Carcinogenesis最新文献

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The interplay of DNA damage and repair, gene expression, and mutagenesis in mammalian cells during oxidative stress. 氧化应激过程中哺乳动物细胞中 DNA 损伤与修复、基因表达和诱变的相互作用。
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae046
Ahmad Besaratinia, Andrew W Caliri, Stella Tommasi
{"title":"The interplay of DNA damage and repair, gene expression, and mutagenesis in mammalian cells during oxidative stress.","authors":"Ahmad Besaratinia, Andrew W Caliri, Stella Tommasi","doi":"10.1093/carcin/bgae046","DOIUrl":"10.1093/carcin/bgae046","url":null,"abstract":"<p><p>We investigated the interplay among oxidative DNA damage and repair, expression of genes encoding major base excision repair (BER) enzymes and bypass DNA polymerases, and mutagenesis in mammalian cells. Primary mouse embryonic fibroblasts were challenged with oxidative stress induced by methylene blue plus visible light, and formation and repair of DNA damage, changes in gene expression, and mutagenesis were determined at increasing intervals posttreatment (0-192 hours). Significant formation of oxidative DNA damage together with upregulation of Ogg1, Polβ, and Polκ, and no changes in Mutyh and Nudt1 expression were found in treated cells. There was a distinct interconnection between Ogg1 and Polβ expression and DNA damage formation and repair whereby changes in expression of these two genes were proportionate to the levels of oxidative DNA damage, once a 3-plus hour lag time passed (P < .05). Equally notable was the matching pattern of Polκ expression and kinetics of oxidative DNA damage and repair (P < .05). The DNA damage and gene expression data were remarkably consistent with mutagenicity data in the treated cells; the induced mutation spectrum is indicative of erroneous bypass of oxidized DNA bases and incorporation of oxidized deoxynucleoside triphosphates during replication of the genomic DNA. Our findings support follow-up functional studies to elucidate how oxidation of DNA bases and the nucleotide pool, overexpression of Polκ, delayed upregulation of Ogg1 and Polβ, and inadequate expression of Nudt1 and Mutyh collectively affect mutagenesis consequent to oxidative stress.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"868-879"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Editorial: special issue on the latest advances and challenges in pancreas cancer research in memory of S. Perwez Hussain. 编辑:纪念 S. Perwez Hussain 的胰腺癌研究最新进展与挑战特刊。
IF 2.9 3区 医学
Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae069
Christine Alewine, Curtis C Harris, Anirban Maitra, Sharon R Pine, David Tuveson
{"title":"Editorial: special issue on the latest advances and challenges in pancreas cancer research in memory of S. Perwez Hussain.","authors":"Christine Alewine, Curtis C Harris, Anirban Maitra, Sharon R Pine, David Tuveson","doi":"10.1093/carcin/bgae069","DOIUrl":"10.1093/carcin/bgae069","url":null,"abstract":"","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"45 11","pages":"799-800"},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The evolving role for surgery in pancreatic cancer. 外科手术在胰腺癌中不断演变的角色。
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae062
David Tuveson, Peter Allen
{"title":"The evolving role for surgery in pancreatic cancer.","authors":"David Tuveson, Peter Allen","doi":"10.1093/carcin/bgae062","DOIUrl":"10.1093/carcin/bgae062","url":null,"abstract":"","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"823-825"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CAFomics: convergence to translation for precision stroma approaches. CAFomics:精准基质方法的转化。
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae063
Ian C McCabe, Xianlu L Peng, Joseph F Kearney, Jen Jen Yeh
{"title":"CAFomics: convergence to translation for precision stroma approaches.","authors":"Ian C McCabe, Xianlu L Peng, Joseph F Kearney, Jen Jen Yeh","doi":"10.1093/carcin/bgae063","DOIUrl":"10.1093/carcin/bgae063","url":null,"abstract":"<p><p>A noticeable characteristic of pancreatic ductal adenocarcinoma (PDAC) tumors is a dense tumor microenvironment with abundant and dense, desmoplastic stroma woven tightly with both cellular and matrix components. The high stromal density is associated with higher intratumor pressures which, until the last decade, was largely assumed to be tumor protective, confirmed by early studies demonstrating that altering the stroma was effective in genetically engineered models of PDAC. However, clinical trials using these approaches have been disappointing. There is increasing recognition that stroma heterogeneity is much greater than initially thought with an explosion of investigation into cancer-associated fibroblast (CAF) subpopulations led by experimental and single-cell transcriptomic studies. This review summarizes and attempts to harmonize the current transcriptomic data of CAF subpopulations. Understanding the heterogeneity of CAFs, the matrix, and other tumor microenvironment features will be critical to developing effective therapeutic approaches. Identifying model systems that best recapitulate the clinical behavior and treatment response of human PDAC will be important. Examining subpopulations as defined by clinical outcome will remain a critical step in defining clinically impactful CAF subtypes in larger clinical cohorts. The future of precision oncology in PDAC will depend on the integration of precision tumor epithelial and precision stroma approaches.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"817-822"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer. BRAF V600E 诱导的独特 DNA 损伤反应决定了 p53 激活对 TP53 野生型结直肠癌的治疗潜力。
