Oncogene最新文献_第10页

tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner tRF-33-P4R8YP9LON4VDP 通过调节 STAT3 信号通路以 AGO2 依赖性方式抑制胃癌进展。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-23 DOI: 10.1038/s41388-024-03062-9

Shuangshuang Zhang, Yeqi Gu, Jiaxin Ge, Yaoyao Xie, Xiuchong Yu, Xinxin Wu, Desen Sun, Xinjun Zhang, Jie Guo, Junming Guo

{"title":"tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner","authors":"Shuangshuang Zhang, Yeqi Gu, Jiaxin Ge, Yaoyao Xie, Xiuchong Yu, Xinxin Wu, Desen Sun, Xinjun Zhang, Jie Guo, Junming Guo","doi":"10.1038/s41388-024-03062-9","DOIUrl":"10.1038/s41388-024-03062-9","url":null,"abstract":"It has been demonstrated that tRNA-derived small RNAs (tsRNAs) perform essential functions in the pathophysiology of cancer. In this study, we focused on the possible mechanisms of tRF-33-P4R8YP9LON4VDP (tRF-33) underlying the development of gastric malignancy. In total, 454 tissue samples with different gastric mucosal lesions were collected. The tRF-33 expression level in different cohorts was determined, and its value for diagnostic efficiency and prognosis evaluation were assessed. Cell proliferation assays, Transwell assay, flow cytometry, and xenotransplantation model were used to evaluate its effect on gastric cancer cells. The molecular mechanism was verified by fluorescence in situ hybridization, dual luciferase assay, Western blot, and RNA binding protein immunoprecipitation. The results showed that the expression of tRF-33 exhibited a gradual modification from normal control samples to gastritis tissues, early and latent stage of gastric cancer tissues. Consequently, tRF-33 holds significant potential as a predictive and diagnostic biomarker for gastric malignancy. Over-expression of tRF-33 inhibited gastric cancer cell progression and metastatic viability, and induced cell apoptosis. Tumorigenicity in nude mice showed the suppressive characteristics of tRF-33. Mechanistic investigation revealed that tRF-33 exerted silencing on STAT3 mRNA via binding to AGO2. In conclusion, tRF-33 exhibited values in diagnosing gastric cancer and evaluating its prognosis, and suppressed tumor cell viability by inhibiting STAT3 signaling pathway.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression 以 AURKA 为靶点，通过抑制 MYC 的表达，诱导 CREBBP 缺失型 B 细胞恶性肿瘤的合成致死率。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-23 DOI: 10.1038/s41388-024-03065-6

Yichen Sun, Jianfeng Chen, Jing Han Hong, Rong Xiao, Yan Teng, Peili Wang, Peng Deng, Zhaoliang Yu, Jason Yongsheng Chan, Kelila Xin Ye Chai, Jiuping Gao, Yali Wang, Lu Pan, Lizhen Liu, Shini Liu, Bin Tean Teh, Qiang Yu, Soon Thye Lim, Wenyu Li, Banglao Xu, Choon Kiat Ong, Jing Tan

{"title":"Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression","authors":"Yichen Sun, Jianfeng Chen, Jing Han Hong, Rong Xiao, Yan Teng, Peili Wang, Peng Deng, Zhaoliang Yu, Jason Yongsheng Chan, Kelila Xin Ye Chai, Jiuping Gao, Yali Wang, Lu Pan, Lizhen Liu, Shini Liu, Bin Tean Teh, Qiang Yu, Soon Thye Lim, Wenyu Li, Banglao Xu, Choon Kiat Ong, Jing Tan","doi":"10.1038/s41388-024-03065-6","DOIUrl":"10.1038/s41388-024-03065-6","url":null,"abstract":"Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Epstein-Barr virus causes vascular abnormalities in epithelial malignancies through upregulating ANXA3-HIF-1α-VEGF pathway Epstein-Barr 病毒通过上调 ANXA3-HIF-1α-VEGF 通路导致上皮恶性肿瘤的血管异常。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-22 DOI: 10.1038/s41388-024-03061-w

Yuanyuan Chen, Muping Di, Yan Tang, Jingjing Zhao, Qijing Wang, Zhixing Guo, Yongqiang Li, Dijun Ouyang, Jieying Yang, Hao Chen, Yan Wang, Desheng Weng, Qiuzhong Pan, Tong Xiang, Jianchuan Xia

