Pub Date : 2024-02-22DOI: 10.1007/s13402-024-00918-w
Haiping Lin, Yang Luo, Tingyue Gong, Hongsheng Fang, Hao Li, Guangyao Ye, Yan Zhang, Ming Zhong
Purpose
Growth differentiating Factor 15 (GDF15) is linked to several cancers, but its effect on chemoresistance in colorectal cancer (CRC) remains unclear. Here, we investigated the role of GDF15 in the chemotherapeutic response of CRC patients to oxaliplatin (L-OHP).
Methods
GDF15 levels in serum and tumour tissues were detected in CRC patients have received L-OHP-based neoadjuvant chemotherapy. The effects of GDF15 neutralization or GDF15 knockdown on cell proliferation, apoptosis and intracellular reactive oxygen species (ROS) levels were analysed in vitro and in vivo. Co-immunoprecipitation (Co-IP), Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the interaction between GDF15 and Nrf2.
Results
In this study, we found that GDF15 alleviates oxidative stress to induce chemoresistance of L-OHP in CRC. Mechanically, GDF15 posttranscriptionally regulates protein stability of Nrf2 through the canonical PI3K/AKT/GSK3β signaling pathway, and in turn, Nrf2 acts as a transcription factor to regulate GDF15 expression to form a positive feedback loop, resulting in the maintenance of redox homeostasis balance in CRC. Furthermore, a positive correlation between GDF15 and Nrf2 was observed in clinical CRC samples, and simultaneous overexpression of both GDF15 and Nrf2 was associated with poor prognosis in CRC patients treated with L-OHP. Simultaneous inhibition of both GDF15 and Nrf2 significantly increases the response to L-OHP in an L-OHP-resistant colorectal cancer cells-derived mouse xenograft model.
Conclusion
This study identified a novel GDF15-Nrf2 positive feedback loop that drives L-OHP resistance and suggested that the GDF15-Nrf2 axis is a potential therapeutic target for the treatment of L-OHP-resistant CRC.
{"title":"GDF15 induces chemoresistance to oxaliplatin by forming a reciprocal feedback loop with Nrf2 to maintain redox homeostasis in colorectal cancer","authors":"Haiping Lin, Yang Luo, Tingyue Gong, Hongsheng Fang, Hao Li, Guangyao Ye, Yan Zhang, Ming Zhong","doi":"10.1007/s13402-024-00918-w","DOIUrl":"https://doi.org/10.1007/s13402-024-00918-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>Growth differentiating Factor 15 (GDF15) is linked to several cancers, but its effect on chemoresistance in colorectal cancer (CRC) remains unclear. Here, we investigated the role of GDF15 in the chemotherapeutic response of CRC patients to oxaliplatin (L-OHP).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>GDF15 levels in serum and tumour tissues were detected in CRC patients have received L-OHP-based neoadjuvant chemotherapy. The effects of GDF15 neutralization or GDF15 knockdown on cell proliferation, apoptosis and intracellular reactive oxygen species (ROS) levels were analysed in vitro and in vivo. Co-immunoprecipitation (Co-IP), Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the interaction between GDF15 and Nrf2.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In this study, we found that GDF15 alleviates oxidative stress to induce chemoresistance of L-OHP in CRC. Mechanically, GDF15 posttranscriptionally regulates protein stability of Nrf2 through the canonical PI3K/AKT/GSK3β signaling pathway, and in turn, Nrf2 acts as a transcription factor to regulate GDF15 expression to form a positive feedback loop, resulting in the maintenance of redox homeostasis balance in CRC. Furthermore, a positive correlation between GDF15 and Nrf2 was observed in clinical CRC samples, and simultaneous overexpression of both GDF15 and Nrf2 was associated with poor prognosis in CRC patients treated with L-OHP. Simultaneous inhibition of both GDF15 and Nrf2 significantly increases the response to L-OHP in an L-OHP-resistant colorectal cancer cells-derived mouse xenograft model.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>This study identified a novel GDF15-Nrf2 positive feedback loop that drives L-OHP resistance and suggested that the GDF15-Nrf2 axis is a potential therapeutic target for the treatment of L-OHP-resistant CRC.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"26 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139919693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood.
Methods
In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.
Results
Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model.
Conclusion
Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.
