首页 > 最新文献

Oncogenesis最新文献

英文 中文
Discovery of neddylation E2s inhibitors with therapeutic activity. 具有治疗活性的类黄酮化E2s抑制剂的发现。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-09-16 DOI: 10.1038/s41389-023-00490-2
Maa Mamun, Ying Liu, Yin-Ping Geng, Yi-Chao Zheng, Ya Gao, Jian-Gang Sun, Long-Fei Zhao, Li-Juan Zhao, Hong-Min Liu

Neddylation is the writing of monomers or polymers of neural precursor cells expressed developmentally down-regulated 8 (NEDD8) to substrate. For neddylation to occur, three enzymes are required: activators (E1), conjugators (E2), and ligators (E3). However, the central role is played by the ubiquitin-conjugating enzymes E2M (UBE2M) and E2F (UBE2F), which are part of the E2 enzyme family. Recent understanding of the structure and mechanism of these two proteins provides insight into their physiological effects on apoptosis, cell cycle arrest and genome stability. To treat cancer, it is therefore appealing to develop novel inhibitors against UBE2M or UBE2F interactions with either E1 or E3. In this evaluation, we summarized the existing understanding of E2 interaction with E1 and E3 and reviewed the prospective of using neddylation E2 as a pharmacological target for evolving new anti-cancer remedies.

类化修饰是神经前体细胞表达发育下调8 (NEDD8)的单体或聚合物向底物的书写。为了发生类化修饰,需要三种酶:激活剂(E1),共轭剂(E2)和结扎剂(E3)。然而,泛素偶联酶E2M (UBE2M)和E2F (UBE2F)起着核心作用,它们是E2酶家族的一部分。最近对这两种蛋白的结构和机制的了解,有助于深入了解它们在细胞凋亡、细胞周期阻滞和基因组稳定性方面的生理作用。因此,为了治疗癌症,开发新的抑制UBE2M或UBE2F与E1或E3相互作用的抑制剂是很有吸引力的。在这篇评价中,我们总结了E2与E1和E3相互作用的现有认识,并展望了利用类化修饰E2作为开发新的抗癌药物的药理学靶点的前景。
{"title":"Discovery of neddylation E2s inhibitors with therapeutic activity.","authors":"Maa Mamun, Ying Liu, Yin-Ping Geng, Yi-Chao Zheng, Ya Gao, Jian-Gang Sun, Long-Fei Zhao, Li-Juan Zhao, Hong-Min Liu","doi":"10.1038/s41389-023-00490-2","DOIUrl":"10.1038/s41389-023-00490-2","url":null,"abstract":"<p><p>Neddylation is the writing of monomers or polymers of neural precursor cells expressed developmentally down-regulated 8 (NEDD8) to substrate. For neddylation to occur, three enzymes are required: activators (E1), conjugators (E2), and ligators (E3). However, the central role is played by the ubiquitin-conjugating enzymes E2M (UBE2M) and E2F (UBE2F), which are part of the E2 enzyme family. Recent understanding of the structure and mechanism of these two proteins provides insight into their physiological effects on apoptosis, cell cycle arrest and genome stability. To treat cancer, it is therefore appealing to develop novel inhibitors against UBE2M or UBE2F interactions with either E1 or E3. In this evaluation, we summarized the existing understanding of E2 interaction with E1 and E3 and reviewed the prospective of using neddylation E2 as a pharmacological target for evolving new anti-cancer remedies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"45"},"PeriodicalIF":6.2,"publicationDate":"2023-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10505188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10670972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Biological differences underlying sex and gender disparities in bladder cancer: current synopsis and future directions. 膀胱癌中潜在的生理差异和性别差异:现状概述和未来发展方向。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-09-04 DOI: 10.1038/s41389-023-00489-9
Bhavisha Doshi, Sarah R Athans, Anna Woloszynska

Sex and gender disparities in bladder cancer have long been a subject of interest to the cancer research community, wherein men have a 4 times higher incidence rate than women, and female patients often present with higher-grade disease and experience worse outcomes. Despite the known differences in disease incidence and clinical outcomes between male and female bladder cancer patients, clinical management remains the same. In this review, we critically analyze studies that report on the biological differences between men and women and evaluate how these differences contribute to sex and gender disparities in bladder cancer. Distinct characteristics of the male and female immune systems, differences in circulating hormone levels and hormone receptor expression, and different genetic and epigenetic alterations are major biological factors that all likely contribute to disparate incidence rates and outcomes for male and female bladder cancer patients. Future preclinical and clinical studies in this area should employ experimental approaches that account for and consider sex and gender disparities in bladder cancer, thereby facilitating the development of precision medicine for the effective treatment of bladder cancer in all patients.