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae040
Shinji Tokuyama, Hisakazu Kato, Hidekazu Takahashi, Kyoko Ueda, Asami Arita, Ryuta Ueda, Hiroto Seto, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Norikatsu Miyoshi, Mamoru Uemura, Ken Matsuoka, Osamu Tsukamoto, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi, Seiji Takashima
{"title":"BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.","authors":"Shinji Tokuyama, Hisakazu Kato, Hidekazu Takahashi, Kyoko Ueda, Asami Arita, Ryuta Ueda, Hiroto Seto, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Norikatsu Miyoshi, Mamoru Uemura, Ken Matsuoka, Osamu Tsukamoto, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi, Seiji Takashima","doi":"10.1093/carcin/bgae040","DOIUrl":"10.1093/carcin/bgae040","url":null,"abstract":"<p><p>BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in the case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"857-867"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Colorectal cancer cells with high metastatic potential drive metastasis by transmitting exosomal miR-20a-3p through modulating NF1/MAPK pathway. 具有高转移潜能的结直肠癌细胞通过调节 NF1/MAPK 通路传递外泌体 miR-20a-3p 推动转移。
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae036
Yahang Liang, Junyu Li, Tao Li, Mingming Li, Hualin Liao, Yang Liu, Yao Yao, Lingling Yang, Xiong Lei
{"title":"Colorectal cancer cells with high metastatic potential drive metastasis by transmitting exosomal miR-20a-3p through modulating NF1/MAPK pathway.","authors":"Yahang Liang, Junyu Li, Tao Li, Mingming Li, Hualin Liao, Yang Liu, Yao Yao, Lingling Yang, Xiong Lei","doi":"10.1093/carcin/bgae036","DOIUrl":"10.1093/carcin/bgae036","url":null,"abstract":"<p><p>Cancer cells exhibit heterogeneous metastatic potential, and high metastatic (HM) subclones can enhance the metastatic potential of low metastatic subclones by transmitting some factors. Exosomal miRNAs play a pivotal role in the crosstalk of heterogeneous metastatic subclones. This study discovered that miR-20a-3p was upregulated in colorectal adenocarcinoma (CRA), correlated with metastasis, and potentially served as a prognostic indicator for CRA. miR-20a-3p could promote the proliferation, migration, and invasion of CRA cells. Interestingly, HM CRA cells could promote malignant phenotypes of low metastatic CRA cells by transmitting exosomal miR-20a-3p. Mechanically, miR-20a-3p could inhibit neurofibromin 1(NF1), thereby activate the rat sarcoma viral oncogene (RAS)-mediated mitogen-activated protein kinases (MAPK) signaling pathway to drive the metastasis of CRA. In summary, our study provided evidence that colorectal cancer cells with HM potential drive metastasis by transmitting exosomal miR-20a-3p through modulating the NF1/MAPK pathway.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"773-785"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer. 脱氢阿糖胞苷胺通过影响胃癌核苷酸代谢发挥抗肿瘤作用
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae037
Jingsong Ma, Jiabao Zhao, Zhengxin Wu, Jinshui Tan, Meijuan Xu, Wenjie Ye, Mengya Zhong, Yubo Xiong, Guangchao Pan, Huiwen Zhou, Shengyi Zhou, Xuehui Hong
{"title":"Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.","authors":"Jingsong Ma, Jiabao Zhao, Zhengxin Wu, Jinshui Tan, Meijuan Xu, Wenjie Ye, Mengya Zhong, Yubo Xiong, Guangchao Pan, Huiwen Zhou, Shengyi Zhou, Xuehui Hong","doi":"10.1093/carcin/bgae037","DOIUrl":"10.1093/carcin/bgae037","url":null,"abstract":"<p><p>Nucleotide metabolism is the ultimate and most critical link in the self-replication process of tumors, including gastric cancer (GC). However, in clinical treatment, classic antitumor drugs such as 5-fluorouracil (5-FU) are mostly metabolic analogs of purines or pyrimidines, which lack specificity for tumor cells and therefore have significant side effects. It is unclear whether there are other drugs that can target nucleotide metabolism, except for nucleic acid analogs. Here, we found that a natural compound, dehydroabietylamine (DHAA), significantly reduced the viability and proliferation of GC cells and organoids. DHAA disrupts the purine and pyrimidine metabolism of GC cells, causing DNA damage and further inducing apoptosis. DHAA treatment decreased transcription and protein levels of key enzymes involved in the nucleotide metabolism pathway, with significant reductions in the expression of pyrimidine metabolism key enzymes CAD, DHODH, and purine metabolism key enzymes PAICS. We also found that DHAA directly binds to and reduces the expression of Forkhead box K2 (FOXK2), a common transcription factor for these metabolic enzymes. Ultimately, DHAA was shown to delay tumorigenesis in K19-Wnt1/C2mE transgenic mice model and reduce levels of CAD, DHODH, and PAICS in vivo. We demonstrate that DHAA exerts an anticancer effect on GC by targeting transcription factor FOXK2, reducing transcription of key genes for nucleotide metabolism and impairing nucleotide biosynthesis, thus DHAA is a promising candidate for GC therapy.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"759-772"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Allura Red AC is a xenobiotic. Is it also a carcinogen? Allura Red AC 是一种异生物。它也是一种致癌物质吗?
