Background: We previously identified a novel lncRNA, CRART16, that could induce cetuximab resistance in colorectal cancer cells. This study explored the relationship of CRART16 expression to gastric cancer progression and the molecular mechanisms involved. Methods: We evaluated CRART16 expression in gastric cancer tissues and adjacent normal tissues from the TCGA database and our hospital. Besides, we assessed its relationship with the overall survival (OS) of patients with gastric cancer. The effects of CRART16 on gastric cancer angiogenesis were determined by endothelial tube formation assay, spheroid sprouting assay, HUVEC invasion assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the lncRNA CRART16/miR-122-5p/FOS axis was analyzed by western blotting and dual-luciferase reporter assay. The functions of CRART16 were confirmed in xenograft mouse models. Results: We found that CRART16 was substantially overexpressed in gastric cancer tissues compared with normal tissues, based on the TCGA database and our clinical samples. High expression of CRART16 correlated with more advanced tumor stages and poor prognosis. Overexpression of CRART16 in gastric cancer cells promoted proliferation, colony formation, angiogenesis, and bevacizumab resistance in vitro, and it promoted tumor growth and angiogenesis in vivo, and vice versa. CRART16 was found to downregulate miR-122-5p by acting as a sponge, upregulating the target oncogene FOS. Afterward, the increased FOS expression led to the upregulation of VEGFD. Conclusion: Our findings demonstrate that CRART16 promotes angiogenesis in vitro and in vivo, and CRART16 is a prognostic marker and therapeutic target in gastric cancer.
{"title":"LncRNA CRART16/miR-122-5p/FOS axis promotes angiogenesis of gastric cancer by upregulating VEGFD expression","authors":"Jun-ling Zhang, Xiaocong Pang, Lili Lei, Ji-xin Zhang, Xiaoqian Zhang, Zi-yi Chen, Jing Zhu, Yong Jiang, Guowei Chen, Yingchao Wu, Tao Wu, Yisheng Pan, Yucun Liu, Yi-min Cui, Xin Wang","doi":"10.18632/aging.204078","DOIUrl":"https://doi.org/10.18632/aging.204078","url":null,"abstract":"Background: We previously identified a novel lncRNA, CRART16, that could induce cetuximab resistance in colorectal cancer cells. This study explored the relationship of CRART16 expression to gastric cancer progression and the molecular mechanisms involved. Methods: We evaluated CRART16 expression in gastric cancer tissues and adjacent normal tissues from the TCGA database and our hospital. Besides, we assessed its relationship with the overall survival (OS) of patients with gastric cancer. The effects of CRART16 on gastric cancer angiogenesis were determined by endothelial tube formation assay, spheroid sprouting assay, HUVEC invasion assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the lncRNA CRART16/miR-122-5p/FOS axis was analyzed by western blotting and dual-luciferase reporter assay. The functions of CRART16 were confirmed in xenograft mouse models. Results: We found that CRART16 was substantially overexpressed in gastric cancer tissues compared with normal tissues, based on the TCGA database and our clinical samples. High expression of CRART16 correlated with more advanced tumor stages and poor prognosis. Overexpression of CRART16 in gastric cancer cells promoted proliferation, colony formation, angiogenesis, and bevacizumab resistance in vitro, and it promoted tumor growth and angiogenesis in vivo, and vice versa. CRART16 was found to downregulate miR-122-5p by acting as a sponge, upregulating the target oncogene FOS. Afterward, the increased FOS expression led to the upregulation of VEGFD. Conclusion: Our findings demonstrate that CRART16 promotes angiogenesis in vitro and in vivo, and CRART16 is a prognostic marker and therapeutic target in gastric cancer.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"40 1","pages":"4137 - 4157"},"PeriodicalIF":0.0,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86325479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lianzhu Zhang, S. Zhou, Junkuo Li, Peinan Chen, X. Zhao, Li-Dong Wang, Xiuling Li, F. Zhou
While genetic alterations in several regulators of the cell cycle have a significant impact on the gastric carcinogenesis process, the prognostic role of them remains to be further elucidated. The TCGA-STAD training set were downloaded and the mRNA expression matrix of cell cycle genes was extracted and corrected for further analysis after taking the intersection with GSE84437 dataset. Differentially expressed mRNAs were identified between tumor and normal tissue samples in TCGA-STAD. Univariate Cox regression analysis and lasso Cox regression model established a novel seven-gene cell cycle signature (including GADD45B, TFDP1, CDC6, CDC25A, CDC7, SMC1A and MCM3) for GC prognosis prediction. Patients in the high-risk group shown significantly poorer survival than patients in the low-risk group. The signature was found to be an independent prognostic factor for GC survival. Nomogram including the signature shown some clinical net benefit for overall survival prediction. The signature was further validated in the GSE84437 dataset. In tissue microarray, CDC6 and MCM3 protein expression were significant differences by the immunohistochemistry-based H-score between tumor tissues and adjacent tissues, and CDC6 is an independent prognostic factor for GC. Interestingly, our GSEA revealed that low-risk patients were more related to cell cycle pathways and might benefit more from therapies targeting cell cycle. Our study identified a novel robust seven-gene cell cycle signature for GC prognosis prediction that may serve as a beneficial complement to clinicopathological staging. The signature might provide potential biomarkers for the application of cell cycle regulators to therapies and treatment response prediction.