长期以来,膀胱癌的性别差异一直是癌症研究界感兴趣的课题,其中男性的发病率是女性的4倍,女性患者往往表现为更高级别的疾病,并经历更糟糕的结果。尽管已知男性和女性膀胱癌患者在发病率和临床结果方面存在差异,但临床管理仍然相同。在这篇综述中,我们批判性地分析了报道男性和女性生物学差异的研究,并评估了这些差异如何导致膀胱癌的性别差异。男性和女性免疫系统的不同特征,循环激素水平和激素受体表达的差异,以及不同的遗传和表观遗传改变是主要的生物学因素,这些因素都可能导致男性和女性膀胱癌患者不同的发病率和预后。未来该领域的临床前和临床研究应采用考虑和考虑膀胱癌性别差异的实验方法,从而促进精准医学的发展,有效治疗所有患者的膀胱癌。
{"title":"Biological differences underlying sex and gender disparities in bladder cancer: current synopsis and future directions.","authors":"Bhavisha Doshi, Sarah R Athans, Anna Woloszynska","doi":"10.1038/s41389-023-00489-9","DOIUrl":"10.1038/s41389-023-00489-9","url":null,"abstract":"<p><p>Sex and gender disparities in bladder cancer have long been a subject of interest to the cancer research community, wherein men have a 4 times higher incidence rate than women, and female patients often present with higher-grade disease and experience worse outcomes. Despite the known differences in disease incidence and clinical outcomes between male and female bladder cancer patients, clinical management remains the same. In this review, we critically analyze studies that report on the biological differences between men and women and evaluate how these differences contribute to sex and gender disparities in bladder cancer. Distinct characteristics of the male and female immune systems, differences in circulating hormone levels and hormone receptor expression, and different genetic and epigenetic alterations are major biological factors that all likely contribute to disparate incidence rates and outcomes for male and female bladder cancer patients. Future preclinical and clinical studies in this area should employ experimental approaches that account for and consider sex and gender disparities in bladder cancer, thereby facilitating the development of precision medicine for the effective treatment of bladder cancer in all patients.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"44"},"PeriodicalIF":6.2,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10171203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Correction: Non-enzymatic heparanase enhances gastric tumor proliferation via TFEB-dependent autophagy. 更正:非酶促肝素酶通过tfeb依赖性自噬促进胃肿瘤增殖。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-08-18 DOI: 10.1038/s41389-023-00487-x
Min Yang, Bo Tang, Sumin Wang, Li Tang, Dalin Wen, Israel Vlodavsky, Shi-Ming Yang
{"title":"Correction: Non-enzymatic heparanase enhances gastric tumor proliferation via TFEB-dependent autophagy.","authors":"Min Yang, Bo Tang, Sumin Wang, Li Tang, Dalin Wen, Israel Vlodavsky, Shi-Ming Yang","doi":"10.1038/s41389-023-00487-x","DOIUrl":"10.1038/s41389-023-00487-x","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"43"},"PeriodicalIF":6.2,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10439136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10413444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer. 糖皮质激素受体诱导的非肌肉caldesmon调节去势抵抗性前列腺癌的转移。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-08-12 DOI: 10.1038/s41389-023-00485-z
Verneri Virtanen, Kreetta Paunu, Antti Kukkula, Saana Niva, Ylva Junila, Mervi Toriseva, Terhi Jokilehto, Sari Mäkelä, Riikka Huhtaniemi, Matti Poutanen, Ilkka Paatero, Maria Sundvall

Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.