Graphical Abstract
背景胆管癌(CCA)是一种原发性肝胆恶性肿瘤,其特点是预后不良且缺乏有效的治疗方法。因此,探索新的治疗方法迫在眉睫。本研究采用组织芯片(TMA)、反转录聚合酶链反应(RT-PCR)和癌症基因组图谱(TCGA)数据库来评估 PIN1 的表达。通过体外和体内功能实验,我们研究了 PIN1 对 CCA 粘附和转移的影响。此外,我们还利用 RNA-seq、Western 印迹、共免疫沉淀、免疫荧光和质谱技术探索了下游分子通路。此外,PIN1 的高表达促进了 CCA 细胞的增殖和迁移。从机理上讲,PIN1 通过调节 ANXA2 磷酸化,从而促进 CCA 的粘附,起到了癌基因的作用。值得注意的是,PIN1 和 ANXA2 之间的相互作用是由 RACK1 促进的。总之,我们的研究强调了 PIN1/RACK1/ANXA2 复合物在 CCA 生长和功能中的关键作用,突出了靶向 PIN1 作为 CCA 治疗策略的潜力。
{"title":"PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2","authors":"Yuming Wang, Yiwei Liu, Hairong Chen, Zhenggang Xu, Wangjie Jiang, Xiao Xu, Jijun Shan, Jiang Chang, Tao Zhou, Jifei Wang, Anlan Chenyan, Shilong Fan, Zifan Tao, Ke Shao, Xiangcheng Li, Xiaofeng Chen, Guwei Ji, Xiaofeng Wu","doi":"10.1007/s13402-024-00924-y","DOIUrl":"https://doi.org/10.1007/s13402-024-00924-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"28 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139919727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1007/s13402-023-00905-7
Abstract
Background
T cell stress response state (TSTR), as a novel immune concept previous studies have proposed, has not yet been explored in prostate cancer (PC). As a type of cellular efflux, exosomes play important roles in the occurrence and development of PC.
Method
Here, we conducted a combined analysis on extracellular vesicle related genes (EVRGs) in PC using data from single-cell RNA (scRNA), spatial transcriptome (ST), and bulk RNA sequencing.
Result
Preliminary findings have revealed that heat shock protein family H (Hsp110) member 1 (HSPH1) possesses two identities, one being EVRGs and the other being a member of the heat shock protein family involved in TSTR, which may promote the differentiation of conventional T cells towards Th1 or Th2 cells through the pathway of IL2-MYC-IL2RA, thereby promoting the increase of CD8 + T cells in the tumor area, especially in the invasive zone, and inhibiting the invasion of PCs. We also notice the negative response of HSPH1 + CD8 + T cell related genes in immune checkpoint blockade (ICB). Western blot (WB) and droplet digital Polymerase Chain Reaction (ddPCR) demonstrated that the mRNA and protein levels of HSPH1 in EVs of PCs were significantly higher than those in adjacent tissues.
Conclusion
Results above indicate the potential of HSPH1 as a critical therapeutic target in PC.
摘要 背景 T细胞应激反应状态(TSTR)是以往研究提出的一种新的免疫概念,但尚未在前列腺癌(PC)中得到探讨。外泌体作为一种细胞外流体,在前列腺癌的发生和发展中发挥着重要作用。 方法 我们利用单细胞 RNA(scRNA)、空间转录组(ST)和大容量 RNA 测序数据,对 PC 中的细胞外囊泡相关基因(EVRGs)进行了综合分析。 结果 初步研究结果表明,热休克蛋白家族 H(Hsp110)成员 1(HSPH1)具有两种身份,一种是 EVRGs,另一种是参与 TSTR 的热休克蛋白家族成员,可能通过 IL2-MYC-IL2RA 途径促进传统 T 细胞向 Th1 或 Th2 细胞分化,从而促进肿瘤区域尤其是侵袭区 CD8 + T 细胞的增加,抑制 PCs 的侵袭。我们还注意到 HSPH1 + CD8 + T 细胞相关基因在免疫检查点阻断(ICB)中的负反应。Western blot(WB)和液滴数字聚合酶链反应(ddPCR)表明,PCs EVs 中 HSPH1 的 mRNA 和蛋白水平明显高于邻近组织。 结论 上述结果表明,HSPH1 有可能成为 PC 的关键治疗靶点。
{"title":"Extracellular vesicles related gene HSPH1 exerts anti-tumor effects in prostate cancer via promoting the stress response of CD8 + T cells","authors":"","doi":"10.1007/s13402-023-00905-7","DOIUrl":"https://doi.org/10.1007/s13402-023-00905-7","url":null,"abstract":"<h3>Abstract</h3> <span> <h3>Background</h3> <p>T cell stress response state (TSTR), as a novel immune concept previous studies have proposed, has not yet been explored in prostate cancer (PC). As a type of cellular efflux, exosomes play important roles in the occurrence and development of PC.