Molecular Cancer Research最新文献

{"title":"PKCδ Regulates DNA Damage and Cell Death through a SIRT6/Nrf2-dependent Antioxidant Response.","authors":"Trisiani Affandi, Angela M Ohm, Jordan T Speidel, M Cecilia Caino, Dillon P Boulton, Mary E Reyland","doi":"10.1158/1541-7786.MCR-24-0805","DOIUrl":"10.1158/1541-7786.MCR-24-0805","url":null,"abstract":"<p><p>Protein kinase C δ (PKCδ) regulates DNA repair and apoptosis, and inhibition of PKCδ provides robust radioprotection. In this study, we show that depletion of PKCδ increases mitochondrial reactive oxygen species (ROS) production and induces an endogenous antioxidant response through nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in decreased basal and irradiation (IR)-induced DNA damage and cell death. Radioprotection by PKCδ depletion can be reversed with the free radical scavenger, N-acetyl-L-cysteine, indicating an essential role for the antioxidant response. Whereas mitochondrial mass and membrane potential are increased in PKCδ-depleted cells, oxidative phosphorylation and the activity of electron transport chain complex I and complex III are reduced, suggesting that electron transport chain dysfunction is the source of the increased mitochondrial ROS. The antioxidant response induced by PKCδ depletion is mediated through Sirtuin 6 (SIRT6) and Nrf2. Increased mitochondrial ROS and Nrf2 activation are reversed in PKCδ/SIRT6 double knockdown cells, indicating a central role for SIRT6 in PKCδ-regulated DNA repair and cell death. Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.</p><p><strong>Implications: </strong>Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"779-791"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005819","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":"DDR2 confers ferroptosis resistance to cancer-associated fibroblasts and attenuates PARPi sensitivity of ovarian tumor cells.","authors":"Julien Lesage, Alessandra DiMauro, Angela M Schab, Seth Stidham, Mary M Mullen, Katherine C Fuh, Gregory D Longmore","doi":"10.1158/1541-7786.MCR-25-0268","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0268","url":null,"abstract":"<p><p>In ovarian cancer, resistance to conventional treatments has prompted the search for alternative targets and/or cells within the tumor microenvironment (TME) that could enhance tumor cell death. Ferroptosis, an iron-dependent, lipid peroxide-triggered form of cell death, is one such pathway. Cancer‑associated fibroblasts (CAFs) are key stromal cells in the ovarian TME that can impact therapeutic responses. Using various genetic approaches, we generated multiple DDR2‑expressing and DDR2‑deficient human ovarian tumor and mouse breast tumor CAFs. We find that DDR2 expression in CAFs protects these cells from ferroptosis by regulating the xCT-GSH-GPX4 antioxidant pathway and cellular iron metabolism. Specifically, DDR2 regulates xCT expression through non-canonical p62‑dependent NRF2 activation and the labile iron pool (LIP) by controlling ferritinophagy. CAFs secrete factors, in a DDR2-dependent manner, that provide protection to ovarian tumor cells against Olaparib‑induced cell death, a clinically relevant PARP inhibitor (PARPi). Finally, we find that high expression of DDR2 in the stromal cells of human ovarian tumors is associated with poor response to PARPi in clinical trials. These findings suggest that ferroptotic regulation by DDR2 in ovarian tumor CAFs could impact therapeutic sensitivity and resistance to PARPi. Implications: The action of the collagen receptor tyrosine kinase DDR2 in CAFs confers PARPi protection to Ovarian tumor cells, by protecting CAFs from ferroptosis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial HSP90 Paralog TRAP1 Deletion Drives Glutamine Addiction in Tumor Cells via Destablization of the Cys/Glu Antiporter SLC7A11/xCT.","authors":"Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers","doi":"10.1158/1541-7786.MCR-24-0194","DOIUrl":"10.1158/1541-7786.MCR-24-0194","url":null,"abstract":"<p><p>TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine (Gln) dependency of mitochondrial respiration following glucose (Glc) withdrawal. In this study, we investigate how TRAP1 deletion impacts Glc metabolism and the mechanisms enabling Gln retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although Glc oxidation remains functional, TRAP1 KO reduces overall Glc uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased Gln retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces Gln-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest that xCT is regulated posttranslationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases Glc uptake while preserving its metabolic fate, promoting Gln conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis.</p><p><strong>Implications: </strong>These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated Gln conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"792-806"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079249","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":"IL-9 Promotes Migratory Dissemination of Malignant T Cells by Activating the HIF-1α-Cofilin-1 Axis in Cutaneous T-cell Lymphoma.","authors":"Ditipriya Mukherjee, Soumitra Marathe, Diksha Attrish, Vinanti Sawant, Bhavuk Dhamija, Sushant Kumar, Siddhi Wad, Moumita Basu, Neha Sharma, Hasmukh Jain, Steven R Barthel, Rahul Purwar","doi":"10.1158/1541-7786.MCR-24-1020","DOIUrl":"10.1158/1541-7786.MCR-24-1020","url":null,"abstract":"<p><p>Cutaneous T-cell lymphoma (CTCL) is a multistage disease characterized by rapid dissemination of malignant T lymphocytes from skin lesions to visceral organs and bone marrow. The cytokine IL-9 and its receptor (IL-9R) are aberrantly overexpressed in CTCL lesions and function to enhance tumor cell survival. In this study, we uncovered a critical new role for IL-9 as a potent inducer of migration of malignant T cells. Stimulation of IL-9R-expressing T-cell lymphoma cells with IL-9 induced a pseudohypoxic cellular state by elevating downstream levels of the promigratory and oxygen-sensing transcription factor hypoxia-inducible factor (HIF)-1α. High-throughput quantitative proteomic analyses of pseudohypoxic malignant T cells identified the actin-modulating protein cofilin-1 (CFL-1) as a promigratory CTCL-intrinsic target downstream of IL-9-HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked coexpression of CFL-1 with HIF-1α in both IL-9-treated human lymphoma cell lines and in patient CTCL skin biopsies compared with normal controls. Genetic knockdown of IL9R or HIF1A in human T-cell lymphoma lines by RNAi significantly reduced both HIF-1α and CFL-1 coexpression and reversed IL-9-induced migration. Finally, pharmacologic antagonism of HIF-1α activity using the FDA-designated orphan drug echinomycin significantly abrogated IL-9-triggered migration of both malignant T-cell lines and patient-derived T-cell lymphoma cells from CTCL biospecimens.</p><p><strong>Implications: </strong>Our results uncover a CTCL-intrinsic IL-9-HIF-1α-CFL-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and CFL-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"807-821"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer genomic alterations and microenvironmental features encode synergistic interactions with disease outcomes.","authors":"Masroor Bayati, Zoe P Klein, Alexander T Bahcheli, Mykhaylo Slobodyanyuk, Jeffrey To, Kevin C L Cheng, Jigyansa Mishra, Diogo Pellegrina, Kissy Guevara-Hoyer, Chris McIntosh, Mamatha Bhat, Jüri Reimand","doi":"10.1158/1541-7786.MCR-25-0475","DOIUrl":"10.1158/1541-7786.MCR-25-0475","url":null,"abstract":"<p><p>Oncogenesis, tumor progression and therapy response are shaped by somatic alterations in the cancer genome and features of the tumor immune microenvironment (TME). How interactions between these two systems influence tumor evolution and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC that systematically integrates genetic cancer drivers and infiltration profiles of immune cells to find pairwise combinations of drivers and TME characteristics that jointly associate with clinical outcomes. By analyzing 8500 primary tumor samples of 26 cancer types, we report 34 immunogenomic interactions (IGXs) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell levels were significantly correlated with patient survival. Subsets of tumor samples defined by some IGXs were characterized by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of immunotherapy target genes. In luminal-A breast cancer, an IGX involving MEN1 deletion combined with reduced levels of neutrophils associated with lower progression-free survival and deregulation of immune signaling pathways, as observed in two independent cancer genomics datasets. These results showcase the ability of PACIFIC to integrate complex multi-omics datasets with clinical information, enabling the identification of clinically relevant immunogenomic interactions. Such interactions provide a rich set of hypotheses for mechanistic studies and the development of biomarkers and therapeutic targets. Implications: Co-occurrence patterns of cancer drivers and TME characteristics highlight synergistic interactions with prognostic potential.