致死性前列腺癌(PCa)的特点是存在转移和对治疗产生耐药性。转移形成一个多步骤的过程,使动态细胞骨架重塑。肌动蛋白细胞骨架调节基因CALD1编码蛋白caldesmon (CaD)。它的异构体,低分子量CaD (l-CaD),在非肌肉细胞中起作用,支持参与力量产生和机械传感的细丝的功能。包括糖皮质激素受体(GR)在内的几个因素已被确定为不同细胞类型中l-CaD的调节因子,但l-CaD在PCa中的调节尚未明确。前列腺癌通过多种策略对雄激素信号的治疗抑制产生耐药性。已知的策略包括雄激素受体(AR)改变、修饰类固醇合成和绕过AR信号,例如通过GR上调。在这里,我们报道了l-CaD的体外下调可促进上皮表型,并在3D中减少球体生长,这反映在斑马鱼PCa异种移植中转移形成的减少。因此,在PCa患者中,CALD1 mRNA表达与上皮-间质转化(EMT)转录物相关。我们还发现CALD1在多个PCa数据集中与GR高度共表达,并且GR激活在体外上调l-CaD。此外,在PCa异种移植小鼠模型中,在抗雄激素治疗产生耐药性后,GR上调与l-CaD表达增加有关。综上所述,GR调节的l-CaD在形成前列腺癌转移中起作用,当通过GR上调绕过AR信号而获得抗雄激素抗性时,具有临床相关性。
{"title":"Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer.","authors":"Verneri Virtanen, Kreetta Paunu, Antti Kukkula, Saana Niva, Ylva Junila, Mervi Toriseva, Terhi Jokilehto, Sari Mäkelä, Riikka Huhtaniemi, Matti Poutanen, Ilkka Paatero, Maria Sundvall","doi":"10.1038/s41389-023-00485-z","DOIUrl":"10.1038/s41389-023-00485-z","url":null,"abstract":"<p><p>Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"42"},"PeriodicalIF":6.2,"publicationDate":"2023-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9988903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer. SLC26A3/ nherf2 - i - κ b / nf - κ b /p65反馈回路抑制结直肠癌的肿瘤发生和转移
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-08-12 DOI: 10.1038/s41389-023-00488-w
Chunlin Lin, Penghang Lin, Huayan Lin, Hengxin Yao, Songyi Liu, Ruofan He, Hui Chen, Zuhong Teng, Robert M Hoffman, Jianxin Ye, Guangwei Zhu

Colorectal cancer (CRC) is a formidable disease due to the intricate mechanisms that drive its proliferation and metastasis. Despite significant progress in cancer research, the integration of these mechanisms that influence cancer cell behavior remains elusive. Therefore, it is imperative to comprehensively elucidate the underlying mechanisms driving CRC proliferation and metastasis. In this study, we reported a novel role of SLC26A3 in suppressing CRC progression. We found that SLC26A3 expression was downregulated in CRC, which was proportionally correlated with survival. Our in vivo and in vitro experiments demonstrated that up-regulation of SLC26A3 inhibited CRC proliferation and metastasis, while down-regulation of SLC26A3 promoted CRC progression by modulating the expression level of IκB. Furthermore, we identified NHERF2 as a novel interacting protein of SLC26A3 responsible for stabilizing the IκB protein and removing ubiquitination modification. Mechanistically, SLC26A3 augmented the interaction between NHERF2 and IκB, subsequently reducing its degradation. This process inhibited the dissociation of p65 from the IκB/p65/p50 complex and reduced the translocation of p65 from the cytoplasm to the nucleus. Moreover, our investigation revealed that NF-κB/p65 directly bound to the promoter of SLC26A3, leading to a decline in its mRNA expression. Thus, SLC26A3 impeded the nuclear translocation of NF-κB/p65, enhancing the transcription of SLC26A3 and establishing a positive regulatory feedback loop in CRC cells. Collectively, these results suggest that a SLC26A3/NHERF2-IκB/NF-κB/p65 signaling loop suppresses proliferation and metastasis in CRC cells. These findings propose a novel SLC26A3-driven signaling loop that regulates proliferation and metastasis in CRC, providing promising therapeutic interventions and prognostic targets for the management of CRC.