{"title":"Identification of a seven-cell cycle signature predicting overall survival for gastric cancer","authors":"Lianzhu Zhang, S. Zhou, Junkuo Li, Peinan Chen, X. Zhao, Li-Dong Wang, Xiuling Li, F. Zhou","doi":"10.18632/aging.204060","DOIUrl":"https://doi.org/10.18632/aging.204060","url":null,"abstract":"While genetic alterations in several regulators of the cell cycle have a significant impact on the gastric carcinogenesis process, the prognostic role of them remains to be further elucidated. The TCGA-STAD training set were downloaded and the mRNA expression matrix of cell cycle genes was extracted and corrected for further analysis after taking the intersection with GSE84437 dataset. Differentially expressed mRNAs were identified between tumor and normal tissue samples in TCGA-STAD. Univariate Cox regression analysis and lasso Cox regression model established a novel seven-gene cell cycle signature (including GADD45B, TFDP1, CDC6, CDC25A, CDC7, SMC1A and MCM3) for GC prognosis prediction. Patients in the high-risk group shown significantly poorer survival than patients in the low-risk group. The signature was found to be an independent prognostic factor for GC survival. Nomogram including the signature shown some clinical net benefit for overall survival prediction. The signature was further validated in the GSE84437 dataset. In tissue microarray, CDC6 and MCM3 protein expression were significant differences by the immunohistochemistry-based H-score between tumor tissues and adjacent tissues, and CDC6 is an independent prognostic factor for GC. Interestingly, our GSEA revealed that low-risk patients were more related to cell cycle pathways and might benefit more from therapies targeting cell cycle. Our study identified a novel robust seven-gene cell cycle signature for GC prognosis prediction that may serve as a beneficial complement to clinicopathological staging. The signature might provide potential biomarkers for the application of cell cycle regulators to therapies and treatment response prediction.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"29 1","pages":"3989 - 3999"},"PeriodicalIF":0.0,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73836552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A thought-provoking article by Gems and de Magalhães suggests that canonic hallmarks of aging are superficial imitations of hallmarks of cancer. I took their work a step further and proposed hallmarks of aging based on a hierarchical principle and the hyperfunction theory. To do this, I first reexamine the hallmarks of cancer proposed by Hanahan and Weinberg in 2000. Although six hallmarks of cancer are genuine, they are not hierarchically arranged, i.e., molecular, intra-cellular, cellular, tissue, organismal and extra-organismal. (For example, invasion and angiogenesis are manifestations of molecular alterations on the tissue level; metastasis on the organismal level, whereas cell immortality is observed outside the host). The same hierarchical approach is applicable to aging. Unlike cancer, however, aging is not a molecular disease. The lowest level of its origin is normal intracellular signaling pathways such as mTOR that drive developmental growth and, later in life, become hyperfunctional, causing age-related diseases, whose sum is aging. The key hallmark of organismal aging, from worms to humans, are age-related diseases. In addition, hallmarks of aging can be arranged as a timeline, wherein initial hyperfunction is followed by dysfunction, organ damage and functional decline.