{"title":"Epstein-Barr virus causes vascular abnormalities in epithelial malignancies through upregulating ANXA3-HIF-1α-VEGF pathway","authors":"Yuanyuan Chen, Muping Di, Yan Tang, Jingjing Zhao, Qijing Wang, Zhixing Guo, Yongqiang Li, Dijun Ouyang, Jieying Yang, Hao Chen, Yan Wang, Desheng Weng, Qiuzhong Pan, Tong Xiang, Jianchuan Xia","doi":"10.1038/s41388-024-03061-w","DOIUrl":"10.1038/s41388-024-03061-w","url":null,"abstract":"Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Correction: O-GlcNAcylation of melanophilin enhances radiation resistance in glioblastoma via suppressing TRIM21 mediated ubiquitination 更正：黑素细胞蛋白的 O-GlcNAcylation 通过抑制 TRIM21 介导的泛素化增强了胶质母细胞瘤的抗辐射能力。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-21 DOI: 10.1038/s41388-024-03045-w

Lei Xu, Yangfan Ye, Zeqiang Tao, Tian Wang, Yutian Wei, Wanzhi Cai, Xin Wan, Pengzhan Zhao, Wei Gu, Bin Gu, Liuchao Zhang, Yufei Tian, Ning Liu, Yiming Tu, Jing Ji

引用次数: 0

p52-ZER6/IGF1R axis maintains cancer stem cell population to promote cancer progression by enhancing pro-survival mitophagy p52-ZER6/IGF1R 轴通过增强促生存的有丝分裂来维持癌症干细胞群，从而促进癌症进展。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-21 DOI: 10.1038/s41388-024-03058-5

Wenfang Li, Can Huang, Li Qiu, Yu Tang, Xia Zhang, Lei Zhang, Hezhao Zhao, Makoto Miyagishi, Vivi Kasim, Shourong Wu

{"title":"p52-ZER6/IGF1R axis maintains cancer stem cell population to promote cancer progression by enhancing pro-survival mitophagy","authors":"Wenfang Li, Can Huang, Li Qiu, Yu Tang, Xia Zhang, Lei Zhang, Hezhao Zhao, Makoto Miyagishi, Vivi Kasim, Shourong Wu","doi":"10.1038/s41388-024-03058-5","DOIUrl":"10.1038/s41388-024-03058-5","url":null,"abstract":"Cancer stem cells (CSCs), which are distinct subpopulations of tumor cells, have a substantially higher tumor-initiating capacity and are closely related to poor clinical outcomes. Damage to organelles can trigger CSC pool exhaustion; however, the underlying mechanisms are poorly understood. ZER6 is a zinc-finger protein with two isoforms possessing different amino termini: p52-ZER6 and p71-ZER6. Since their discovery, almost no study reported on their biological and pathological functions. Herein, we found that p52-ZER6 was crucial for CSC population maintenance; p52-ZER6-knocking down almost abolished the tumor initiation capability. Through transcriptomic analyses together with in vitro and in vivo studies, we identified insulin like growth factor 1 receptor (IGF1R) as the transcriptional target of p52-ZER6 that mediated p52-ZER6 regulation of CSC by promoting pro-survival mitophagy. Moreover, this regulation of mitophagy-mediated CSC population maintenance is specific to p52-ZER6, as p71-ZER6 failed to exert the same effect, most possibly due to the presence of the HUB1 domain at its N-terminus. These results provide a new perspective on the regulatory pathway of pro-survival mitophagy in tumor cells and the molecular mechanism underlying p52-ZER6 oncogenic activity, suggesting that targeting p52-ZER6/IGF1R axis to induce CSC pool exhaustion may be a promising anti-tumor therapeutic strategy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03058-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer 针对癌症中伪激酶 PTK7 的治疗策略的最新见解。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-21 DOI: 10.1038/s41388-024-03060-x