结直肠癌(CRC)是一种可怕的疾病,由于其复杂的机制驱动其增殖和转移。尽管癌症研究取得了重大进展,但影响癌细胞行为的这些机制的整合仍然难以捉摸。因此,全面阐明CRC增殖和转移的潜在机制势在必行。在这项研究中,我们报道了SLC26A3在抑制结直肠癌进展中的新作用。我们发现SLC26A3在结直肠癌中表达下调,与生存率成比例相关。我们的体内和体外实验表明,上调SLC26A3抑制结直肠癌的增殖和转移,下调SLC26A3通过调节i - κ b的表达水平促进结直肠癌的进展。此外,我们发现NHERF2是SLC26A3的一种新的相互作用蛋白,负责稳定IκB蛋白并去除泛素化修饰。在机制上,SLC26A3增强了NHERF2和i - κ b之间的相互作用,随后减少了其降解。这一过程抑制了p65与IκB/p65/p50复合物的分离,减少了p65从细胞质向细胞核的易位。此外,我们的研究发现NF-κB/p65直接结合SLC26A3的启动子,导致其mRNA表达下降。因此,SLC26A3阻碍了NF-κB/p65的核易位,增强了SLC26A3的转录,并在CRC细胞中建立了正调节反馈回路。综上所述,这些结果表明SLC26A3/ nherf2 - i -κB/ NF-κB/p65信号环抑制结直肠癌细胞的增殖和转移。这些发现提出了一种新的slc26a3驱动的信号环,可以调节CRC的增殖和转移,为CRC的治疗提供了有希望的治疗干预措施和预后靶点。
{"title":"SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer.","authors":"Chunlin Lin, Penghang Lin, Huayan Lin, Hengxin Yao, Songyi Liu, Ruofan He, Hui Chen, Zuhong Teng, Robert M Hoffman, Jianxin Ye, Guangwei Zhu","doi":"10.1038/s41389-023-00488-w","DOIUrl":"10.1038/s41389-023-00488-w","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a formidable disease due to the intricate mechanisms that drive its proliferation and metastasis. Despite significant progress in cancer research, the integration of these mechanisms that influence cancer cell behavior remains elusive. Therefore, it is imperative to comprehensively elucidate the underlying mechanisms driving CRC proliferation and metastasis. In this study, we reported a novel role of SLC26A3 in suppressing CRC progression. We found that SLC26A3 expression was downregulated in CRC, which was proportionally correlated with survival. Our in vivo and in vitro experiments demonstrated that up-regulation of SLC26A3 inhibited CRC proliferation and metastasis, while down-regulation of SLC26A3 promoted CRC progression by modulating the expression level of IκB. Furthermore, we identified NHERF2 as a novel interacting protein of SLC26A3 responsible for stabilizing the IκB protein and removing ubiquitination modification. Mechanistically, SLC26A3 augmented the interaction between NHERF2 and IκB, subsequently reducing its degradation. This process inhibited the dissociation of p65 from the IκB/p65/p50 complex and reduced the translocation of p65 from the cytoplasm to the nucleus. Moreover, our investigation revealed that NF-κB/p65 directly bound to the promoter of SLC26A3, leading to a decline in its mRNA expression. Thus, SLC26A3 impeded the nuclear translocation of NF-κB/p65, enhancing the transcription of SLC26A3 and establishing a positive regulatory feedback loop in CRC cells. Collectively, these results suggest that a SLC26A3/NHERF2-IκB/NF-κB/p65 signaling loop suppresses proliferation and metastasis in CRC cells. These findings propose a novel SLC26A3-driven signaling loop that regulates proliferation and metastasis in CRC, providing promising therapeutic interventions and prognostic targets for the management of CRC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"41"},"PeriodicalIF":6.2,"publicationDate":"2023-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10000486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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: 1
Loss of Pkd1 limits susceptibility to colitis and colorectal cancer. Pkd1的缺失限制了对结肠炎和结直肠癌癌症的易感性。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-08-05 DOI: 10.1038/s41389-023-00486-y
Anna S Nikonova, Alexander Y Deneka, Flaviane N Silva, Shabnam Pirestani, Rossella Tricarico, Anna A Kiseleva, Yan Zhou, Emmanuelle Nicolas, Douglas B Flieder, Sergei I Grivennikov, Erica A Golemis

Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1-/-;Apc-/- organoids was reduced relative to Apc-/- organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.