{"title":"Hallmarks of cancer and hallmarks of aging","authors":"M. Blagosklonny","doi":"10.18632/aging.204082","DOIUrl":"https://doi.org/10.18632/aging.204082","url":null,"abstract":"A thought-provoking article by Gems and de Magalhães suggests that canonic hallmarks of aging are superficial imitations of hallmarks of cancer. I took their work a step further and proposed hallmarks of aging based on a hierarchical principle and the hyperfunction theory. To do this, I first reexamine the hallmarks of cancer proposed by Hanahan and Weinberg in 2000. Although six hallmarks of cancer are genuine, they are not hierarchically arranged, i.e., molecular, intra-cellular, cellular, tissue, organismal and extra-organismal. (For example, invasion and angiogenesis are manifestations of molecular alterations on the tissue level; metastasis on the organismal level, whereas cell immortality is observed outside the host). The same hierarchical approach is applicable to aging. Unlike cancer, however, aging is not a molecular disease. The lowest level of its origin is normal intracellular signaling pathways such as mTOR that drive developmental growth and, later in life, become hyperfunctional, causing age-related diseases, whose sum is aging. The key hallmark of organismal aging, from worms to humans, are age-related diseases. In addition, hallmarks of aging can be arranged as a timeline, wherein initial hyperfunction is followed by dysfunction, organ damage and functional decline.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"134 1","pages":"4176 - 4187"},"PeriodicalIF":0.0,"publicationDate":"2022-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81742828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-07DOI: 10.1101/2022.05.07.491023
Lars Erichsen, J. Adjaye
The aging process is manifested by a multitude of interlinked biological processes. These processes contribute to genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Together these are recognized as of the main risk factors of the world’s most prevalent diseases, such as neurodegenerative disorders, cancer, cardiovascular disease, and metabolic disease. The mammalian ortholog of the yeast silent information regulator (Sir2) SIRT1 is a NAD+-dependent class III histone deacetylase and has been recognized to be involved in many of the forementioned processes. Therefore, its activity is connected to aging via the regulation of apoptosis, cell differentiation, development, stress response, metabolism, and tumorigenesis. Furthermore, the physiological activity of several sirtuin family members has been connected to the regulation of life span of lower organisms (Caenorhabditis elegans and Drosophila melanogaster) as well as mammals. Aging in somatic cells of mammals is accompanied by mutations and other forms of DNA damage. These might manifest in transient cell cycle arrest associated with DNA repair, apoptosis, senescence, or cell differentiation. The activity of SIRT1 has previously been reported to be regulated by the DNA damage response pathway. On the one hand, SIRT1 is recruited from ATM to DBS and is required for DNA damage repair, but on the other hand, SIRT1 activity was also found to be negatively regulated by genotoxic stress via the interaction of ATM with Deleted in Breast Cancer 1 (DBC1). Increased levels of DBS are associated with downregulation of ATM and lower phosphorylation levels of AKT and GSK3ß, with significant implications for mesenchymal stem cell (MSC) maintenance and differentiation. In this proposed “stem cell checkpoint,” the ATM signalling pathway initiated by DBS maintains MSCs and blocks their differentiation. Based on this, it has already been established that in senescent mesenchymal stem cells, SIRT1 expression is decreased, while its overexpression delays the onset of senescence and loss of differentiation capacity/ability. In the present study, we provide evidence that SIX2-positive urine derived renal progenitor cells-UdRPCs isolated directly from human urine show typical hallmarks of aging when obtained from elderly donors. This includes the transcriptional downregulation of SIRT1 and its downstream targets AKT and GSK3ß. This transcriptional downregulation is accompanied by an increase in DNA damage and transcriptional levels several cell cycle inhibitors such as P16, reflecting possibly the ATM induced “stemness checkpoint” to maintain UdRPC stemness and differentiation capacity. We provide evidence that the renal progenitor transcription factor SIX2 binds to the coding sequence of SIRT1 and both factors mutually influence the transcripti