Charlotte Dessaux, Laetitia Ganier, Louis Guiraud, Jean-Paul Borg

{"title":"Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer","authors":"Charlotte Dessaux, Laetitia Ganier, Louis Guiraud, Jean-Paul Borg","doi":"10.1038/s41388-024-03060-x","DOIUrl":"10.1038/s41388-024-03060-x","url":null,"abstract":"The generation of drugs counteracting deregulated protein kinases has been a major focus in cancer therapy development. Breakthroughs in this effort have produced many therapeutic agents to the benefit of patients, mostly through the development of chemical or antibody-based drugs targeting active kinases. These strategies are challenged when considering catalytically inactive protein kinases (or pseudokinases), which represent 10% of the human kinome with many of relevance in cancer. Among the so-called pseudotyrosine kinases, the PTK7 receptor tyrosine kinase (RTK) stands as a bona fide target overexpressed in several solid tumors and hematological malignancies and linked to metastasis, poor prognosis, and resistance to treatment. Despite the lack of catalytic activity, PTK7 has signaling capacities through heterodimerization with active RTKs and offers pharmacological targeting opportunities through its inactive kinase domain. Moreover, PTK7-targeting strategies based on antibody-drug conjugates, aptamers, and CAR-T cell-based therapies have demonstrated encouraging results in preclinical and clinical settings. We review the most recent data assigning to PTK7 a prominent role in cancer progression as well as current preclinical and clinical targeting strategies against RTK family pseudokinases including PTK7.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03060-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

AR loss in prostate cancer stroma mediated by NF-κB and p38-MAPK signaling disrupts stromal morphogen production 前列腺癌基质中 AR 的缺失由 NF-κB 和 p38-MAPK 信号介导，会破坏基质形态发生。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-20 DOI: 10.1038/s41388-024-03064-7

Shekha Tahsin, Neha S. Sane, Brent Cernyar, Linan Jiang, Yitshak Zohar, Benjamin R. Lee, Cindy K. Miranti

{"title":"AR loss in prostate cancer stroma mediated by NF-κB and p38-MAPK signaling disrupts stromal morphogen production","authors":"Shekha Tahsin, Neha S. Sane, Brent Cernyar, Linan Jiang, Yitshak Zohar, Benjamin R. Lee, Cindy K. Miranti","doi":"10.1038/s41388-024-03064-7","DOIUrl":"10.1038/s41388-024-03064-7","url":null,"abstract":"Androgen Receptor (AR) activity in prostate stroma is required to maintain prostate homeostasis. This is mediated through androgen-dependent induction and secretion of morphogenic factors that drive epithelial cell differentiation. However, stromal AR expression is lost in aggressive prostate cancer. The mechanisms leading to stromal AR loss and morphogen production are unknown. We identified TGFβ1 and TNFα as tumor-secreted factors capable of suppressing AR mRNA and protein expression in prostate stromal fibroblasts. Pharmacological and RNAi approaches identified NF-κB as the major signaling pathway involved in suppressing AR expression by TNFα. In addition, p38α- and p38δ-MAPK were identified as suppressors of AR expression independent of TNFα. Two regions of the AR promoter were responsible for AR suppression through TNFα. FGF10 and Wnt16 were identified as androgen-induced morphogens, whose expression was lost upon TNFα treatment and enhanced upon p38-MAPK inhibition. Wnt16, through non-canonical Jnk signaling, was required for prostate basal epithelial cell survival. These findings indicate that stromal AR loss is mediated by secreted factors within the TME. We identified TNFα/TGFβ as two possible factors, with TNFα mediating its effects through NF-κB or p38-MAPK to suppress AR mRNA transcription. This leads to loss of androgen-regulated stromal morphogens necessary to maintain normal epithelial homeostasis.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03064-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer 癌症相关成纤维细胞分泌的miR-432-5p靶向CHAC1，抑制前列腺癌的铁变态反应并促进获得性化疗耐药性。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-20 DOI: 10.1038/s41388-024-03057-6

Jun Zhao, Jijie Shen, Liang Mao, Tianli Yang, Jingyu Liu, Sun Hongbin

{"title":"Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer","authors":"Jun Zhao, Jijie Shen, Liang Mao, Tianli Yang, Jingyu Liu, Sun Hongbin","doi":"10.1038/s41388-024-03057-6","DOIUrl":"10.1038/s41388-024-03057-6","url":null,"abstract":"Prostate cancer (PCa) ranks as the sixth most serious male malignant disease globally. While docetaxel (DTX) chemotherapy is the standard treatment for advanced PCa patients with distant metastasis, some individuals exhibit insensitivity or resistance to DTX. Cancer-associated fibroblasts (CAFs) play a pivotal role as stromal cells within the tumor microenvironment, influencing tumor development, progression, and drug resistance through exosomes. Ferroptosis, a novel form of programmed cell death, is characterized by intracellular iron accumulation that triggers lipid peroxidation, ultimately leading to cell demise. To delve into the potential mechanisms of chemotherapy resistance in prostate cancer, our research delved into the impact of CAF-derived exosomes on ferroptosis. Our findings revealed that CAF exosomes hindered the buildup of lipid reactive oxygen species (ROS) in prostate cancer cells induced by erastin, as well as mitigated erastin-induced mitochondrial damage, thereby impeding iron-induced cell death in prostate cancer cells. Furthermore, miR-432-5p was identified to diminish glutathione (GSH) consumption by targeting CHAC1, consequently inhibiting ferroptosis in prostate cancer cells. Our study found that miR-432-5p, originating from cancer-associated fibroblast (CAF) exosomes, suppresses ferroptosis by targeting CHAC1, thereby increasing resistance to docetaxel (DTX) in PCa. This research introduces a novel approach to address resistance to DTX.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor RAF1 促进 KIT 信号转导，是胃肠道间质瘤的潜在治疗靶点。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-17 DOI: 10.1038/s41388-024-03063-8