癌症(CRC)是最常见的癌症之一,在美国每年的发病率约为135000,与约50000人的死亡有关。常染色体显性多囊肾病(ADPKD)与使PKD1基因失效的突变有关,其影响率高达千分之一。有趣的是,一些研究表明,PKD1种系突变的个体降低了CRC的发病率,这表明存在遗传修饰功能。使用小鼠模型,我们在此确定Pkd1的缺失大大降低了CRC的发生率和由肿瘤抑制因子Apc的缺失诱导的肿瘤生长。Pkd1-/-的增长;相对于Apc-/-类器官,Apc-/--类器官减少,表明癌症细胞内在活性,尽管Pkd1损失增强了促癌信号通路的活性。值得注意的是,Pkd1缺失增加了结肠屏障功能,其中Pkd1缺乏的动物对DSS诱导的结肠炎具有耐药性,这与claudins的上调有关,claudins降低了通透性,并减少了T细胞浸润。值得注意的是,Pkd1缺失对CRC中的肿瘤抑制因子CFTR的激活更敏感,与ADPKD中的信号传导关系平行。总之,这些数据和其他数据表明,PKD1的种系和体细胞突变可能影响人类CRC和其他涉及结肠的病理的发生率、表现和治疗反应。
{"title":"Loss of Pkd1 limits susceptibility to colitis and colorectal cancer.","authors":"Anna S Nikonova, Alexander Y Deneka, Flaviane N Silva, Shabnam Pirestani, Rossella Tricarico, Anna A Kiseleva, Yan Zhou, Emmanuelle Nicolas, Douglas B Flieder, Sergei I Grivennikov, Erica A Golemis","doi":"10.1038/s41389-023-00486-y","DOIUrl":"10.1038/s41389-023-00486-y","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1<sup>-/-</sup>;Apc<sup>-/-</sup> organoids was reduced relative to Apc<sup>-/-</sup> organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"40"},"PeriodicalIF":6.2,"publicationDate":"2023-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10403611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9946275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Retraction Note: Acetyl-CoA synthetase 3 promotes bladder cancer cell growth under metabolic stress. 备注:乙酰辅酶a合成酶3促进代谢应激下膀胱癌细胞生长。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-07-26 DOI: 10.1038/s41389-023-00484-0
Jianhao Zhang, Hongjian Duan, Zhipeng Feng, Xinwei Han, Chaohui Gu
{"title":"Retraction Note: Acetyl-CoA synthetase 3 promotes bladder cancer cell growth under metabolic stress.","authors":"Jianhao Zhang,&nbsp;Hongjian Duan,&nbsp;Zhipeng Feng,&nbsp;Xinwei Han,&nbsp;Chaohui Gu","doi":"10.1038/s41389-023-00484-0","DOIUrl":"https://doi.org/10.1038/s41389-023-00484-0","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"39"},"PeriodicalIF":6.2,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9886760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Correction: Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming. 校正:将IL-3Rα靶向肿瘤来源的内皮细胞,通过细胞外囊泡重编程使三阴性乳腺癌的转移性扩散减弱。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-07-25 DOI: 10.1038/s41389-023-00483-1
Tatiana Lopatina, Cristina Grange, Claudia Cavallari, Victor Navarro-Tableros, Giusy Lombardo, Arturo Rosso, Massimo Cedrino, Margherita Alba Carlotta Pomatto, Malvina Koni, Francesca Veneziano, Isabella Castellano, Giovanni Camussi, Maria Felice Brizzi
{"title":"Correction: Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming.","authors":"Tatiana Lopatina,&nbsp;Cristina Grange,&nbsp;Claudia Cavallari,&nbsp;Victor Navarro-Tableros,&nbsp;Giusy Lombardo,&nbsp;Arturo Rosso,&nbsp;Massimo Cedrino,&nbsp;Margherita Alba Carlotta Pomatto,&nbsp;Malvina Koni,&nbsp;Francesca Veneziano,&nbsp;Isabella Castellano,&nbsp;Giovanni Camussi,&nbsp;Maria Felice Brizzi","doi":"10.1038/s41389-023-00483-1","DOIUrl":"https://doi.org/10.1038/s41389-023-00483-1","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"38"},"PeriodicalIF":6.2,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9882004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Deep learning identifies a T-cell exhaustion-dependent transcriptional signature for predicting clinical outcomes and response to immune checkpoint blockade. 深度学习识别t细胞耗竭依赖的转录特征,用于预测临床结果和对免疫检查点封锁的反应。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-07-11 DOI: 10.1038/s41389-023-00482-2
Zicheng Zhang, Hongyan Chen, Dongxue Yan, Lu Chen, Jie Sun, Meng Zhou

