Molecular Cancer最新文献

{"title":"Targeting KRAS: from metabolic regulation to cancer treatment","authors":"Yanyan Shi, Huiling Zheng, Tianzhen Wang, Shengpu Zhou, Shiqing Zhao, Mo Li, Baoshan Cao","doi":"10.1186/s12943-024-02216-3","DOIUrl":"https://doi.org/10.1186/s12943-024-02216-3","url":null,"abstract":"The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the role of metabolic alterations in KRAS-driven cancers, providing a scientific rationale for targeting metabolism in cancer treatment. The development of KRAS-specific inhibitors has also garnered considerable attention, partly due to the challenge of acquired treatment resistance. Here, we review the metabolic reprogramming of glucose, glutamine, and lipids regulated by oncogenic KRAS, with an emphasis on recent insights into the relationship between changes in metabolic mechanisms driven by KRAS mutant and related advances in targeted therapy. We also focus on advances in KRAS inhibitor discovery and related treatment strategies in colorectal, pancreatic, and non-small cell lung cancer, including current clinical trials. Therefore, this review provides an overview of the current understanding of metabolic mechanisms associated with KRAS mutation and related therapeutic strategies, aiming to facilitate the understanding of current challenges in KRAS-driven cancer and to support the investigation of therapeutic strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy","authors":"Kun Huang, Ying Han, Yihong Chen, Hong Shen, Shan Zeng, Changjing Cai","doi":"10.1186/s12943-024-02205-6","DOIUrl":"https://doi.org/10.1186/s12943-024-02205-6","url":null,"abstract":"Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming. Refining the key regulatory factors and their mechanisms within the complex network of tumor metabolic reprogramming. Depicting the metabolic crosstalk between tumor cells, immune cells, and tumor stromal cells during tumor progression. Emphasizing the unresolved challenges of metabolic therapy in clinical translation and the advantages of personalized treatment. Providing theoretical support and research direction for new strategies for metabolic therapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"204 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intra-tumoral sphingobacterium multivorum promotes triple-negative breast cancer progression by suppressing tumor immunosurveillance","authors":"Zhikai Mai, Liwu Fu, Jiyan Su, Kenneth K.W. To, Chuansheng Yang, Chenglai Xia","doi":"10.1186/s12943-024-02202-9","DOIUrl":"https://doi.org/10.1186/s12943-024-02202-9","url":null,"abstract":"Intratumor-resident bacteria represent an integral component of the tumor microenvironment (TME). Microbial dysbiosis, which refers to an imbalance in the bacterial composition and bacterial metabolic activities, plays an important role in regulating breast cancer development and progression. However, the impact of specific intratumor-resident bacteria on tumor progression and their underlying mechanisms remain elusive. 16S rDNA gene sequencing was used to analyze the cancerous and paracancerous tissues from breast cancer patients. The mouse models of bearing 4T1 cell tumors were employed to assess the influence of bacterial colonization on tumor growth. Tissue infiltration of regulatory T (Treg) cells and CD8+ T cells was evaluated through immunohistochemistry and flow cytometric analysis. Comparative metabolite profiling in mice tumors was conducted using targeted metabolomics. Differential genes of tumor cells stimulated by bacteria were analyzed by transcriptomics and validated by qPCR assay. We found that Sphingobacterium displayed high abundance in cancerous tissues. Intra-tumoral colonization of Sphingobacterium multivorum (S. multivorum) promoted tumor progression in 4T1 tumor-bearing mice. Moreover, S. multivorum diminished the therapeutic efficacy of αPD-1 mAb, which was associated with the increase of regulatory T cell (Treg) infiltration, and decrese of the CD8+ T cell infiltration. Targeted metabolomics revealed a conspicuous reduction of propionylcarnitine in tumors colonized by S. multivorum Furthermore, the combination of metabolite propionylcarnitine and S. multivorum shown to suppress tumor growth compared that in S. multivorum alone in vivo. Mechanistically, S. multivorum promoted the secretion of chemokines CCL20 and CXCL8 from tumor cells. CCL20 secreted into the TME facilitated the recruitment of Treg cells and reduced CD8+ T cell infiltration, thus promoting tumor immune escape. This study reveals S. multivorum suppresses immune surveillance within the TME, thereby promoting breast cancer progression.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"22 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy","authors":"Shuyan He, Lu Zheng, Chunjian Qi","doi":"10.1186/s12943-024-02208-3","DOIUrl":"https://doi.org/10.1186/s12943-024-02208-3","url":null,"abstract":"The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy. Myeloid-derived suppressor cells (MDSCs), due to their potent immunosuppressive capabilities, emerged as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells. In addition to their immunosuppressive functions, MDSCs also promote tumor growth and metastasis through non-immunological mechanisms, such as angiogenesis and the formation of pre-metastatic niches. Consequently, MDSCs in the TME are key regulators of cancer immune responses and potential therapeutic targets in cancer treatment. This review describes the origins and phenotypes of MDSCs, their biological roles in tumor progression, and regulatory mechanisms, with a focus on current therapeutic approaches targeting tumor-associated MDSCs. Furthermore, the synergistic effects of targeting MDSCs in combination with immunotherapy are explored, aiming to