Molecular Cancer Research最新文献

{"title":"Kindlin-2-Mediated Hematopoiesis Remodeling Regulates Triple-Negative Breast Cancer Immune Evasion.","authors":"Wei Wang, Rahul Chaudhary, Justin Szpendyk, Lamyae El Khalki, Neelum Aziz Yousafzai, Ricky Chan, Amar Desai, Khalid Sossey-Alaoui","doi":"10.1158/1541-7786.MCR-24-0698","DOIUrl":"10.1158/1541-7786.MCR-24-0698","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) presents significant clinical challenges because of its limited treatment options and aggressive behavior, often associated with poor prognosis. This study focuses on kindlin-2, an adapter protein, and its role in TNBC progression, particularly in hematopoiesis-mediated immune evasion. TNBC tumors expressing high levels of kindlin-2 induce a notable reshaping of hematopoiesis, promoting the expansion of myeloid cells in the bone marrow and spleen. This shift correlated with increased levels of neutrophils and monocytes in tumor-bearing mice over time. Conversely, genetic knockout (KO) of kindlin-2 mitigated this myeloid bias and fostered T-cell infiltration within the tumor microenvironment, indicating the pivotal role of kindlin-2 in immune modulation. Further investigations revealed that kindlin-2 deficiency led to reduced expression of PD-L1, a critical immune checkpoint inhibitor, in TNBC tumors. This molecular change sensitized kindlin-2-deficient tumors to host antitumor immune responses, resulting in enhanced tumor suppression in immunocompetent mouse models. Single-cell RNA sequencing, bulk RNA sequencing, and IHC data supported these findings by highlighting enriched immune-related pathways and increased infiltration of immune cells in kindlin-2-deficient tumors. Therapeutically, targeting PD-L1 in kindlin-2-expressing TNBC tumors effectively inhibited tumor growth, akin to the effects observed with genetic kindlin-2 KO or PD-L1 KO. Our data underscore kindlin-2 as a promising therapeutic target in combination with immune checkpoint blockade to bolster antitumor immunity and counteract resistance mechanisms typical of TNBC and other immune-evasive solid tumors. Implications: Kindlin-2 regulates tumor immune evasion through the systemic modulation of hematopoiesis and PD-L1 expression, which warrants therapeutic targeting of kindlin-2 in patients with TNBC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"450-462"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365293","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":"Identifying and Targeting Key Driver Genes for Collagen Production within the 11q13/14 Breast Cancer Amplicon.","authors":"Daniela Araiza-Olivera, Tatiana Y Prudnikova, Cristina Uribe-Alvarez, Kathy Q Cai, Janusz Franco-Barraza, Jesus M Dones, Ronald T Raines, Jonathan Chernoff","doi":"10.1158/1541-7786.MCR-24-0331","DOIUrl":"10.1158/1541-7786.MCR-24-0331","url":null,"abstract":"<p><p>Breast cancers of the Integrative Cluster 2 (IntClust-2) type, characterized by amplification of a small portion of chromosome 11, have a median survival of only 5 years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study, we used a gene editing method to knock out, one by one, each of the 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3) that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function for IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"405-415"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008965","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":"Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors.","authors":"Leslie Cuellar-Vite, Elyse M Donaubauer, Kristen L Weber-Bonk, Jessica R Bobbitt, Natasha N Ingles, Taylor L Brzozowski, Fadi W Abdul-Karim, Christine N Booth, Ruth A Keri","doi":"10.1158/1541-7786.MCR-24-0309","DOIUrl":"10.1158/1541-7786.MCR-24-0309","url":null,"abstract":"<p><p>EGFR is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors (EGFRi) is limited to cancers that harbor sensitizing mutations in the EGFR gene because of dose-limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wild-type (WT) or mutant EGFR. We found that YES1 is highly expressed in triple-negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer cells, including those that harbor the EGFR gatekeeper mutation T790M. The novel ability of YES1 to regulate the expression of WT and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we observed synergy within in vitro and in vivo models of TNBC and non-small cell lung cancer, even in the absence of EGFR-activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by the WT or mutant receptor.