Immune checkpoint blockade (ICB) therapies have brought unprecedented advances in cancer treatment, but responses are limited to a fraction of patients. Therefore, sustained and substantial efforts are required to advance clinical and translational investigation on managing patients receiving ICB. In this study, we investigated the dynamic changes in molecular profiles of T-cell exhaustion (TEX) during ICB treatment using single-cell and bulk transcriptome analysis, and demonstrated distinct exhaustion molecular profiles associated with ICB response. By applying an ensemble deep-learning computational framework, we identified an ICB-associated transcriptional signature consisting of 16 TEX-related genes, termed ITGs. Incorporating 16 ITGs into a machine-learning model called MLTIP achieved reliable predictive power for clinical ICB response with an average AUC of 0.778, and overall survival (pooled HR = 0.093, 95% CI, 0.031-0.28, P < 0.001) across multiple ICB-treated cohorts. Furthermore, the MLTIP consistently demonstrated superior predictive performance compared to other well-established markers and signatures, with an average increase in AUC of 21.5%. In summary, our results highlight the potential of this TEX-dependent transcriptional signature as a tool for precise patient stratification and personalized immunotherapy, with clinical translation in precision medicine.

免疫检查点阻断(ICB)疗法在癌症治疗方面取得了前所未有的进展,但反应仅限于一小部分患者。因此,需要持续和大量的努力来推进临床和转化研究,以管理接受ICB的患者。在这项研究中,我们利用单细胞和大量转录组分析研究了ICB治疗期间t细胞衰竭(TEX)分子谱的动态变化,并证明了与ICB反应相关的不同的衰竭分子谱。通过应用集成深度学习计算框架,我们确定了由16个texg相关基因组成的icb相关转录特征,称为ITGs。将16个ITGs纳入名为MLTIP的机器学习模型中,获得了临床ICB反应的可靠预测能力,平均AUC为0.778,总生存期(合并HR = 0.093, 95% CI, 0.031-0.28, P
{"title":"Deep learning identifies a T-cell exhaustion-dependent transcriptional signature for predicting clinical outcomes and response to immune checkpoint blockade.","authors":"Zicheng Zhang,&nbsp;Hongyan Chen,&nbsp;Dongxue Yan,&nbsp;Lu Chen,&nbsp;Jie Sun,&nbsp;Meng Zhou","doi":"10.1038/s41389-023-00482-2","DOIUrl":"https://doi.org/10.1038/s41389-023-00482-2","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) therapies have brought unprecedented advances in cancer treatment, but responses are limited to a fraction of patients. Therefore, sustained and substantial efforts are required to advance clinical and translational investigation on managing patients receiving ICB. In this study, we investigated the dynamic changes in molecular profiles of T-cell exhaustion (TEX) during ICB treatment using single-cell and bulk transcriptome analysis, and demonstrated distinct exhaustion molecular profiles associated with ICB response. By applying an ensemble deep-learning computational framework, we identified an ICB-associated transcriptional signature consisting of 16 TEX-related genes, termed ITGs. Incorporating 16 ITGs into a machine-learning model called MLTIP achieved reliable predictive power for clinical ICB response with an average AUC of 0.778, and overall survival (pooled HR = 0.093, 95% CI, 0.031-0.28, P < 0.001) across multiple ICB-treated cohorts. Furthermore, the MLTIP consistently demonstrated superior predictive performance compared to other well-established markers and signatures, with an average increase in AUC of 21.5%. In summary, our results highlight the potential of this TEX-dependent transcriptional signature as a tool for precise patient stratification and personalized immunotherapy, with clinical translation in precision medicine.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"37"},"PeriodicalIF":6.2,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10336094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9815245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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: 1
MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5. MLK4通过creb介导的磷酸烯醇丙酮酸羧激酶激活促进肺腺癌中的葡萄糖代谢,并受KLF5调控。
IF 6.2 2区 医学 Q1 ONCOLOGY Pub Date : 2023-07-05 DOI: 10.1038/s41389-023-00478-y
Alvin Ho-Kwan Cheung, Kit-Yee Wong, Xiaoli Liu, Fenfen Ji, Chris Ho-Lam Hui, Yihan Zhang, Johnny Sheung-Him Kwan, Bonan Chen, Yujuan Dong, Raymond Wai-Ming Lung, Jun Yu, Kwok Wai Lo, Chi Chun Wong, Wei Kang, Ka-Fai To

