NAR Cancer最新文献_第7页

Multiple-low-dose therapy: effective killing of high-grade serous ovarian cancer cells with ATR and CHK1 inhibitors. 多重低剂量疗法：利用 ATR 和 CHK1 抑制剂有效杀死高级别浆液性卵巢癌细胞。

NAR Cancer Pub Date : 2022-11-12 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac036

Anya Golder, Louisa Nelson, Anthony Tighe, Bethany Barnes, Camilla Coulson-Gilmer, Robert D Morgan, Joanne C McGrail, Stephen S Taylor

{"title":"Multiple-low-dose therapy: effective killing of high-grade serous ovarian cancer cells with ATR and CHK1 inhibitors.","authors":"Anya Golder, Louisa Nelson, Anthony Tighe, Bethany Barnes, Camilla Coulson-Gilmer, Robert D Morgan, Joanne C McGrail, Stephen S Taylor","doi":"10.1093/narcan/zcac036","DOIUrl":"10.1093/narcan/zcac036","url":null,"abstract":"High-grade serous ovarian cancer (HGSOC) is an aggressive disease that typically develops drug resistance, thus novel biomarker-driven strategies are required. Targeted therapy focuses on synthetic lethality-pioneered by PARP inhibition of BRCA1/2-mutant disease. Subsequently, targeting the DNA replication stress response (RSR) is of clinical interest. However, further mechanistic insight is required for biomarker discovery, requiring sensitive models that closely recapitulate HGSOC. We describe an optimized proliferation assay that we use to screen 16 patient-derived ovarian cancer models (OCMs) for response to RSR inhibitors (CHK1i, WEE1i, ATRi, PARGi). Despite genomic heterogeneity characteristic of HGSOC, measurement of OCM proliferation was reproducible and reflected intrinsic tumour-cell properties. Surprisingly, RSR targeting drugs were not interchangeable, as sensitivity to the four inhibitors was not correlated. Therefore, to overcome RSR redundancy, we screened the OCMs with all two-, three- and four-drug combinations in a multiple-low-dose strategy. We found that low-dose CHK1i-ATRi had a potent anti-proliferative effect on 15 of the 16 OCMs, and was synergistic with potential to minimise treatment resistance and toxicity. Low-dose ATRi-CHK1i induced replication catastrophe followed by mitotic exit and post-mitotic arrest or death. Therefore, this study demonstrates the potential of the living biobank of OCMs as a drug discovery platform for HGSOC.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac036"},"PeriodicalIF":0.0,"publicationDate":"2022-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40687225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation. 前列腺癌的耐药性导致了全球对翻译因素的放松管制和非传统翻译。

NAR Cancer Pub Date : 2022-11-04 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac034

Emeline I J Lelong, Gabriel Khelifi, Pauline Adjibade, France-Hélène Joncas, Valérie Grenier St-Sauveur, Virginie Paquette, Typhaine Gris, Amina Zoubeidi, Etienne Audet-Walsh, Jean-Philippe Lambert, Paul Toren, Rachid Mazroui, Samer M I Hussein

{"title":"Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation.","authors":"Emeline I J Lelong, Gabriel Khelifi, Pauline Adjibade, France-Hélène Joncas, Valérie Grenier St-Sauveur, Virginie Paquette, Typhaine Gris, Amina Zoubeidi, Etienne Audet-Walsh, Jean-Philippe Lambert, Paul Toren, Rachid Mazroui, Samer M I Hussein","doi":"10.1093/narcan/zcac034","DOIUrl":"https://doi.org/10.1093/narcan/zcac034","url":null,"abstract":"Emerging evidence associates translation factors and regulators to tumorigenesis. However, our understanding of translational changes in cancer resistance is still limited. Here, we generated an enzalutamide-resistant prostate cancer (PCa) model, which recapitulated key features of clinical enzalutamide-resistant PCa. Using this model and poly(ribo)some profiling, we investigated global translation changes that occur during acquisition of PCa resistance. We found that enzalutamide-resistant cells exhibit an overall decrease in mRNA translation with a specific deregulation in the abundance of proteins involved in mitochondrial processes and in translational regulation. However, several mRNAs escape this translational downregulation and are nonetheless bound to heavy polysomes in enzalutamide-resistant cells suggesting active translation. Moreover, expressing these corresponding genes in enzalutamide-sensitive cells promotes resistance to enzalutamide treatment. We also found increased association of long non-coding RNAs (lncRNAs) with heavy polysomes in enzalutamide-resistant cells, suggesting that some lncRNAs are actively translated during enzalutamide resistance. Consistent with these findings, expressing the predicted coding sequences of known lncRNAs JPX, CRNDE and LINC00467 in enzalutamide-sensitive cells drove resistance to enzalutamide. Taken together, this suggests that aberrant translation of specific mRNAs and lncRNAs is a strong indicator of PCa enzalutamide resistance, which points towards novel therapeutic avenues that may target enzalutamide-resistant PCa.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac034"},"PeriodicalIF":0.0,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9634437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40672645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress. UBE2T 通过抑制 DNA 复制应激促进乳腺癌肿瘤生长。