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"391-404"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028909","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":"ATAD2 Drives Prostate Cancer Progression to Metastasis.","authors":"Anindita Dutta, Antonio Rodriguez-Calero, Kacey Ronaldson-Bouchard, Anne Offermann, Daoud Rahman, Twinkle Bapuji Vhatkar, Dan Hasson, Mohammed Alshalalfa, Elai Davicioni, R Jeffrey Karnes, Mark A Rubin, Gordana Vunjak-Novakovic, Cory Abate-Shen, Juan Martin Arriaga","doi":"10.1158/1541-7786.MCR-24-0544","DOIUrl":"10.1158/1541-7786.MCR-24-0544","url":null,"abstract":"<p><p>Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other's expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"379-390"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190024","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":"Editor's Note: AMPK Causes Cell Cycle Arrest in LKB1-Deficient Cells via Activation of CAMKK2.","authors":"Sarah Fogarty, Fiona A Ross, Diana Vara Ciruelos, Alexander Gray, Graeme J Gowans, D Grahame Hardie","doi":"10.1158/1541-7786.MCR-25-0265","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0265","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"23 5","pages":"477"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972484","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":"THG-1/TSC22D4 Promotes IL-1 Signaling through Stabilization of TRAF6 in Squamous Cell Carcinoma.","authors":"Yasuhito Okano, Hiroyuki Suzuki, Yukihide Watanabe, Mohammed Abdelaziz, Lev Manevich, Kunio Kawanishi, Haruka Ozaki, Ryota Ishii, Shin Matsumoto, Nohara Goto, Ling Zheng, Yukari Okita, Jongchan Hwang, Masahiro Nakayama, Yoshihide Shima, Noriaki Sakamoto, Masayuki Noguchi, Keiji Tabuchi, Mitsuyasu Kato","doi":"10.1158/1541-7786.MCR-24-0120","DOIUrl":"10.1158/1541-7786.MCR-24-0120","url":null,"abstract":"<p><p>Malignant neoplasms arise within a region of chronic inflammation, which is a key factor in all aspects of tumorigenesis including initiation, proliferation, invasion, angiogenesis, and metastasis. IL-1 plays critical functions in tumor development by influencing the tumor microenvironment and promoting cancer progression. However, the mechanism of continuous activation of the IL-1-mediated inflammatory pathway in tumors has not been fully elucidated. This study provides a novel mechanism of the autocrine activation of IL-1 signaling in squamous cell carcinoma (SCC) through a novel oncoprotein, TSC-22 homologous gene-1 (THG-1, also known as TSC22D4). The RNA sequencing analysis revealed that THG-1 overexpression enhances the transcription of NF-κB targets including IL1A, IL1B, TNFA, and IL8. Furthermore, THG-1 knockdown reduced the responsiveness to IL-1 through the suppression of NF-κB nuclear translocation. To elucidate the mechanism, we focused on a THG-1 interacting protein, NRBP1. We found that NRBP1 facilitates the degradation of TNF receptor-associated factor 6 (TRAF6) through its E3 ubiquitin ligase activity. THG-1 bound to NRBP1 and suppressed the degradation of TRAF6. Furthermore, THG-1 knockdown reduced TRAF6 abundance and NF-κB activity in SCC cells. Public database analyses of head and neck SCC revealed that high expression of THG-1 is associated with the activation of the IL-1 and TNF pathways, which share TRAF6 in the signal transductions. Finally, THG-1 abundance in laryngeal SCC specimens is elevated in patients with recurrence. These results indicated that THG-1 drives the self-sufficiency of IL-1-mediated inflammatory pathway, which could contribute to the future diagnosis and immunotherapy of SCCs. Implications: An oncoprotein, THG-1/TSC22D4 activates the IL-1-mediated inflammatory pathway through the suppression of TRAF6 degradation, which mediates the continuous inflammation in tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"463-476"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047081","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":"Targeted Deletion of Cxcl1 in MSCs Promotes 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":"https://doi.org/10.1158/1541-7786.MCR-24-0672","url":null,"abstract":"<p><p>Bone metastasis continues to be the greatest challenge in treating prostate cancer (PCa) patients, despite