MLK4, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, has been implicated in cancer progression. However, its role in lung adenocarcinoma has not been characterized. Here, we showed that MLK4 was overexpressed in a significant subset of lung adenocarcinoma, associated with a worse prognosis, and exerted an oncogenic function in vitro and in vivo. Bioinformatics analyses of clinical datasets identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a novel target of MLK4. We validated that MLK4 regulated PCK1 expression at transcriptional level, by phosphorylating the transcription factor CREB, which in turn mediated PCK1 expression. We further demonstrated that PCK1 is an oncogenic factor in lung adenocarcinoma. Given the importance of PCK1 in the regulation of cellular metabolism, we next deciphered the metabolic effects of MLK4. Metabolic and mass spectrometry analyses showed that MLK4 knockdown led to significant reduction of glycolysis and decreased levels of glycolytic pathway metabolites including phosphoenolpyruvate and lactate. Finally, the promoter analysis of MLK4 unravelled a binding site of transcription factor KLF5, which in turn, positively regulated MLK4 expression in lung adenocarcinoma. In summary, we have revealed a KLF5-MLK4-PCK1 signalling pathway involved in lung tumorigenesis and established an unusual link between MAP3K signalling and cancer metabolism.

MLK4是丝裂原活化蛋白激酶激酶(MAP3K)家族的一员,与癌症进展有关。然而,其在肺腺癌中的作用尚未明确。在这里,我们发现MLK4在肺腺癌的一个重要亚群中过表达,与较差的预后相关,并在体外和体内发挥致癌功能。临床数据集的生物信息学分析确定磷酸烯醇丙酮酸羧激酶1 (PCK1)是MLK4的新靶点。我们证实MLK4通过磷酸化转录因子CREB在转录水平上调控PCK1的表达,从而介导PCK1的表达。我们进一步证明PCK1是肺腺癌的致癌因子。鉴于PCK1在调节细胞代谢中的重要性,我们接下来破译了MLK4的代谢作用。代谢和质谱分析表明,MLK4敲低导致糖酵解显著减少,糖酵解途径代谢物(包括磷酸烯醇丙酮酸酯和乳酸酯)水平降低。最后,通过对MLK4的启动子分析,揭示了转录因子KLF5的一个结合位点,进而正调控MLK4在肺腺癌中的表达。总之,我们发现了KLF5-MLK4-PCK1信号通路参与肺肿瘤发生,并在MAP3K信号通路与肿瘤代谢之间建立了不寻常的联系。
{"title":"MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5.","authors":"Alvin Ho-Kwan Cheung,&nbsp;Kit-Yee Wong,&nbsp;Xiaoli Liu,&nbsp;Fenfen Ji,&nbsp;Chris Ho-Lam Hui,&nbsp;Yihan Zhang,&nbsp;Johnny Sheung-Him Kwan,&nbsp;Bonan Chen,&nbsp;Yujuan Dong,&nbsp;Raymond Wai-Ming Lung,&nbsp;Jun Yu,&nbsp;Kwok Wai Lo,&nbsp;Chi Chun Wong,&nbsp;Wei Kang,&nbsp;Ka-Fai To","doi":"10.1038/s41389-023-00478-y","DOIUrl":"https://doi.org/10.1038/s41389-023-00478-y","url":null,"abstract":"<p><p>MLK4, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, has been implicated in cancer progression. However, its role in lung adenocarcinoma has not been characterized. Here, we showed that MLK4 was overexpressed in a significant subset of lung adenocarcinoma, associated with a worse prognosis, and exerted an oncogenic function in vitro and in vivo. Bioinformatics analyses of clinical datasets identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a novel target of MLK4. We validated that MLK4 regulated PCK1 expression at transcriptional level, by phosphorylating the transcription factor CREB, which in turn mediated PCK1 expression. We further demonstrated that PCK1 is an oncogenic factor in lung adenocarcinoma. Given the importance of PCK1 in the regulation of cellular metabolism, we next deciphered the metabolic effects of MLK4. Metabolic and mass spectrometry analyses showed that MLK4 knockdown led to significant reduction of glycolysis and decreased levels of glycolytic pathway metabolites including phosphoenolpyruvate and lactate. Finally, the promoter analysis of MLK4 unravelled a binding site of transcription factor KLF5, which in turn, positively regulated MLK4 expression in lung adenocarcinoma. In summary, we have revealed a KLF5-MLK4-PCK1 signalling pathway involved in lung tumorigenesis and established an unusual link between MAP3K signalling and cancer metabolism.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"35"},"PeriodicalIF":6.2,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
期刊
Oncogenesis
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1