Oncogenesis最新文献

{"title":"Kinesin family member 18B activates mTORC1 signaling via actin gamma 1 to promote the recurrence of human hepatocellular carcinoma.","authors":"Qian Li, Mengqing Sun, Yao Meng, Mengqing Feng, Menglan Wang, Cunjie Chang, Heng Dong, Fangtian Bu, Chao Xu, Jing Liu, Qi Ling, Yiting Qiao, Jianxiang Chen","doi":"10.1038/s41389-023-00499-7","DOIUrl":"10.1038/s41389-023-00499-7","url":null,"abstract":"<p><p>The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"54"},"PeriodicalIF":6.2,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92155922","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}

{"title":"Coordinate transcriptional regulation of ErbB2/3 by C-terminal binding protein 2 signals sensitivity to ErbB2 inhibition in pancreatic adenocarcinoma.","authors":"Kranthi Kumar Chougoni, Haemin Park, Priyadarshan K Damle, Travis Mason, Bo Cheng, Martin M Dcona, Barbara Szomju, Mikhail G Dozmorov, Michael O Idowu, Steven R Grossman","doi":"10.1038/s41389-023-00498-8","DOIUrl":"10.1038/s41389-023-00498-8","url":null,"abstract":"<p><p>There is a critical need to identify new therapeutic vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). Transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 are highly overexpressed in human PDAC, and CRISPR-based homozygous deletion of Ctbp2 in a mouse PDAC cell line (CKP) dramatically decreased tumor growth, reduced metastasis, and prolonged survival in orthotopic mouse allografts. Transcriptomic profiling of tumors derived from CKP vs. Ctbp2-deleted CKP cells (CKP/KO) revealed significant downregulation of the EGFR-superfamily receptor Erbb3, the heterodimeric signaling partner for both EGFR and ErbB2. Compared with CKP cells, CKP/KO cells also demonstrated reduced Erbb2 expression and did not activate downstream Akt signaling after stimulation of Erbb3 by its ligand neuregulin-1. ErbB3 expression in human PDAC cell lines was similarly dependent on CtBP2 and depletion of ErbB3 in a human PDAC cell line severely attenuated growth, demonstrating the critical role of ErbB3 signaling in maintaining PDAC cell growth. Sensitivity to the ErbB2-targeted tyrosine kinase inhibitor lapatinib, but not the EGFR-targeted agent erlotinib, varied in proportion to the level of ErbB3 expression in mouse and human PDAC cells, suggesting that an ErBb2 inhibitor can effectively leverage CtBP2-driven transcriptional activation of physiologic ErbB2/3 expression and signaling in PDAC cells for therapeutic benefit.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"53"},"PeriodicalIF":6.2,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10638350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72210277","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}

{"title":"Correction: PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma.","authors":"Meng-Yao Wang, Bin Qi, Fang Wang, Zhi-Rui Lin, Ming-Yi Li, Wen-Jing Yin, Yan-Yi Zhu, Lu He, Yi Yu, Fang Yang, Jin-Quan Liu, Dong-Ping Chen","doi":"10.1038/s41389-022-00399-2","DOIUrl":"10.1038/s41389-022-00399-2","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"52"},"PeriodicalIF":6.2,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71484538","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}

{"title":"Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance.","authors":"Gang Yan, Meiou Dai, Sophie Poulet, Ni Wang, Julien Boudreault, Girija Daliah, Suhad Ali, Jean-Jacques Lebrun","doi":"10.1038/s41389-023-00497-9","DOIUrl":"10.1038/s41389-023-00497-9","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"51"},"PeriodicalIF":6.2,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71484491","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}

{"title":"Fibroblasts in metastatic lymph nodes confer cisplatin resistance to ESCC tumor cells via PI16.","authors":"Lily Liang,&nbsp;Xu Zhang,&nbsp;Xiaodong Su,&nbsp;Tingting Zeng,&nbsp;Daqin Suo,&nbsp;Jingping Yun,&nbsp;Xin Wang,&nbsp;Xin-Yuan Guan,&nbsp;Yan Li","doi":"10.1038/s41389-023-00495-x","DOIUrl":"10.1038/s41389-023-00495-x","url":null,"abstract":"<p><p>Although many studies have compared tumor fibroblasts (T-Fbs) and nontumor fibroblasts (N-Fbs), less is understood about the stromal contribution of metastatic lymph node fibroblasts (LN-Fbs) to the evolving microenvironment. Here, we explored the characteristics of LN-Fbs in esophageal squamous cell carcinoma (ESCC) and the interactions between fibroblasts and ESCC tumor cells in metastatic lymph nodes. Fibroblasts were isolated from tumor, nontumor and metastatic lymph node tissues from different patients with ESCC. Transcriptome sequencing was performed on the fibroblasts. Tumor growth and drug-resistance assays were carried out, and characteristics of T-Fbs, N-Fbs and LN-Fbs were determined. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assay the culture medium of fibroblasts. The results demonstrated that fibroblasts derived from different tissues had different characteristics. Coculture with LN-Fbs conditioned medium inhibited ESCC tumor cell growth and induced chemoresistance in ESCC cells. LN-Fbs induced chemoresistance to cisplatin in ESCC cells by secreting PI16. Coculture with LN-Fbs conditioned medium decreased cisplatin-induced apoptosis in ESCC cells by regulating the p38 and JNK cell signaling pathways. Survival analyses showed that patients with high PI16 expression in Fbs of lymph nodes exhibited worse overall survival. We also examined PI16 expression in interstitial tissues in ESCC tumor samples of patients receiving platinum-based therapy postsurgery and found that high PI16 expression in tumor interstitial tissues was an independent prognostic factor for ESCC patients. In addition, an in vivo assay demonstrated that PI16 knockdown increased the sensitivity of ESCC cells to cisplatin. Our results suggest that fibroblasts in metastatic lymph nodes decrease apoptosis of ESCC cells via PI16, thereby providing a cisplatin-resistance niche and supporting ESCC tumor cells to survive in metastatic lymph nodes. PI16 is also a potential target for effectively blocking the chemoresistance niche signaling circuit in response to cisplatin.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"50"},"PeriodicalIF":6.2,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10620422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425621","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}

