DNASE1L3 arrests tumor angiogenesis by impairing the senescence-associated secretory phenotype in response to stress.
DNASE1L3 arrests tumor angiogenesis by impairing the senescence-associated secretory phenotype in response to stress.
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DNASE1L3 通过损害衰老相关的应激反应分泌表型来阻止肿瘤血管生成
DOI：
10.18632/aging.202740
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发表时间：
2021-03-19
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
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作者：
Guo D;Ma D;Liu P;Lan J;Liu Z;Liu Q
肝细胞癌是最具挑战性和侵袭性的癌症之一，由于肿瘤的异质性，治疗选择有限。肿瘤血管生成是肝细胞癌的一个标志，是肿瘤生长和发展所必需的。DNA损伤应激及其相关的脱氧核糖核酸酶1-样3(DNASE1L3)参与了肝细胞癌的进展。在此，我们探讨了DNA损伤应激下DNASE1L3在体内外影响肿瘤血管生成的机制。DNASE1L3基因表达下调与可切除和不可切除的肝癌患者预后不良呈负相关。肝细胞癌组织芯片显示DNASE1L3与肿瘤血管侵袭呈负相关。从机制上讲，DNASE_1L3可减轻损伤应激下肝癌细胞胞浆内的DNA积聚，进而通过P53和NF-κB信号通路阻止细胞衰老和衰老相关的分泌表型，从而抑制肿瘤血管生成。此外，我们通过免疫共沉淀和荧光共振能量转移实验发现，在DNA损伤胁迫下，DNASE1L3通过移位到细胞核并与H2BE相互作用而取消了这些功能。综上所述，DNASE1L3通过损伤衰老相关的分泌表型来应对DNA损伤应激，从而抑制肿瘤血管生成。
Hepatocellular carcinoma (HCC) is one of the most challenging and aggressive cancers with limited treatment options because of tumor heterogeneity. Tumor angiogenesis is a hallmark of HCC and is necessary for tumor growth and progression. DNA damage stress and its associated deoxyribonuclease1-like 3 (DNASE1L3) are involved in HCC progression. Here, we explored the influence mechanism of DNASE1L3 on tumor angiogenesis under DNA damage stress in vitro and in vivo. DNASE1L3 was found downregulated and negatively correlated with poor prognosis of resectable and unresectable HCC patients. The tissue microarray of HCC revealed the negative association between DNASE1L3 and cancer vasculature invasion. Mechanistically, DNASE1L3 was found to relieve cytoplasmic DNA accumulation under DNA damage stress in HCC cell lines, in turn cell senescence and senescence-associated secretory phenotype were arrested via the p53 and NF-κB signal pathway, and hence, tumor angiogenesis was impaired. Furthermore, we found that DNASE1L3 excised these functions by translocating to the nucleus and interacting with H2BE under DNA damage stress using co-immunoprecipitation and fluorescence resonance energy transfer assay. In conclusion, DNASE1L3 inhibits tumor angiogenesis via impairing the senescence-associated secretory phenotype in response to DNA damage stress.