衰老过程是由许多相互联系的生物过程表现出来的。这些过程导致基因组不稳定、端粒磨损、表观遗传改变、蛋白质稳态丧失、营养感知失调、线粒体功能障碍、细胞衰老、干细胞衰竭和细胞间通讯改变。这些因素被认为是世界上最流行疾病的主要危险因素，如神经退行性疾病、癌症、心血管疾病和代谢性疾病。酵母沉默信息调节因子(Sir2)的哺乳动物同源物SIRT1是一种依赖NAD+的III类组蛋白去乙酰化酶，已被认为参与了许多上述过程。因此，它的活性通过调控细胞凋亡、细胞分化、发育、应激反应、代谢和肿瘤发生与衰老有关。此外，一些sirtuin家族成员的生理活性与低等生物(秀丽隐杆线虫和黑腹果蝇)以及哺乳动物的寿命调节有关。哺乳动物体细胞的衰老伴随着突变和其他形式的DNA损伤。这些可能表现为与DNA修复、细胞凋亡、衰老或细胞分化相关的短暂细胞周期阻滞。先前有报道称SIRT1的活性受DNA损伤反应途径的调控。一方面，SIRT1从ATM募集到DBS，是DNA损伤修复所必需的，但另一方面，SIRT1活性也被发现通过ATM与DBC1 (Deleted in Breast Cancer 1)的相互作用受到基因毒性应激的负调控。DBS水平的升高与ATM的下调以及AKT和GSK3ß磷酸化水平的降低有关，对间充质干细胞(MSC)的维持和分化具有重要意义。在这个提出的“干细胞检查点”中，DBS启动的ATM信号通路维持MSCs并阻止其分化。基于此，我们已经证实，在衰老的间充质干细胞中，SIRT1表达降低，而其过表达延迟了衰老的发生和分化能力的丧失。在本研究中，我们提供的证据表明，直接从人类尿液中分离的six2阳性尿源性肾祖细胞- udrpc从老年供体中获得时显示出典型的衰老特征。这包括SIRT1及其下游靶标AKT和GSK3ß的转录下调。这种转录下调伴随着一些细胞周期抑制剂(如P16)的DNA损伤和转录水平的增加，这可能反映了ATM诱导的“干性检查点”，以维持UdRPC的干性和分化能力。我们提供的证据表明，肾祖转录因子SIX2与SIRT1的编码序列结合，并且这两个因子相互影响彼此的转录。此外，我们发现SIRT1启动子区域是甲基化敏感的，随后在来自老年供体的udrpc中甲基化，将它们分为SIRT1高表达和低表达的udrpc。这种下调可能使细胞更容易受到内源性毒素的伤害，加速DNA损伤的积累，最终积累衰老相关的标志。
{"title":"Crosstalk between age accumulated DNA-damage and the SIRT1-AKT-GSK3ß axis in urine derived renal progenitor cells","authors":"Lars Erichsen, J. Adjaye","doi":"10.1101/2022.05.07.491023","DOIUrl":"https://doi.org/10.1101/2022.05.07.491023","url":null,"abstract":"The aging process is manifested by a multitude of interlinked biological processes. These processes contribute to genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Together these are recognized as of the main risk factors of the world’s most prevalent diseases, such as neurodegenerative disorders, cancer, cardiovascular disease, and metabolic disease. The mammalian ortholog of the yeast silent information regulator (Sir2) SIRT1 is a NAD+-dependent class III histone deacetylase and has been recognized to be involved in many of the forementioned processes. Therefore, its activity is connected to aging via the regulation of apoptosis, cell differentiation, development, stress response, metabolism, and tumorigenesis. Furthermore, the physiological activity of several sirtuin family members has been connected to the regulation of life span of lower organisms (Caenorhabditis elegans and Drosophila melanogaster) as well as mammals. Aging in somatic cells of mammals is accompanied by mutations and other forms of DNA damage. These might manifest in transient cell cycle arrest associated with DNA repair, apoptosis, senescence, or cell differentiation. The activity of SIRT1 has previously been reported to be regulated by the DNA damage response pathway. On the one hand, SIRT1 is recruited from ATM to DBS and is required for DNA damage repair, but on the other hand, SIRT1 activity was also found to be negatively regulated by genotoxic stress via the interaction of ATM with Deleted in Breast Cancer 1 (DBC1). Increased levels of DBS are associated with downregulation of ATM and lower phosphorylation levels of AKT and GSK3ß, with significant implications for mesenchymal stem cell (MSC) maintenance and differentiation. In this proposed “stem cell checkpoint,” the ATM signalling pathway initiated by DBS maintains MSCs and blocks their differentiation. Based on this, it has already been established that in senescent mesenchymal stem cells, SIRT1 expression is decreased, while its overexpression delays the onset of senescence and loss of differentiation capacity/ability. In the present study, we provide evidence that SIX2-positive urine derived renal progenitor cells-UdRPCs isolated directly from human urine show typical hallmarks of aging when obtained from elderly donors. This includes the transcriptional downregulation of SIRT1 and its downstream targets AKT and GSK3ß. This transcriptional downregulation is accompanied by an increase in DNA damage and transcriptional levels several cell cycle inhibitors such as P16, reflecting possibly the ATM induced “stemness checkpoint” to maintain UdRPC stemness and differentiation capacity. We provide evidence that the renal progenitor transcription factor SIX2 binds to the coding sequence of SIRT1 and both factors mutually influence the transcripti","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"44 1","pages":"8179 - 8204"},"PeriodicalIF":0.0,"publicationDate":"2022-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82568298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI. Methods: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings. Results: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment. Conclusions: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.