NAR Cancer Pub Date : 2022-11-02 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac035

Roshan Dutta, Praveen Guruvaiah, Kiran Kumar Reddi, Suresh Bugide, Dhana Sekhar Reddy Bandi, Yvonne J K Edwards, Kamaljeet Singh, Romi Gupta

{"title":"UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress.","authors":"Roshan Dutta, Praveen Guruvaiah, Kiran Kumar Reddi, Suresh Bugide, Dhana Sekhar Reddy Bandi, Yvonne J K Edwards, Kamaljeet Singh, Romi Gupta","doi":"10.1093/narcan/zcac035","DOIUrl":"10.1093/narcan/zcac035","url":null,"abstract":"Breast cancer is a leading cause of cancer-related deaths among women, and current therapies benefit only a subset of these patients. Here, we show that ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in patient-derived breast cancer samples, and UBE2T overexpression predicts poor prognosis. We demonstrate that the transcription factor AP-2 alpha (TFAP2A) is necessary for the overexpression of UBE2T in breast cancer cells, and UBE2T inhibition suppresses breast cancer tumor growth in cell culture and in mice. RNA sequencing analysis identified interferon alpha-inducible protein 6 (IFI6) as a key downstream mediator of UBE2T function in breast cancer cells. Consistently, UBE2T inhibition downregulated IFI6 expression, promoting DNA replication stress, cell cycle arrest, and apoptosis and suppressing breast cancer cell growth. Breast cancer cells with IFI6 inhibition displayed similar phenotypes as those with UBE2T inhibition, and ectopic IFI6 expression in UBE2T-knockdown breast cancer cells prevented DNA replication stress and apoptosis and partly restored breast cancer cell growth. Furthermore, UBE2T inhibition enhanced the growth-suppressive effects of DNA replication stress inducers. Taken together, our study identifies UBE2T as a facilitator of breast cancer tumor growth and provide a rationale for targeting UBE2T for breast cancer therapies.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":"4 4","pages":"zcac035"},"PeriodicalIF":0.0,"publicationDate":"2022-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10256277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pancancer transcriptomic profiling identifies key PANoptosis markers as therapeutic targets for oncology. 胰腺癌转录组分析确定了作为肿瘤学治疗靶点的关键 PANoptosis 标记。

NAR Cancer Pub Date : 2022-11-01 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac033

Raghvendra Mall, Ratnakar R Bynigeri, Rajendra Karki, R K Subbarao Malireddi, Bhesh Raj Sharma, Thirumala-Devi Kanneganti

