Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
|
| Series: | Pathology and Oncology Research |
| Subjects: | |
| Online Access: | https://www.por-journal.com/articles/10.3389/pore.2022.1610401/full |
| _version_ | 1797220986255310848 |
|---|---|
| author | Li Liang Yijie Chai Fei Chai Haijing Liu Ningning Ma Hong Zhang Shuang Zhang Lin Nong Ting Li Bo Zhang |
| author_facet | Li Liang Yijie Chai Fei Chai Haijing Liu Ningning Ma Hong Zhang Shuang Zhang Lin Nong Ting Li Bo Zhang |
| author_sort | Li Liang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T12:58:15Z |
| format | Article |
| id | doaj.art-0ca335637ad54bc4926fd4b370696b7f |
| institution | Directory Open Access Journal |
| issn | 1532-2807 |
| language | English |
| last_indexed | 2024-04-24T12:58:15Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Pathology and Oncology Research |
| spelling | doaj.art-0ca335637ad54bc4926fd4b370696b7f2024-04-05T16:24:46ZengFrontiers Media S.A.Pathology and Oncology Research1532-28072022-08-012810.3389/pore.2022.16104011610401Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical SignificanceLi Liang0Yijie Chai1Fei Chai2Haijing Liu3Ningning Ma4Hong Zhang5Shuang Zhang6Lin Nong7Ting Li8Bo Zhang9Department of Pathology, Peking University First Hospital, Beijing, ChinaDepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, ChinaDepartment of Pathology, Fenyang College of Shanxi Medical University, Fenyang, ChinaDepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, ChinaDepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, ChinaDepartment of Pathology, Peking University First Hospital, Beijing, ChinaDepartment of Pathology, Peking University First Hospital, Beijing, ChinaDepartment of Pathology, Peking University First Hospital, Beijing, ChinaDepartment of Pathology, Peking University First Hospital, Beijing, ChinaDepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, ChinaThe 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.https://www.por-journal.com/articles/10.3389/pore.2022.1610401/fullimmunohistochemistrygastric cancerp53DNA damage responseendoscopic submucosal dissectionsenescence-associated secretory phenotype |
| spellingShingle | Li Liang Yijie Chai Fei Chai Haijing Liu Ningning Ma Hong Zhang Shuang Zhang Lin Nong Ting Li Bo Zhang Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance Pathology and Oncology Research immunohistochemistry gastric cancer p53 DNA damage response endoscopic submucosal dissection senescence-associated secretory phenotype |
| title | Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance |
| title_full | Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance |
| title_fullStr | Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance |
| title_full_unstemmed | Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance |
| title_short | Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance |
| title_sort | expression of sasp dna damage response and cell proliferation factors in early gastric neoplastic lesions correlations and clinical significance |
| topic | immunohistochemistry gastric cancer p53 DNA damage response endoscopic submucosal dissection senescence-associated secretory phenotype |
| url | https://www.por-journal.com/articles/10.3389/pore.2022.1610401/full |
| work_keys_str_mv | AT liliang expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT yijiechai expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT feichai expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT haijingliu expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT ningningma expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT hongzhang expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT shuangzhang expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT linnong expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT tingli expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance AT bozhang expressionofsaspdnadamageresponseandcellproliferationfactorsinearlygastricneoplasticlesionscorrelationsandclinicalsignificance |