{"title":"Pentraxin 3 depletion (PTX3 KD) inhibited myocardial fibrosis in heart failure after myocardial infarction","authors":"Yufang Xu, Yiting Hu, Yanping Geng, N. Zhao, Caiyun Jia, Haojing Song, Wanjun Bai, Caihui Guo, Lili Wang, Yanhui Ni, X. Qi","doi":"10.18632/aging.204070","DOIUrl":"https://doi.org/10.18632/aging.204070","url":null,"abstract":"Background: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI. Methods: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings. Results: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment. Conclusions: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"31 1","pages":"4036 - 4049"},"PeriodicalIF":0.0,"publicationDate":"2022-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76476326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Runt-related transcription factors (RUNX) are involved in numerous fundamental biological processes and play crucial parts in tumorigenesis and metastasis both directly and indirectly. However, the pan-cancer evidence of the RUNX gene family is not available. Methods: In this study, we analyzed the potential association between RUNX gene family expression and patient’s prognosis, immune cell infiltration, drug response, and genetic mutation data across different types of tumors using based on The Cancer Genome Atlas, Gene Expression Omnibus, and Oncomine database. Results: The results showed that the expression of the RUNX gene family varied among different cancer types, revealing its heterogeneity in cancers and that expression of RUNX2 was lower than that of RUNX1 and RUNX3 across all cancer types. RUNX gene family gene expression was related to prognosis in several cancers. Furthermore, our study revealed a clear association between RUNX gene family expression and ESTIMATE score, RNA stemness, and DNA stemness scores. Compared with RUNX1 and RUNX2, RUNX3 showed relatively low levels of genetic alterations. RUNX gene family genes had clear associations with immune infiltrate subtypes, and their expression was positively related to immune checkpoint genes and drug sensitivity in most cases. Two immunotherapy cohorts confirm that the expression of RUNX was correlated with the clinical response of immunotherapy. Conclusions: These findings will help to elucidate the potential oncogenic roles of RUNX gene family genes in different types of cancer and it can function as a prognostic marker in various malignant tumors.
背景:runt相关转录因子(RUNX)参与了许多基本的生物学过程，在肿瘤发生和转移中直接或间接地起着至关重要的作用。然而，RUNX基因家族的泛癌证据尚不存在。方法:本研究基于the Cancer Genome Atlas、gene expression Omnibus和Oncomine数据库，分析RUNX基因家族表达与不同类型肿瘤患者预后、免疫细胞浸润、药物反应和基因突变数据之间的潜在关联。结果:结果显示，RUNX基因家族在不同癌症类型中的表达存在差异，揭示了其在癌症中的异质性，且RUNX2在所有癌症类型中的表达均低于RUNX1和RUNX3。RUNX基因家族基因表达与多种肿瘤的预后有关。此外，我们的研究揭示了RUNX基因家族表达与ESTIMATE评分、RNA干性和DNA干性评分之间的明确关联。与RUNX1和RUNX2相比，RUNX3的遗传改变水平相对较低。RUNX基因家族基因与免疫浸润亚型有明显的关联，其表达在多数情况下与免疫检查点基因和药物敏感性呈正相关。两个免疫治疗队列证实RUNX的表达与免疫治疗的临床反应相关。结论:这些发现有助于阐明RUNX基因家族基因在不同类型肿瘤中的潜在致癌作用，并可作为各种恶性肿瘤的预后标志物。
{"title":"Prognostic value and immune characteristics of RUNX gene family in human cancers: a pan-cancer analysis","authors":"Han Zhao, Yun Chen, Peijun Shen, Lan Gong","doi":"10.18632/aging.204065","DOIUrl":"https://doi.org/10.18632/aging.204065","url":null,"abstract":"Background: Runt-related transcription factors (RUNX) are involved in numerous fundamental biological processes and play crucial parts in tumorigenesis and metastasis both directly and indirectly. However, the pan-cancer evidence of the RUNX gene family is not available. Methods: In this study, we analyzed the potential association between RUNX gene family expression and patient’s prognosis, immune cell infiltration, drug response, and genetic mutation data across different types of tumors using based on The Cancer Genome Atlas, Gene Expression Omnibus, and Oncomine database. Results: The results showed that the expression of the RUNX gene family varied among different cancer types, revealing its heterogeneity in cancers and that expression of RUNX2 was lower than that of RUNX1 and RUNX3 across all cancer types. RUNX gene family gene expression was related to prognosis in several cancers. Furthermore, our study revealed a clear association between RUNX gene family expression and ESTIMATE score, RNA stemness, and DNA stemness scores. Compared with RUNX1 and RUNX2, RUNX3 showed relatively low levels of genetic alterations. RUNX gene family genes had clear associations with immune infiltrate subtypes, and their expression was positively related to immune checkpoint genes and drug sensitivity in most cases. Two immunotherapy cohorts confirm that the expression of RUNX was correlated with the clinical response of immunotherapy. Conclusions: These findings will help to elucidate the potential oncogenic roles of RUNX gene family genes in different types of cancer and it can function as a prognostic marker in various malignant tumors.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"42 1","pages":"4014 - 4035"},"PeriodicalIF":0.0,"publicationDate":"2022-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85677413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: This study aimed to investigate the relationship of dyslipidemia and interleukin-enhancer binding factor 3 (ILF3) in gastric cancer, and provide insights into the potential application of statins as an agent to prevent and treat gastric cancer. Methods: The expression levels of ILF3 in gastric cancer were examined with publicly available datasets such as TCGA, and western blotting and immunohistochemistry were performed to determine the expression of ILF3 in clinical specimens. The effects of ox-LDL on expression of ILF3 were further verified with western blot analyses. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) pathway analyses were performed to reveal the potential downstream signaling pathway targets of ILF3. The effects of statins and ILF3 on PI3K/AKT/mTOR signaling pathway, cell proliferation, cell cycle, migration and invasion of gastric cancer cells were investigated with Edu assay, flow cytometry and transwell assay. Results: Immunohistochemistry and western blot demonstrated that the positive expression rates of ILF3 in gastric cancer tissues were higher than adjacent mucosa tissues. The ox-LDL promoted the expression of ILF3 in a time-concentration-dependent manner. ILF3 promoted the proliferation, cell cycle, migration and invasion by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibited the proliferation, cell cycle, migration and invasion of gastric cancer by inhibiting the expression of ILF3. Conclusions: These findings demonstrate that ox-LDL promotes ILF3 overexpression to regulate gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibits the expression of ILF3, which might be a new targeted therapy for gastric cancer.