{"title":"Pancancer transcriptomic profiling identifies key PANoptosis markers as therapeutic targets for oncology.","authors":"Raghvendra Mall, Ratnakar R Bynigeri, Rajendra Karki, R K Subbarao Malireddi, Bhesh Raj Sharma, Thirumala-Devi Kanneganti","doi":"10.1093/narcan/zcac033","DOIUrl":"10.1093/narcan/zcac033","url":null,"abstract":"Resistance to programmed cell death (PCD) is a hallmark of cancer. While some PCD components are prognostic in cancer, the roles of many molecules can be masked by redundancies and crosstalks between PCD pathways, impeding the development of targeted therapeutics. Recent studies characterizing these redundancies have identified PANoptosis, a unique innate immune-mediated inflammatory PCD pathway that integrates components from other PCD pathways. Here, we designed a systematic computational framework to determine the pancancer clinical significance of PANoptosis and identify targetable biomarkers. We found that high expression of PANoptosis genes was detrimental in low grade glioma (LGG) and kidney renal cell carcinoma (KIRC). ZBP1, ADAR, CASP2, CASP3, CASP4, CASP8 and GSDMD expression consistently had negative effects on prognosis in LGG across multiple survival models, while AIM2, CASP3, CASP4 and TNFRSF10 expression had negative effects for KIRC. Conversely, high expression of PANoptosis genes was beneficial in skin cutaneous melanoma (SKCM), with ZBP1, NLRP1, CASP8 and GSDMD expression consistently having positive prognostic effects. As a therapeutic proof-of-concept, we treated melanoma cells with combination therapy that activates ZBP1 and showed that this treatment induced PANoptosis. Overall, through our systematic framework, we identified and validated key innate immune biomarkers from PANoptosis which can be targeted to improve patient outcomes in cancers.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac033"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9623737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40446188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Translational alterations in pancreatic cancer: a central role for the integrated stress response. 胰腺癌的翻译改变:综合应激反应的中心作用。

NAR Cancer Pub Date : 2022-10-28 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac031

Sauyeun Shin, Jacobo Solorzano, Mehdi Liauzun, Stéphane Pyronnet, Corinne Bousquet, Yvan Martineau

{"title":"Translational alterations in pancreatic cancer: a central role for the integrated stress response.","authors":"Sauyeun Shin, Jacobo Solorzano, Mehdi Liauzun, Stéphane Pyronnet, Corinne Bousquet, Yvan Martineau","doi":"10.1093/narcan/zcac031","DOIUrl":"https://doi.org/10.1093/narcan/zcac031","url":null,"abstract":"mRNA translation is a key mechanism for cancer cell proliferation and stress adaptation. Regulation of this machinery implicates upstream pathways such as PI3K/AKT/mTOR, RAS/MEK/ERK and the integrated stress response (ISR), principally coordinating the translation initiation step. During the last decade, dysregulation of the mRNA translation process in pancreatic cancer has been widely reported, and shown to critically impact on cancer initiation, development and survival. This includes translation dysregulation of mRNAs encoding oncogenes and tumor suppressors. Hence, cancer cells survive a stressful microenvironment through a flexible regulation of translation initiation for rapid adaptation. The ISR pathway has an important role in chemoresistance and shows high potential therapeutic interest. Despite the numerous translational alterations reported in pancreatic cancer, their consequences are greatly underestimated. In this review, we summarize the different translation dysregulations described in pancreatic cancer, which make it invulnerable, as well as the latest drug discoveries bringing a glimmer of hope.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac031"},"PeriodicalIF":0.0,"publicationDate":"2022-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f2/d5/zcac031.PMC9615149.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40441745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

The limits of molecular signatures for pancreatic ductal adenocarcinoma subtyping. 胰腺导管腺癌亚型分型分子特征的局限性。

NAR Cancer Pub Date : 2022-10-17 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac030

Manuela Lautizi, Jan Baumbach, Wilko Weichert, Katja Steiger, Markus List, Nicole Pfarr, Tim Kacprowski

{"title":"The limits of molecular signatures for pancreatic ductal adenocarcinoma subtyping.","authors":"Manuela Lautizi, Jan Baumbach, Wilko Weichert, Katja Steiger, Markus List, Nicole Pfarr, Tim Kacprowski","doi":"10.1093/narcan/zcac030","DOIUrl":"https://doi.org/10.1093/narcan/zcac030","url":null,"abstract":"Molecular signatures have been suggested as biomarkers to classify pancreatic ductal adenocarcinoma (PDAC) into two, three, four or five subtypes. Since the robustness of existing signatures is controversial, we performed a systematic evaluation of four established signatures for PDAC stratification across nine publicly available datasets. Clustering revealed inconsistency of subtypes across independent datasets and in some cases a different number of PDAC subgroups than in the original study, casting doubt on the actual number of existing subtypes. Next, we built sixteen classification models to investigate the ability of the signatures for tumor subtype prediction. The overall classification performance ranged from ∼35% to ∼90% accuracy, suggesting instability of the signatures. Notably, permuted subtypes and random gene sets achieved very similar performance. Cellular decomposition and functional pathway enrichment analysis revealed strong tissue-specificity of the predicted classes. Our study highlights severe limitations and inconsistencies that can be attributed to technical biases in sample preparation and tumor purity, suggesting that PDAC molecular signatures do not generalize across datasets. How stromal heterogeneity and immune compartment interplay in the diverging development of PDAC is still unclear. Therefore, a more mechanistic or a cross-platform multi-omic approach seems necessary to extract more robust and clinically exploitable insights.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac030"},"PeriodicalIF":0.0,"publicationDate":"2022-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40562873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Escape from G1 arrest during acute MEK inhibition drives the acquisition of drug resistance. 在急性 MEK 抑制过程中摆脱 G1 停顿是获得耐药性的驱动因素。