ongoing research. In bone, PCa tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive BM-PCa growth in the bone environment. To understand the mechanisms associated with BM-PCa regulation of MSCs, we previously identified that BM-PCa induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homolog Cxcl1. To date, there has been little to no information as to 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 PCa, co-injection of Cxcl1 knockout (KO) MSCs with BM-PCa in bone significantly suppressed tumor growth compared to co-injection with Scrambled Control (non-targeting) MSCs, even in the presence of 3 times more prostate cancer to MSCs. Further, bulk RNAseq revealed immune response pathways, both in Cxcl1 KO MSCs and BM-PCa 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 for in BM-PCa progression. Implications: MSC-derived CXCL1 regulates PCa progression in bone.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial analysis of hereditary diffuse gastric cancer reveals indolent phenotype of signet ring cell precursors.","authors":"Amber F Gallanis, Lauren A Gamble, Cihan Oguz, Sarah G Samaranayake, Noemi Kedei, Maria O Hernandez, Madeline Wong, Desiree Tillo, Benjamin L Green, Paul McClelland, Cassidy Bowden, Irene Gullo, Mark Raffeld, Liqiang Xi, Michael Kelly, Markku Miettinen, Martha Quezado, Sun A Kim, Andrew M Blakely, Justin Lack, Theo Heller, Jonathan M Hernandez, Jeremy L Davis","doi":"10.1158/1541-7786.MCR-24-1039","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-1039","url":null,"abstract":"<p><p>Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multi-omics analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of ECM remodeling in SRC lesions compared to unaffected adjacent gastric epithelium. Single cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin re-expression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared to SRC lesions. Implications: The marked differences in genomic and transcriptomic profile of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795849","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":"VAV2 drives EGFR-mediated Rac1 responses in prostate cancer.","authors":"Martin J Baker, Suli Zhang, Daniel Zhang, Joshua Searle, Priti Lal, Cornelis P Vlaar, Suranganie Dharmawardhane, Martín C Abba, Marcelo G Kazanietz, Mariana Cooke","doi":"10.1158/1541-7786.MCR-24-0957","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0957","url":null,"abstract":"<p><p>The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. Here, we show that CRISPR/Cas9-based knockout of Rac1 leads to impaired prostate cancer cell proliferation and migration. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix (ECM) regulation. Combined expression profiling and unbiased RNAi screening of Rac1 Guanine nucleotide Exchange Factors (Rac-GEFs) identified VAV2 as the foremost mediator of epidermal growth factor (EGF)-induced GTP loading onto Rac1 in prostate cancer cells. VAV2 depletion from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. Immunohistochemical assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression. Implications: This study highlights VAV2's central role in prostate cancer cell proliferation and migration and its potential prognostic value in disease progression.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780616","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":"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":"https://doi.org/10.1158/1541-7786.MCR-24-0499","url":null,"abstract":"<p><p>SFTA1P is a pseudogene-derived lncRNA 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 down-regulation 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 played 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 P-TEFb and subsequently inhibit the transcriptase activity of RNA polymerase II. The regulation of TGFBR2 and P-TEFb via SFTA1P depends on its subcellular localization, which was affected by the status of the N6-methyladenosine (m6A) RNA modification of SFTA1P. Our research demonstrated that the candidate tumor suppressor SFTA1P is extensively involved in NSCLC, which may offer novel insight into NSCLC oncogenesis. Implications: SFTA1P is down regulated in non-small cell lung cancer and played dual functions in the cytoplasm and nucleus.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","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}