{"title":"Ox-LDL-mediated ILF3 overexpression in gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway","authors":"Danping Sun, Mingxiang Zhang, Meng Wei, Zhaoyang Wang, Wen Qiao, Peng Liu, Xin Zhong, Yize Liang, Yuanyuan Chen, Yadi Huang, Wenbin Yu","doi":"10.18632/aging.204051","DOIUrl":"https://doi.org/10.18632/aging.204051","url":null,"abstract":"Background: This study aimed to investigate the relationship of dyslipidemia and interleukin-enhancer binding factor 3 (ILF3) in gastric cancer, and provide insights into the potential application of statins as an agent to prevent and treat gastric cancer. Methods: The expression levels of ILF3 in gastric cancer were examined with publicly available datasets such as TCGA, and western blotting and immunohistochemistry were performed to determine the expression of ILF3 in clinical specimens. The effects of ox-LDL on expression of ILF3 were further verified with western blot analyses. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) pathway analyses were performed to reveal the potential downstream signaling pathway targets of ILF3. The effects of statins and ILF3 on PI3K/AKT/mTOR signaling pathway, cell proliferation, cell cycle, migration and invasion of gastric cancer cells were investigated with Edu assay, flow cytometry and transwell assay. Results: Immunohistochemistry and western blot demonstrated that the positive expression rates of ILF3 in gastric cancer tissues were higher than adjacent mucosa tissues. The ox-LDL promoted the expression of ILF3 in a time-concentration-dependent manner. ILF3 promoted the proliferation, cell cycle, migration and invasion by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibited the proliferation, cell cycle, migration and invasion of gastric cancer by inhibiting the expression of ILF3. Conclusions: These findings demonstrate that ox-LDL promotes ILF3 overexpression to regulate gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibits the expression of ILF3, which might be a new targeted therapy for gastric cancer.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"110 1","pages":"3887 - 3909"},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80679058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Object: Maternal embryonic leucine zipper kinase (MELK) is involved in the development and progression of various cancers. This work investigated the usefulness of MELK in the prediction of hepatocellular carcinoma (HCC) prognosis. Methods: Information on MELK expression was obtained by pan-cancer analysis using The Cancer Genome Atlas (TCGA) database. The TCGA-liver hepatic cancer (TCGA-LIHC), Oncomine datasets, International Cancer Genome Consortium (ICGC) datasets were used to investigate MELK expression in HCC. The prognostic roles of MELK in HCC were assessed by univariate and multivariate survival analyses. The underlying mechanism for noncoding RNAs (ncRNAs) involved in MELK expression was investigated by in silico studies, correlation, methylation, and survival analyses. The relationships between MELK expression and immune cells, immune markers, and checkpoint markers were also analyzed. Results: (1) MELK was identified as an independent predictor of overall survival (OS) in HCC patients (MELK high vs. low expression, HR 2.469; 95% CI 1.217–5.008; p = 0.012) in a multivariate Cox analysis, with a concordance index (C-index) value of 0.727 (95% CI 0.750–0.704). (2) The noncoding RNA miR3142HG and the LINC00265/has-miR-101-3p axis were found to regulate MELK expression in HCC tissue. (3) MELK levels were linked to various immune functions, including tumor infiltration and the expression of immune checkpoints and biomarkers in HCC. Conclusion: MELK may have an oncogenic function in HCC and was found to be up-regulated by ncRNAs and associated with immune cell infiltration and unfavorable prognosis.