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae057
Lorne J Hofseth, James R Hebert, Elizabeth Angela Murphy, Erica Trauner, Athul Vikas, Quinn Harris, Alexander A Chumanevich
{"title":"Allura Red AC is a xenobiotic. Is it also a carcinogen?","authors":"Lorne J Hofseth, James R Hebert, Elizabeth Angela Murphy, Erica Trauner, Athul Vikas, Quinn Harris, Alexander A Chumanevich","doi":"10.1093/carcin/bgae057","DOIUrl":"10.1093/carcin/bgae057","url":null,"abstract":"<p><p>Merriam-Webster and Oxford define a xenobiotic as any substance foreign to living systems. Allura Red AC (a.k.a., E129; FD&C Red No. 40), a synthetic food dye extensively used in manufacturing ultra-processed foods and therefore highly prevalent in our food supply, falls under this category. The surge in synthetic food dye consumption during the 70s and 80s was followed by an epidemic of metabolic diseases and the emergence of early-onset colorectal cancer in the 1990s. This temporal association raises significant concerns, particularly given the widespread inclusion of synthetic food dyes in ultra-processed products, notably those marketed toward children. Given its interactions with key contributors to colorectal carcinogenesis such as inflammatory mediators, the microbiome, and DNA damage, there is growing interest in understanding Allura Red AC's potential impact on colon health as a putative carcinogen. This review discusses the history of Allura Red AC, current research on its effects on the colon and rectum, potential mechanisms underlying its impact on colon health, and provides future considerations. Indeed, although no governing agencies classify Allura Red AC as a carcinogen, its interaction with key guardians of carcinogenesis makes it suspect and worthy of further molecular investigation. The goal of this review is to inspire research into the impact of synthetic food dyes on colon health.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"711-720"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma. CDK12 是转移性骨肉瘤转录周期和 DNA 损伤反应的一个很有前景的治疗靶点。
IF 3.3 3区 医学
Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae051
Zihao Li, Xiaoyang Li, Nicole A Seebacher, Xu Liu, Wence Wu, Shengji Yu, Francis J Hornicek, Changzhi Huang, Zhenfeng Duan
{"title":"CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma.","authors":"Zihao Li, Xiaoyang Li, Nicole A Seebacher, Xu Liu, Wence Wu, Shengji Yu, Francis J Hornicek, Changzhi Huang, Zhenfeng Duan","doi":"10.1093/carcin/bgae051","DOIUrl":"10.1093/carcin/bgae051","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents, and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel therapeutic strategies for the treatment of osteosarcoma remains an important clinical need. Cyclin-dependent kinases (CDKs) have been considered promising molecular targets in cancer therapy. Among these, CDK12 has been shown to play a crucial role in the pathogenesis of malignancies, but its clinical significance and biological mechanisms in osteosarcoma remain unclear. In the present study, we aim to determine the expression and function of CDK12 and evaluate its prognostic and therapeutic value in metastatic osteosarcoma. We found that overexpression of CDK12 was associated with high tumor grade, tumor progression and reduced patient survival. The underlying mechanism revealed that knockdown of CDK12 expression with small interfering RNA or functional inhibition with the CDK12-targeting agent THZ531 effectively exhibited time- and dose-dependent cytotoxicity. Downregulation of CDK12 paused transcription by reducing RNAP II phosphorylation, interfered with DNA damage repair with increased γH2AX, and decreased cell proliferation through the PI3K-AKT pathway. This was accompanied by the promotion of apoptosis, as evidenced by enhanced Bax expression and reduced Bcl-xL expression. Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"786-798"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Intratumoral vitamin D signaling and lethal prostate cancer. 肿瘤内维生素 D 信号传导与致命性前列腺癌
IF 2.9 3区 医学
Carcinogenesis Pub Date : 2024-10-10 DOI: 10.1093/carcin/bgae055
Jane B Vaselkiv, Irene M Shui, Sydney T Grob, Caroline I Ericsson, Isabel Giovannucci, Cheng Peng, Stephen P Finn, Lorelei A Mucci, Kathryn L Penney, Konrad H Stopsack
{"title":"Intratumoral vitamin D signaling and lethal prostate cancer.","authors":"Jane B Vaselkiv, Irene M Shui, Sydney T Grob, Caroline I Ericsson, Isabel Giovannucci, Cheng Peng, Stephen P Finn, Lorelei A Mucci, Kathryn L Penney, Konrad H Stopsack","doi":"10.1093/carcin/bgae055","DOIUrl":"10.1093/carcin/bgae055","url":null,"abstract":"<p><p>High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"735-744"},"PeriodicalIF":2.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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