Liangying Zhang, Shaoting Zhang, Xu Cao, Jun Shi, Sien Zhao, Jinhai Tian, Kun Xiao, Ming Wang, Jing Liu, Chengdong Wang, Liangji Zhou, Yuanyuan Yu, Hui Zhao, Shujing Li, Jianmin Sun

{"title":"RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor","authors":"Liangying Zhang, Shaoting Zhang, Xu Cao, Jun Shi, Sien Zhao, Jinhai Tian, Kun Xiao, Ming Wang, Jing Liu, Chengdong Wang, Liangji Zhou, Yuanyuan Yu, Hui Zhao, Shujing Li, Jianmin Sun","doi":"10.1038/s41388-024-03063-8","DOIUrl":"10.1038/s41388-024-03063-8","url":null,"abstract":"The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

TRIM45 facilitates NASH-progressed HCC by promoting fatty acid synthesis via catalyzing FABP5 ubiquitylation TRIM45 通过催化 FABP5 泛素化促进脂肪酸合成，从而促进 NASH 进展型 HCC。

IF 6.9 1区医学

Oncogene Pub Date : 2024-05-16 DOI: 10.1038/s41388-024-03056-7

Xiaomian Li, Wenzhi He, Xi Chen, Yangwenqing Zhang, Jia Zhang, Fusheng Liu, Jinghua Li, Dongli Zhao, Peng Xia, Weijie Ma, Tiangen Wu, Haitao Wang, Yufeng Yuan

{"title":"TRIM45 facilitates NASH-progressed HCC by promoting fatty acid synthesis via catalyzing FABP5 ubiquitylation","authors":"Xiaomian Li, Wenzhi He, Xi Chen, Yangwenqing Zhang, Jia Zhang, Fusheng Liu, Jinghua Li, Dongli Zhao, Peng Xia, Weijie Ma, Tiangen Wu, Haitao Wang, Yufeng Yuan","doi":"10.1038/s41388-024-03056-7","DOIUrl":"10.1038/s41388-024-03056-7","url":null,"abstract":"Non-alcoholic steatohepatitis (NASH) is rapidly surpassing viral hepatitis as the primary cause of hepatocellular carcinoma (HCC). However, understanding of NASH-progressed HCC remains poor, which might impede HCC diagnosis and therapy. In this study, we aim to identify shared transcriptional changes between NASH and HCC, of which we focused on E3 ligase TRIM45. We found TRIM45 exacerbates HCC cells proliferation and metastasis in vitro and in vivo. Further transcriptome analysis revealed TRIM45 predominantly affects fatty acid metabolism and oleic acid restored impaired proliferation and metastasis of TRIM45-deficient HCC cells. IP-tandem mass spectrum and FABP5 depriving experiment indicated that TRIM45 enhance fatty acid synthesis depending on FABP5 presence. Interestingly, we found TRIM45 directly added K33-type and K63-type poly-ubiquitin chains to FABP5 NLS domain, which ultimately promoted FABP5 nuclear translocation. Nuclear FABP5 interacted with PPARγ to facilitate downstream lipid synthesis gene expression. We observed TRIM45 accelerated NASH-to-HCC transition and exacerbated both NASH and NASH-HCC with the enhanced fatty acid production in vivo. Moreover, high concentration of fatty acid increased TRIM45 expression. The established mechanism was substantiated by gene expression correlation in TCGA-LIHC. Collectively, our research revealed a common lipid reprograming process in NASH and HCC and identified the cyclical amplification of the TRIM45-FABP5-PPARγ-fatty acid axis. This signaling pathway offers potential therapeutic targets for therapeutic intervention in NASH and NASH-progressed HCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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