目的:母体胚胎亮氨酸拉链激酶(MELK)参与多种癌症的发生发展。本研究探讨MELK在预测肝细胞癌(HCC)预后中的作用。方法:利用美国癌症基因组图谱(TCGA)数据库进行泛癌分析，获取MELK的表达信息。使用tcga -肝肝癌(TCGA-LIHC)、Oncomine数据集、国际癌症基因组联盟(ICGC)数据集研究MELK在HCC中的表达。通过单因素和多因素生存分析评估MELK在HCC中的预后作用。非编码rna (ncRNAs)参与MELK表达的潜在机制通过计算机研究、相关性、甲基化和生存分析进行了研究。分析MELK表达与免疫细胞、免疫标记物和检查点标记物的关系。结果:(1)MELK被确定为HCC患者总生存期(OS)的独立预测因子(MELK高表达vs低表达，HR 2.469;95% ci 1.217-5.008;p = 0.012)，一致性指数(C-index)值为0.727 (95% CI 0.750-0.704)。(2)发现非编码RNA miR3142HG和LINC00265/has-miR-101-3p轴调控HCC组织中MELK的表达。(3) MELK水平与多种免疫功能相关，包括肝癌中肿瘤浸润、免疫检查点和生物标志物的表达。结论:MELK在HCC中可能具有致瘤功能，并被ncrna上调表达，与免疫细胞浸润及不良预后相关。
{"title":"Comprehensive analysis to identify noncoding RNAs mediated upregulation of maternal embryonic leucine zipper kinase (MELK) correlated with poor prognosis in hepatocellular carcinoma","authors":"Ziyi Guo, Zhitu Zhu","doi":"10.18632/aging.204059","DOIUrl":"https://doi.org/10.18632/aging.204059","url":null,"abstract":"Object: Maternal embryonic leucine zipper kinase (MELK) is involved in the development and progression of various cancers. This work investigated the usefulness of MELK in the prediction of hepatocellular carcinoma (HCC) prognosis. Methods: Information on MELK expression was obtained by pan-cancer analysis using The Cancer Genome Atlas (TCGA) database. The TCGA-liver hepatic cancer (TCGA-LIHC), Oncomine datasets, International Cancer Genome Consortium (ICGC) datasets were used to investigate MELK expression in HCC. The prognostic roles of MELK in HCC were assessed by univariate and multivariate survival analyses. The underlying mechanism for noncoding RNAs (ncRNAs) involved in MELK expression was investigated by in silico studies, correlation, methylation, and survival analyses. The relationships between MELK expression and immune cells, immune markers, and checkpoint markers were also analyzed. Results: (1) MELK was identified as an independent predictor of overall survival (OS) in HCC patients (MELK high vs. low expression, HR 2.469; 95% CI 1.217–5.008; p = 0.012) in a multivariate Cox analysis, with a concordance index (C-index) value of 0.727 (95% CI 0.750–0.704). (2) The noncoding RNA miR3142HG and the LINC00265/has-miR-101-3p axis were found to regulate MELK expression in HCC tissue. (3) MELK levels were linked to various immune functions, including tumor infiltration and the expression of immune checkpoints and biomarkers in HCC. Conclusion: MELK may have an oncogenic function in HCC and was found to be up-regulated by ncRNAs and associated with immune cell infiltration and unfavorable prognosis.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"49 1","pages":"3973 - 3988"},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76388707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kejie Huang, Lijuan Xu, M. Jia, Wenmin Liu, Shijie Wang, Jianglong Han, Yanbo Li, Q. Song, Zhenming Fu
Background: We evaluated the relative attribution and interactions of treatment and patient-related risk factors for second primary malignancies (SPMs) in cervical and endometrial cancer survivors. Methods: Stage I–III cervical and endometrial cancer survivors’ data from the Surveillance, Epidemiology, and End Results (SEER) registry between January 1988 and December 2015 were analyzed. The standardized incidence ratio (SIR), excess absolute risk (EAR), and corresponding 95% confidence interval (95% CI) values were calculated. Analyses were classified based on proxies of human papillomavirus (HPV), smoking, hormone, and radiotherapy (RT) status. Additive and multiplicative interactions were assessed. Results: Cervical cancer survivors had a higher risk for developing potentially HPV and smoking-related SPMs, especially in the RT group (SIRHPV = 3.7, 95% CI: 2.9–4.6; SIRsmoking = 3.2, 95% CI: 2.8–3.6). Second vaginal cancer patients had the highest SIR (23.8, 95% CI: 14.9–36.0). There were strong synergistic interactions between RT and the proxy of smoking (Pinteraction < 0.001), accounting for 36% of potentially smoking-related SPMs in cervical cancer survivors. Conclusions: RT, HPV, and smoking promote SPMs in cervical cancer to different extents. The SPM burden in cervical cancer survivors could be mostly attributed to smoking and RT and their interactions.