</p> </span> <span> <h3>Method</h3> <p>Here, we conducted a combined analysis on extracellular vesicle related genes (EVRGs) in PC using data from single-cell RNA (scRNA), spatial transcriptome (ST), and bulk RNA sequencing.</p> </span> <span> <h3>Result</h3> <p>Preliminary findings have revealed that heat shock protein family H (Hsp110) member 1 (HSPH1) possesses two identities, one being EVRGs and the other being a member of the heat shock protein family involved in TSTR, which may promote the differentiation of conventional T cells towards Th1 or Th2 cells through the pathway of IL2-MYC-IL2RA, thereby promoting the increase of CD8 + T cells in the tumor area, especially in the invasive zone, and inhibiting the invasion of PCs. We also notice the negative response of HSPH1 + CD8 + T cell related genes in immune checkpoint blockade (ICB). Western blot (WB) and droplet digital Polymerase Chain Reaction (ddPCR) demonstrated that the mRNA and protein levels of HSPH1 in EVs of PCs were significantly higher than those in adjacent tissues.</p> </span> <span> <h3>Conclusion</h3> <p>Results above indicate the potential of HSPH1 as a critical therapeutic target in PC.</p> </span>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"9 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139078519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-19DOI: 10.1007/s13402-023-00910-w
Garam Kim, Poshan Yugal Bhattarai, Sung-Chul Lim, Kwang Youl Lee, Hong Seok Choi
Purpose
Nuclear accumulation of YAP/TAZ promotes tumorigenesis in several cancers, including melanoma. Although the mechanisms underlying the nuclear retention of YAP are known, those underlying the retention of TAZ remain unclear. Our study investigates a novel acetylation/deacetylation switch in TAZ, governing its subcellular localization in melanoma tumorigenesis.
Methods
Immunoprecipitation/Western blot assessed TAZ protein interactions and acetylation. SIRT5 activity was quantified with enzyme-linked immunosorbent assay. Immunofluorescence indicated TAZ nuclear localization. TEAD transcriptional activity was measured through luciferase reporter assays. ChIP detected TAZ binding to the CTGF promoter. Transwell and wound healing assays quantified melanoma cell invasiveness and migration. Metastasis was evaluated using a mouse model via tail vein injections. Clinical relevance was explored via immunohistochemical staining of patient tumors.
Results
CBP facilitated TAZ acetylation at K54 in response to epidermal growth factor stimulation, while SIRT5 mediated deacetylation. Acetylation correlated with phosphorylation, regulating TAZ’s binding with LATS2 or TEAD. TAZ K54 acetylation enhanced its S89 phosphorylation, promoting cytosolic retention via LATS2 interaction. SIRT5-mediated deacetylation enhanced TAZ-TEAD interaction and nuclear retention. Chromatin IP showed SIRT5-deacetylated TAZ recruited to CTGF promoter, boosting transcriptional activity. In a mouse model, SIRT5 overexpression induced melanoma metastasis to lung tissue following the injection of B16F10 melanocytes via the tail vein, and this effect was prevented by verteporfin treatment.
Conclusions
Our study revealed a novel mechanism of TAZ nuclear retention regulated by SIRT5-mediated K54 deacetylation and demonstrated the significance of TAZ deacetylation in CTGF expression. This study highlights the potential implications of the SIRT5/TAZ axis for treating metastatic melanoma.
