Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance.
Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance.
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早期胃肿瘤病变中 SASP、DNA 损伤反应和细胞增殖因子的表达：相关性和临床意义
DOI：
10.3389/pore.2022.1610401
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Liang L;Chai Y;Chai F;Liu H;Ma N;Zhang H;Zhang S;Nong L;Li T;Zhang B
环鸟苷酸 - 腺苷酸合酶（cGAS） - 干扰素基因刺激因子（STING）介导的衰老相关分泌表型（SASP）通路最近在癌症的抑制和促进中被发现。然而，其在致癌作用中的实际角色仍有待全面阐明。在此，我们描述了一项研究，该研究分析了30例具有早期肿瘤性病变（包括低级别上皮内瘤变[LGD]、高级别上皮内瘤变[HGD]和黏膜内癌）的内镜黏膜下剥离术（ESD）标本中，SASP活性及其与DNA损伤反应（DDR）、基因突变和细胞增殖在胃癌发生中的相关性。衰老相关β - 半乳糖苷酶染色的阳性细胞以及使用免疫染色检测的cGAS、STING、干扰素调节因子3（IRF3）和信号转导及转录激活因子6（STAT6）的表达水平在HGD和癌症中升高。同样，在HGD和癌症中检测到范可尼贫血D2组蛋白（FANCD2）、肿瘤抑制蛋白p53结合蛋白1（TP53BP1）和复制蛋白A（RPA2）（即主要的DDR因子）表达增加；这些增加的表达水平与Ki67和微小染色体维持复合体成分7（MCM7）蛋白的高表达密切相关。此外，使用新一代测序技术在56.67%的评估病例（17/30）中检测到TP53基因的基因突变，并且在HGD和癌症中验证了阳性染色。统计分析显示，细胞增殖与DDR因子的表达密切相关，其中TP53BP1与SASP因子呈正相关，IRF3与细胞增殖呈正相关。此外，一项评估临床特征的分析表明，STAT6阳性病例比STAT6阴性病例显示出更长的无进展生存期。我们使用有限数量的标本进行的评估表明，SASP可能在早期胃肿瘤性病变中普遍存在，并且可能由加速的细胞增殖诱导的DDR激活。SASP的临床意义仍需确定。
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated senescence-associated secretory phenotype (SASP) pathway has recently been identified in the suppression and promotion of cancers. However, its practical role in carcinogenesis remains to be comprehensively elucidated. Here, we describe an investigation analysing SASP activity and its correlations with DNA damage response (DDR), genomic mutations, and cell proliferation in gastric carcinogenesis among 30 cases with available endoscopic submucosal dissection (ESD) specimens of early neoplastic lesions (including low-grade dysplasia [LGD], high-grade dysplasia [HGD], and intramucosal carcinoma). The positive cells of senescence-associated β-galactosidase staining and cGAS, STING, interferon-regulatory factor 3 (IRF3), and signal transducer and activator of transcription 6 (STAT6) expression levels using immunostaining were elevated in HGD and in cancers. Similarly, increased expression of the Fanconi anemia group D2 (FANCD2) protein, tumour suppressor p53 binding protein 1 (TP53BP1), and replication protein A (RPA2) (i.e., primary DDR factors) was detected in HGD and in cancers; these increased expression levels were closely correlated with high expression of Ki67 and minichromosome maintenance complex component 7 (MCM7) proteins. Moreover, genomic mutations in TP53 gene were detected in 56.67% of the evaluated cases (17/30) using next-generation sequencing, and positive staining was verified in HGD and in cancers. Statistical analysis revealed that cell proliferation closely correlated with the expression of DDR factors, of which TP53BP1 was positively associated with SASP factors and IRF3 was positively correlated with cell proliferation. In addition, an analysis evaluating clinical features demonstrated that STAT6-positive cases showed a longer progression-free survival time than STAT6-negative cases. Our evaluation, conducted using a limited number of specimens, suggests SASP may be prevalent in early gastric neoplastic lesions and could be activated by accelerated cell proliferation-induced DDR. The clinical significance of SASP still needs to be determined.
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影响因子：
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作者：
Nishizawa T;Suzuki H
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影响因子：
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作者：
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