NAR Cancer Pub Date : 2022-10-17 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac032

Prasanna Channathodiyil, Kieron May, Anne Segonds-Pichon, Paul D Smith, Simon J Cook, Jonathan Houseley

{"title":"Escape from G1 arrest during acute MEK inhibition drives the acquisition of drug resistance.","authors":"Prasanna Channathodiyil, Kieron May, Anne Segonds-Pichon, Paul D Smith, Simon J Cook, Jonathan Houseley","doi":"10.1093/narcan/zcac032","DOIUrl":"10.1093/narcan/zcac032","url":null,"abstract":"Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we investigate BRAFV600E amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that BRAF amplifications acquired de novo are the primary cause of resistance. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2; however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation, including TIPIN, PLK2 and PLK3, remain at low abundance. This suggests that DNA replication following escape from G1 arrest in drug is more error prone and provides a potential explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that escape from G1 arrest in drug promotes de novo BRAF amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through de novo gene amplification and can be suppressed by impeding cell cycle entry in drug.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac032"},"PeriodicalIF":0.0,"publicationDate":"2022-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40562874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells. 高通量筛选，以确定化合物，防止或靶端粒损失的人类癌细胞。

NAR Cancer Pub Date : 2022-10-03 eCollection Date: 2022-12-01 DOI: 10.1093/narcan/zcac029

Chris Wilson, John P Murnane

{"title":"High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells.","authors":"Chris Wilson, John P Murnane","doi":"10.1093/narcan/zcac029","DOIUrl":"https://doi.org/10.1093/narcan/zcac029","url":null,"abstract":"Chromosome instability (CIN) is an early step in carcinogenesis that promotes tumor cell progression and resistance to therapy. Using plasmids integrated adjacent to telomeres, we have previously demonstrated that the sensitivity of subtelomeric regions to DNA double-strand breaks (DSBs) contributes to telomere loss and CIN in cancer. A high-throughput screen was created to identify compounds that affect telomere loss due to subtelomeric DSBs introduced by I-SceI endonuclease, as detected by cells expressing green fluorescent protein (GFP). A screen of a library of 1832 biologically-active compounds identified a variety of compounds that increase or decrease the number of GFP-positive cells following activation of I-SceI. A curated screen done in triplicate at various concentrations found that inhibition of classical nonhomologous end joining (C-NHEJ) increased DSB-induced telomere loss, demonstrating that C-NHEJ is functional in subtelomeric regions. Compounds that decreased DSB-induced telomere loss included inhibitors of mTOR, p38 and tankyrase, consistent with our earlier hypothesis that the sensitivity of subtelomeric regions to DSBs is a result of inappropriate resection during repair. Although this assay was also designed to identify compounds that selectively target cells experiencing telomere loss and/or chromosome instability, no compounds of this type were identified in the current screen.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac029"},"PeriodicalIF":0.0,"publicationDate":"2022-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/ff/zcac029.PMC9527662.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33487944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer. PLK3扩增和转移性肿瘤的肿瘤免疫微环境与子宫浆液性癌的辅助治疗结果有关。

NAR Cancer Pub Date : 2022-09-27 eCollection Date: 2022-09-01 DOI: 10.1093/narcan/zcac026