{"title":"Sirtuin 5-mediated deacetylation of TAZ at K54 promotes melanoma development","authors":"Garam Kim, Poshan Yugal Bhattarai, Sung-Chul Lim, Kwang Youl Lee, Hong Seok Choi","doi":"10.1007/s13402-023-00910-w","DOIUrl":"https://doi.org/10.1007/s13402-023-00910-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>Nuclear accumulation of YAP/TAZ promotes tumorigenesis in several cancers, including melanoma. Although the mechanisms underlying the nuclear retention of YAP are known, those underlying the retention of TAZ remain unclear. Our study investigates a novel acetylation/deacetylation switch in TAZ, governing its subcellular localization in melanoma tumorigenesis.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Immunoprecipitation/Western blot assessed TAZ protein interactions and acetylation. SIRT5 activity was quantified with enzyme-linked immunosorbent assay. Immunofluorescence indicated TAZ nuclear localization. TEAD transcriptional activity was measured through luciferase reporter assays. ChIP detected TAZ binding to the CTGF promoter. Transwell and wound healing assays quantified melanoma cell invasiveness and migration. Metastasis was evaluated using a mouse model via tail vein injections. Clinical relevance was explored via immunohistochemical staining of patient tumors.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>CBP facilitated TAZ acetylation at K54 in response to epidermal growth factor stimulation, while SIRT5 mediated deacetylation. Acetylation correlated with phosphorylation, regulating TAZ’s binding with LATS2 or TEAD. TAZ K54 acetylation enhanced its S89 phosphorylation, promoting cytosolic retention via LATS2 interaction. SIRT5-mediated deacetylation enhanced TAZ-TEAD interaction and nuclear retention. Chromatin IP showed SIRT5-deacetylated TAZ recruited to CTGF promoter, boosting transcriptional activity. In a mouse model, SIRT5 overexpression induced melanoma metastasis to lung tissue following the injection of B16F10 melanocytes via the tail vein, and this effect was prevented by verteporfin treatment.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Our study revealed a novel mechanism of TAZ nuclear retention regulated by SIRT5-mediated K54 deacetylation and demonstrated the significance of TAZ deacetylation in <i>CTGF</i> expression. This study highlights the potential implications of the SIRT5/TAZ axis for treating metastatic melanoma.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"5 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138743669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy.
Methods
In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay).
Results
According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells.
Conclusion
Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer.
{"title":"ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma","authors":"Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, Baiyong Shen","doi":"10.1007/s13402-023-00907-5","DOIUrl":"https://doi.org/10.1007/s13402-023-00907-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"197 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138682630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-14DOI: 10.1007/s13402-023-00906-6
Antonella Porrazzo, Matteo Cassandri, Andrea D’Alessandro, Patrizia Morciano, Rossella Rota, Francesco Marampon, Giovanni Cenci
Background
Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy.
Conclusion
Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on Drosophila melanogaster we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.
{"title":"DNA repair in tumor radioresistance: insights from fruit flies genetics","authors":"Antonella Porrazzo, Matteo Cassandri, Andrea D’Alessandro, Patrizia Morciano, Rossella Rota, Francesco Marampon, Giovanni Cenci","doi":"10.1007/s13402-023-00906-6","DOIUrl":"https://doi.org/10.1007/s13402-023-00906-6","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on <i>Drosophila melanogaster</i> we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"82 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138629657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain.
Methods
The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2.
Results
We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy.
Conclusion
As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.
{"title":"CSGALNACT2 restricts ovarian cancer migration and invasion by modulating MAPK/ERK pathway through DUSP1","authors":"Mingjun Ma, Chao Wang, Meixuan Wu, Sijia Gu, Jiani Yang, Yue Zhang, Shanshan Cheng, Shilin Xu, Minghai Zhang, Yongsong Wu, Yaqian Zhao, Xiu Tian, Dominic Chih-Cheng Voon, Chiaki Takahashi, Jindan Sheng, Yu Wang","doi":"10.1007/s13402-023-00903-9","DOIUrl":"https://doi.org/10.1007/s13402-023-00903-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"19 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138576620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-06DOI: 10.1007/s13402-022-00680-x
Stefania Tocci, Stella-Rita C. Ibeawuchi, Soumita Das, I. Sayed
{"title":"Role of ELMO1 in inflammation and cancer—clinical implications","authors":"Stefania Tocci, Stella-Rita C. Ibeawuchi, Soumita Das, I. Sayed","doi":"10.1007/s13402-022-00680-x","DOIUrl":"https://doi.org/10.1007/s13402-022-00680-x","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"45 1","pages":"505 - 525"},"PeriodicalIF":6.6,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47085860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.
Methods: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.
Results: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.
Conclusion: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.
{"title":"GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.","authors":"Shilong Han, Chuanwu Cao, Rui Liu, YiFeng Yuan, Long Pan, Minjie Xu, Chao Hu, Xiaojun Zhang, Maoquan Li, Xiaoping Zhang","doi":"10.1007/s13402-022-00675-8","DOIUrl":"10.1007/s13402-022-00675-8","url":null,"abstract":"<p><strong>Purpose: </strong>GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.</p><p><strong>Methods: </strong>GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.</p><p><strong>Results: </strong>We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.</p><p><strong>Conclusion: </strong>Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"45 1","pages":"429-446"},"PeriodicalIF":6.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46937389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}