnSCs. The present study highlights oncogene-induced senescence as an antitumor defense mechanism of EnSCs controlled by multiple backup molecular pathways.
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页数:16
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