{"title":"Second primary malignancies in cervical cancer and endometrial cancer survivors: a population-based analysis","authors":"Kejie Huang, Lijuan Xu, M. Jia, Wenmin Liu, Shijie Wang, Jianglong Han, Yanbo Li, Q. Song, Zhenming Fu","doi":"10.18632/aging.204047","DOIUrl":"https://doi.org/10.18632/aging.204047","url":null,"abstract":"Background: We evaluated the relative attribution and interactions of treatment and patient-related risk factors for second primary malignancies (SPMs) in cervical and endometrial cancer survivors. Methods: Stage I–III cervical and endometrial cancer survivors’ data from the Surveillance, Epidemiology, and End Results (SEER) registry between January 1988 and December 2015 were analyzed. The standardized incidence ratio (SIR), excess absolute risk (EAR), and corresponding 95% confidence interval (95% CI) values were calculated. Analyses were classified based on proxies of human papillomavirus (HPV), smoking, hormone, and radiotherapy (RT) status. Additive and multiplicative interactions were assessed. Results: Cervical cancer survivors had a higher risk for developing potentially HPV and smoking-related SPMs, especially in the RT group (SIRHPV = 3.7, 95% CI: 2.9–4.6; SIRsmoking = 3.2, 95% CI: 2.8–3.6). Second vaginal cancer patients had the highest SIR (23.8, 95% CI: 14.9–36.0). There were strong synergistic interactions between RT and the proxy of smoking (Pinteraction < 0.001), accounting for 36% of potentially smoking-related SPMs in cervical cancer survivors. Conclusions: RT, HPV, and smoking promote SPMs in cervical cancer to different extents. The SPM burden in cervical cancer survivors could be mostly attributed to smoking and RT and their interactions.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"52 1","pages":"3836 - 3855"},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81436606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lung cancer is one of the most common malignancies with a high mortality rate worldwide. POSTN has been shown to be strongly correlated with the poor prognosis of lung cancer patients. However, the function and mechanism of action of POSTN in lung cancer remain unclear. Here, we carried out a pan-cancer analysis to assess the clinical prognostic value of POSTN based on the TCGA, TIMER, Oncomine, Kaplan-Meier, and UALCAN databases. We found that upregulated POSTN can be a promising biomarker to predict the prognosis of patients with lung cancer. High levels of POSTN correlated with immune cell infiltration in lung cancer, especially lung squamous cell carcinoma (LUSC), which was further confirmed based on the results from the TISIDB database. Moreover, the expression analysis, correlation analysis, and survival analysis revealed that POSTN-targeted miRNAs, downregulation of has-miR-144-3p and has-miR-30e-3p, were significantly linked to poor prognosis in patients with LUSC. Taken together, we identified that POSTN can act as a novel biomarker for determining the prognosis related to immune infiltration in patients with LUSC and deserves further research.
{"title":"miRNAs-mediated overexpression of Periostin is correlated with poor prognosis and immune infiltration in lung squamous cell carcinoma","authors":"X. Bai, Hui Chen, B. Oliver","doi":"10.18632/aging.204056","DOIUrl":"https://doi.org/10.18632/aging.204056","url":null,"abstract":"Lung cancer is one of the most common malignancies with a high mortality rate worldwide. POSTN has been shown to be strongly correlated with the poor prognosis of lung cancer patients. However, the function and mechanism of action of POSTN in lung cancer remain unclear. Here, we carried out a pan-cancer analysis to assess the clinical prognostic value of POSTN based on the TCGA, TIMER, Oncomine, Kaplan-Meier, and UALCAN databases. We found that upregulated POSTN can be a promising biomarker to predict the prognosis of patients with lung cancer. High levels of POSTN correlated with immune cell infiltration in lung cancer, especially lung squamous cell carcinoma (LUSC), which was further confirmed based on the results from the TISIDB database. Moreover, the expression analysis, correlation analysis, and survival analysis revealed that POSTN-targeted miRNAs, downregulation of has-miR-144-3p and has-miR-30e-3p, were significantly linked to poor prognosis in patients with LUSC. Taken together, we identified that POSTN can act as a novel biomarker for determining the prognosis related to immune infiltration in patients with LUSC and deserves further research.","PeriodicalId":7669,"journal":{"name":"Aging (Albany NY)","volume":"67 1","pages":"3757 - 3781"},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72869734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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