{"title":"Decreased B4GALT1 promotes hepatocellular carcinoma cell invasiveness by regulating the laminin-integrin pathway.","authors":"Po-Da Chen,&nbsp;Ying-Yu Liao,&nbsp;Yu-Chia Cheng,&nbsp;Hsin-Yi Wu,&nbsp;Yao-Ming Wu,&nbsp;Min-Chuan Huang","doi":"10.1038/s41389-023-00494-y","DOIUrl":"https://doi.org/10.1038/s41389-023-00494-y","url":null,"abstract":"<p><p>Beta1,4-galactosyltransferases (B4GALTs) play a crucial role in several diseases, including cancer. B4GALT1 is highly expressed in the liver, and patients with mutations in B4GALT1 exhibit hepatopathy. However, the role of B4GALT1 in liver cancer remains unclear. Here, we found that B4GALT1 was significantly downregulated in hepatocellular carcinoma (HCC) tissue compared with the adjacent liver tissue, and low B4GALT1 expression was associated with vascular invasion and poor overall survival in patients with HCC. Additionally, silencing or loss of B4GALT1 enhanced HCC cell migration and invasion in vitro and promoted lung metastasis of HCC in NOD/SCID mice. Moreover, B4GALT1 knockdown or knockout increased cell adhesion to laminin, whereas B4GALT1 overexpression decreased the adhesion. Through a mass spectrometry-based approach and Griffonia simplicifolia lectin II (GSL-II) pull-down assays, we identified integrins α6 and β1 as the main protein substrates of B4GALT1 and their N-glycans were modified by B4GALT1. Further, the increased cell migration and invasion induced by B4GALT1 knockdown or knockout were significantly reversed using a blocking antibody against integrin α6 or integrin β1. These results suggest that B4GALT1 downregulation alters N-glycosylation and enhances the laminin-binding activity of integrin α6 and integrin β1 to promote invasiveness of HCC cells. Our findings provide novel insights into the role of B4GALT1 in HCC metastasis and highlight targeting the laminin-integrin axis as a potential therapeutic strategy for HCC with low B4GALT1 expression.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"49"},"PeriodicalIF":6.2,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425620","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}

{"title":"Molecular mechanisms in colitis-associated colorectal cancer.","authors":"Royce W Zhou, Noam Harpaz, Steven H Itzkowitz, Ramon E Parsons","doi":"10.1038/s41389-023-00492-0","DOIUrl":"10.1038/s41389-023-00492-0","url":null,"abstract":"<p><p>Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the \"field cancerization\" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells. In contrast, the \"Big Bang\" model posits that tumorigenic clones with multiple driver gene mutations emerge spontaneously. The details of CAC tumorigenesis-and how they differ from sCRC-are not yet fully understood. In this Review, we discuss recent genetic, epigenetic, and environmental findings related to CAC pathogenesis in the past five years, with a focus on unbiased, high-resolution genetic profiling of non-dysplastic field cancerization in the context of inflammatory bowel disease (IBD).</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"48"},"PeriodicalIF":5.9,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230386","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}

{"title":"WDR4 promotes the progression and lymphatic metastasis of bladder cancer via transcriptional down-regulation of ARRB2.","authors":"Guoli Wang, Xin He, Huiqi Dai, Lingyi Lin, Wenmin Cao, Yao Fu, Wenli Diao, Meng Ding, Qing Zhang, Wei Chen, Hongqian Guo","doi":"10.1038/s41389-023-00493-z","DOIUrl":"10.1038/s41389-023-00493-z","url":null,"abstract":"<p><p>Lymph node (LN) metastasis is one of the key prognostic factors in bladder cancer, but its underlying mechanisms remain unclear. Here, we found that elevated expression of WD repeat domain 4 (WDR4) in bladder cancer correlated with worse prognosis. WDR4 can promote the LN metastasis and proliferation of bladder cancer cells. Mechanistic studies showed that WDR4 can promote the nuclear localization of DEAD-box helicase 20 (DDX20) and act as an adaptor to bind DDX20 and Early growth response 1 (Egr1), thereby inhibiting Egr1-promoted transcriptional expression of arrestin beta 2 (ARRB2) and ultimately contributing to the progression of bladder cancer. Immunohistochemical analysis confirmed that WDR4 expression is also an independent predictor of LN metastasis in bladder cancer. Our results reveal a novel mechanism of LN metastasis and progression in bladder cancer and identify WDR4 as a potential therapeutic target for metastatic bladder cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"47"},"PeriodicalIF":6.2,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41109846","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}

{"title":"AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.","authors":"Sanxing Guo, Fengying Li, Yixuan Liang, Yufei Zheng, Yingyi Mo, Deyao Zhao, Zhixiong Jiang, Mengmeng Cui, Lixia Qi, Jiaxing Chen, Lixin Wan, Guoyong Chen, Sidong Wei, Qi Yang, Junqi Liu","doi":"10.1038/s41389-023-00491-1","DOIUrl":"10.1038/s41389-023-00491-1","url":null,"abstract":"<p><p>AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD⁺. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"46"},"PeriodicalIF":6.2,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41125830","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}

{"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}