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2.","authors":"Rosemary N Plagens, Carla S Rodriquez Tirado, Shen Li, Natalia Maldonado-Vazquez, Ingrid M Montes-Rodriguez, Julie Dutil, Christine A Mills, Laura E Herring, Hector L Franco","doi":"10.1158/1541-7786.MCR-25-0085","DOIUrl":"10.1158/1541-7786.MCR-25-0085","url":null,"abstract":"<p><p>FOXA1 is a pioneer transcription factor essential for chromatin accessibility and transcriptional regulation in hormone-driven cancers. In breast cancer, FOXA1 plays a central role in facilitating nuclear receptor binding, reprogramming enhancer landscapes, and promoting transcriptional changes associated with therapy resistance. While FOXA1's function has been primarily studied in the context of estrogen receptor-α (ER), its broader protein interaction network remains incompletely defined. Here, we systematically map FOXA1-interacting proteins in ER-positive breast cancer cells using proximity-dependent biotin labeling (miniTurbo) combined with quantitative LC-MS/MS proteomics. We engineered MCF-7 cell lines stably expressing miniTurbo-tagged FOXA1 at either the N-terminus or C-terminus to ensure comprehensive coverage of interaction interfaces. This approach recovered known FOXA1 partners, including AR, MLL3, YAP1, and GATA3, and identified 157 previously unreported FOXA1 interactors. Notably, 42 of these novel partners, including NR2C2, were significantly associated with poor relapse-free survival in ER+ breast cancer patients. To demonstrate the utility of this resource, we characterized the FOXA1-NR2C2 interaction in depth. Integrating ChIP-seq and RNA-seq, we show that FOXA1 and NR2C2 co-occupy a subset of genomic regions and drive co-regulated transcriptional programs involved in tumor progression. Our study reveals an expanded FOXA1 interactome and new insights into its functional network in breast cancer, providing candidate proteins for further exploration as biomarkers or therapeutic targets. Implications: These findings expand the FOXA1 interactome in breast cancer and uncover new candidate proteins with potential as biomarkers and therapeutic targets in hormone-driven tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962363","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":"MACC1-AS1: An Emerging Star in The Field of Tumor Biology with Bright Futures in Medicine.","authors":"Li Dong, Weidong Li, Wei Zhu, YaMin Sun","doi":"10.1158/1541-7786.MCR-25-0170","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0170","url":null,"abstract":"<p><p>Long non-coding RNAs act as modulators, with significant influence on a wide array of biological functions. They form an extensive communication network between genes and contribute to the pathophysiology of various human diseases, especially cancer. A growing body of research has demonstrated that LncRNAs, acting either as promoters or inhibitors of oncogenesis, are intricately linked to the initiation and progression of cancer. MACC1-AS1 is a newly identified LncRNA that is abnormally expressed in various types of human tumors. Poor clinical characteristics, such as larger tumor size, advanced tumor stage, lymph node metastasis, and a lower overall survival rate, are linked to overexpression of MACC1-AS1. MACC1-AS1 exerts a complex regulatory function: it acts as a competitive RNA, interacts with multiple proteins, and influences diverse pathways, leading to tumor development. It is essential to note the decreased efficacy of conventional chemotherapy drugs, which diminishes the efficacy of cancer treatment. Ongoing research has been highlighting the multifaceted functions of MACC1-AS1, and thus, it is required to unravel its exact molecular mechanisms. In this overarching review, we explore the significance of MACC1-AS1 as a potential cancer treatment target and biomarker. This study can potentially play an important role in the advancement of the field and confirm its potential clinical applicability.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Cholesterol Synthesis, Statin Use, and Lethal Prostate Cancer.","authors":"Sinead Flanagan, Rosina T Lis, Ying Huang, Lina Jehane, Jane B Vaselkiv, Emma H Allott, Stephen P Finn, Tamara L Lotan, Michelangelo Fiorentino, Massimo Loda, Gwo-Shu Mary Lee, Goutam Chakraborty, Philip W Kantoff, Lorelei A Mucci, Konrad H Stopsack","doi":"10.1158/1541-7786.MCR-24-0864","DOIUrl":"10.1158/1541-7786.MCR-24-0864","url":null,"abstract":"<p><p>Prostate tumor cells produce cholesterol de novo, and statin therapy targets the initial rate-limiting enzyme in this process, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). The extent to which the expression of HMGCR in prostate tumors could influence progression and predict the potential anti-neoplastic effects of statins remains unclear. In a prospective cohort study of 1098 men diagnosed with primary prostate cancer in 1982-2009 from the Health Professionals Follow-up Study and Physicians' Health Study, 16% of prostate tumors showed strong HMGCR staining intensity and 31% no staining. HMGCR expression was higher in tumors with PTEN loss but did not differ by statin use or long-term dietary cholesterol or saturated fat intake. Participants were followed for lethal events (distant metastases or prostate cancer-related death) over up to 32 years, and 96 lethal events occurred in those without metastases at diagnosis. Strong HMGCR expression was associated with higher rates of lethal prostate cancer (hazard ratio 2.2, 95% confidence interval 1.3-3.7), adjusting for age at diagnosis