Wendell Jones, David Tait, Chad Livasy, Mahrukh Ganapathi, Ram Ganapathi

{"title":"PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer.","authors":"Wendell Jones, David Tait, Chad Livasy, Mahrukh Ganapathi, Ram Ganapathi","doi":"10.1093/narcan/zcac026","DOIUrl":"https://doi.org/10.1093/narcan/zcac026","url":null,"abstract":"Uterine serous carcinoma (USC), an aggressive variant of endometrial cancer representing approximately 10% of endometrial cancer diagnoses, accounts for ∼39% of endometrial cancer-related deaths. We examined the role of genomic alterations in advanced-stage USC associated with outcome using paired primary-metastatic tumors (n = 29) treated with adjuvant platinum and taxane chemotherapy. Comparative genomic analysis of paired primary-metastatic patient tumors included whole exome sequencing and targeted gene expression. Both PLK3 amplification and the tumor immune microenvironment (TIME) in metastatic tumors were linked to time-to-recurrence (TTR) risk without any such association observed with primary tumors. TP53 loss was significantly more frequent in metastatic tumors of platinum-resistant versus platinum-sensitive patients and was also associated with increased recurrence and mortality risk. Increased levels of chr1 breakpoints in USC metastatic versus primary tumors co-occur with PLK3 amplification. PLK3 and the TIME are potential targets for improving outcomes in USC adjuvant therapy.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac026"},"PeriodicalIF":0.0,"publicationDate":"2022-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d2/76/zcac026.PMC9513840.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40386220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

SFPQ promotes RAS-mutant cancer cell growth by modulating 5'-UTR mediated translational control of CK1α. SFPQ 通过调节 5'-UTR 介导的 CK1α 翻译控制，促进 RAS 突变癌细胞的生长。

NAR Cancer Pub Date : 2022-09-27 eCollection Date: 2022-09-01 DOI: 10.1093/narcan/zcac027

Venetia Jing Tong Kok, Jia Ying Tang, Gracie Wee Ling Eng, Shin Yi Tan, Joseph Tin Foong Chin, Chun Hian Quek, Wei Xuan Lai, Teck Kwang Lim, Qingsong Lin, John Jia En Chua, Jit Kong Cheong

{"title":"SFPQ promotes RAS-mutant cancer cell growth by modulating 5'-UTR mediated translational control of CK1α.","authors":"Venetia Jing Tong Kok, Jia Ying Tang, Gracie Wee Ling Eng, Shin Yi Tan, Joseph Tin Foong Chin, Chun Hian Quek, Wei Xuan Lai, Teck Kwang Lim, Qingsong Lin, John Jia En Chua, Jit Kong Cheong","doi":"10.1093/narcan/zcac027","DOIUrl":"10.1093/narcan/zcac027","url":null,"abstract":"Oncogenic mutations in the RAS family of small GTPases are commonly found in human cancers and they promote tumorigenesis by altering gene expression networks. We previously demonstrated that Casein Kinase 1α (CK1α), a member of the CK1 family of serine/threonine kinases, is post-transcriptionally upregulated by oncogenic RAS signaling. Here, we report that the CK1α mRNA contains an exceptionally long 5'-untranslated region (UTR) harbouring several translational control elements, implicating its involvement in translational regulation. We demonstrate that the CK1α 5'-UTR functions as an IRES element in HCT-116 colon cancer cells to promote cap-independent translation. Using tobramycin-affinity RNA-pulldown assays coupled with identification via mass spectrometry, we identified several CK1α 5'-UTR-binding proteins, including SFPQ. We show that RNA interference targeting SFPQ reduced CK1α protein abundance and partially blocked RAS-mutant colon cancer cell growth. Importantly, transcript and protein levels of SFPQ and other CK1α 5'-UTR-associated RNA-binding proteins (RBPs) are found to be elevated in early stages of RAS-mutant cancers, including colorectal and lung adenocarcinoma. Taken together, our study uncovers a previously unappreciated role of RBPs in promoting RAS-mutant cancer cell growth and their potential to serve as promising biomarkers as well as tractable therapeutic targets in cancers driven by oncogenic RAS.","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":" ","pages":"zcac027"},"PeriodicalIF":0.0,"publicationDate":"2022-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2e/b0/zcac027.PMC9513841.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40385657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0