and Gleason score but without a linear dose response. In vitro in the LNCaP human prostate cancer cell line, atorvastatin impacted tumor cell viability in cells with experimentally lowered HMGCR expression. This study corroborates that high cholesterol synthesis in prostate tumor cells is associated with PTEN loss, aggressive tumor characteristics, and a greater risk of lethality. Implications: High expression of HMGCR, the first rate-limited enzyme of cholesterol synthesis, is a feature of prostate tumors that are more likely to progress to metastatic disease or death from prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784869","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":"Targeted Deletion of Cxcl1 in MSCs Regulates Osteogenesis and Suppresses Bone-Metastatic Prostate Cancer.","authors":"Catherine S Johnson, Diane Costanzo-Garvey, Julio C Valencia, Sanjana Rajgopal, Theodore Reed, Emma R Brannon, Jeremy S Frieling, Deanna D Mosley, Todd A Wyatt, Elijah F Edmondson, Kabhilan Mohan, Grinu Mathew, Leah M Cook","doi":"10.1158/1541-7786.MCR-24-0672","DOIUrl":"10.1158/1541-7786.MCR-24-0672","url":null,"abstract":"<p><p>Bone metastasis continues to be the greatest challenge in treating patients with prostate cancer despite ongoing research. In bone, prostate cancer tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive bone-metastatic prostate cancer growth in the bone environment. To understand the mechanisms associated with bone-metastatic prostate cancer regulation of mesenchymal stem cells (MSC), we previously identified that bone-metastatic prostate cancer induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homologue Cxcl1. To date, there has been little to no information about the role of CXCL1/8 in MSC biology and its impact in the tumor-bone environment. Using genetic deletion of Cxcl1, we discovered a novel role for Cxcl1/8 in regulating MSC osteoblast differentiation, such that targeted deletion of Cxcl1 enhanced MSC osteoblastogenesis. Despite the osteogenic nature of prostate cancer, co-injection of Cxcl1 knockout (KO) MSCs with bone-metastatic prostate cancer in bone significantly suppressed tumor growth compared with co-injection with scrambled control (non-targeting) MSCs, even in the presence of three times more prostate cancer to MSCs. Furthermore, bulk RNA sequencing revealed immune response pathways, both in Cxcl1-KO MSCs and bone-metastatic prostate cancer tumors containing Cxcl1-KO MSCs. In support of this, Cxcl1-KO MSCs reduced immature neutrophils in the bone environment, while increasing monocytes. These findings demonstrate the importance of MSC-derived Cxcl1 in the bone microenvironment and highlight the importance of Cxcl1 in bone-metastatic prostate cancer progression.</p><p><strong>Implications: </strong>MSC-derived Cxcl1 regulates prostate cancer progression in bone.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"739-758"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12319404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973533","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":"m6A-Modified SFTA1P Acts as a Tumor Suppressor in Non-Small Cell Lung Cancer by Regulating TGFBR2 and P-TEFb.","authors":"Tingting Xia, Menglei Chen, Meiyu Zhou, Weiping Wan, Yifan Shan, Weijia Xie, Na Wu, Chengying Li, Zhiquan Yuan, Tongjian Cai, Zubin Yu, Ying Xiang, Li Bai, Yafei Li","doi":"10.1158/1541-7786.MCR-24-0499","DOIUrl":"10.1158/1541-7786.MCR-24-0499","url":null,"abstract":"<p><p>SFTA1P is a pseudogene-derived long noncoding RNA and has become a master regulator in tumor carcinogenesis and progression processes. SFTA1P has been reported as a potential diagnostic and prognostic biomarker in non-small cell lung cancer (NSCLC). The downregulation of SFTA1P in tumor tissue has been associated with poor prognosis; however, the detailed molecular mechanism and biological functions still need to be investigated. We demonstrated that SFTA1P inhibited the growth and metastasis of NSCLC in vitro and in vivo. SFTA1P had dual functions in the cytoplasm and nucleus: In the cytoplasm, SFTA1P can serve as a \"sponge\" for miR-665 to increase the expression level of TGFBR2; in the nucleus, SFTA1P can bind the positive transcription elongation factor b and subsequently inhibit the transcriptase activity of RNA polymerase II. The regulation of TGFBR2 and positive transcription elongation factor b via SFTA1P depends on its subcellular localization, which was affected by the status of the N6-methyladenosine RNA modification of SFTA1P. Our research demonstrated that the candidate tumor-suppressor SFTA1P is extensively involved in NSCLC, which may offer novel insights into NSCLC oncogenesis.</p><p><strong>Implications: </strong>SFTA1P is downregulated in NSCLC and had dual functions in the cytoplasm and nucleus.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"710-723"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}