provide new insights and directions for cancer therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"133 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response","authors":"Benjamin H. Jenkins, Ian Tracy, Maria Fernanda S. D. Rodrigues, Melanie J. L. Smith, Begoña R. Martinez, Mark Edmond, Sangeetha Mahadevan, Anjali Rao, Hailing Zong, Kai Liu, Abhishek Aggarwal, Li Li, Lauri Diehl, Emma V. King, Jamie G. Bates, Christopher J. Hanley, Gareth J. Thomas","doi":"10.1186/s12943-024-02191-9","DOIUrl":"https://doi.org/10.1186/s12943-024-02191-9","url":null,"abstract":"Cancer-associated Fibroblasts (CAFs) have emerged as critical regulators of anti-tumour immunity, with both beneficial and detrimental properties that remain poorly characterised. To investigate this, we performed single-cell and spatial transcriptomic analysis, comparing head & neck squamous cell carcinoma (HNSCC) subgroups, which although heterogenous, can be considered broadly immune-hot and immune-cold (human papillomavirus [HPV]+ve and HPV-ve tumours respectively). This identified six fibroblast subpopulations, including two with immunomodulatory gene expression profiles (IL-11 + inflammatory [i]CAF and CCL19 + fibroblastic reticular cell [FRC]-like). IL-11 + iCAF were spatially associated with inflammatory monocytes and regulated in vitro through synergistic activation of canonical NF-κB signalling by IL-1β and TNF-α. FRC-like were enriched in immune-hot HPV+ve tumours, associated with CD4 + T-cells and B-cells in tertiary lymphoid structures and regulated through non-canonical NF-κB signalling via lymphotoxin. Pan-cancer analysis revealed several ‘iCAF’ subgroups present in both normal and cancer tissues; IL11 + iCAF were found in cancers from the gastrointestinal (GI) tract and transcriptomically distinct from iCAFs previously described in pancreatic and breast cancers with greater inflammatory properties; FRC-like fibroblasts were present at low frequencies in all tumour types, and were associated with significantly better survival in patients receiving checkpoint immunotherapy. This work clarifies and expands current literature on immunomodulatory CAFs, highlighting links with important immunological niches.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"1 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal circ_0006896 promotes AML progression via interaction with HDAC1 and restriction of antitumor immunity","authors":"Can Can, Xinyu Yang, Hexiao Jia, Hanyang Wu, Xiaodong Guo, Yihong Wei, Ziting Jia, Wancheng Liu, Amin Zhang, Na He, Hailei Zhang, Daoxin Ma","doi":"10.1186/s12943-024-02203-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02203-8","url":null,"abstract":"Drug resistance and immune escape continue to contribute to poor prognosis in AML. Increasing evidence suggests that exosomes play a crucial role in AML immune microenvironment. Sanger sequencing, RNase R and fluorescence in situ hybridization were performed to confirm the existence of circ_0006896. The role of circ_0006896 in the progression of AML was assessed by in vitro and in vivo functional experiments. Flow cytometry, RT-qPCR and adoptive T cell-transfer immunotherapy were conducted to assess the function of exosomal circ_0006896 in CD8+ T cell dysfunction. RNA pull-down assay, mass spectrometry, immunofluorescence, co-immunoprecipitation and western blot were performed to identify and confirm the circ_0006896 interacting proteins. CircRNA expression patterns in exosomes differ significantly between AML and controls compared to lncRNAs or mRNAs. A new crucial exosomal circRNA, circ_0006896, is upregulated in both AML cells and exosomes and correlates with the prognosis and relapse of AML. In vitro and in vivo studies suggest that circ_0006896 significantly promotes AML cell proliferation, reduces chemotherapy sensitivity, and more importantly, impairs the efficacy of adoptive T cell-transfer immunotherapy. Mechanistically, circ_0006896 physically interacts with the catalytic domain of histone deacetylase HDAC1, decreasing histone H3 acetylation, and impairing the transcription of genes involved in arachidonic acid metabolism, ultimately inhibiting lipid peroxidation and ferroptosis in AML cells. Exosomal circ_0006896 disrupts CD8+ T cell function by interacting with HDAC1, impairing LEF1 transcription and subsequently decreasing the expression of cytotoxic molecules IFN-γ and Granzyme B. We demonstrate a self-driven progression mediated by exosomal circRNAs and CD8+ T cells, highlighting the potential of targeting circRNAs in AML immunotherapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"203 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circASAP1 induces renal clear cell carcinoma ferroptosis by binding to HNRNPC and thereby regulating GPX4","authors":"Yunfei Wang, Taowei Yang, Qihao Li, Zhousan Zheng, Lican Liao, Junjie Cen, Wei Chen, Junhang Luo, Yi Xu, Mi Zhou, Jiaxing Zhang","doi":"10.1186/s12943-024-02122-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02122-8","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) represents the most prevalent subtype, accounting for nearly 80% of all RCC cases. Recent research has shown that high expression of circular non-coding RNA (circRNA) is associated with poor prognosis in patients with renal clear cell carcinoma (ccRCC), however, the underlying mechanism remains unclear. After analysing self-sequenced renal cancer and paracancer circRNA sequencing data and comparing it with the GEO public database, we discovered that circASAP1 expression was significantly up-regulated in renal cancers. We also tested circASAP1 levels in 102 renal cancer patients and found that high expression of circASAP1 was associated with poor prognosis and metastasis. The interaction between circASAP1, HNRNPC and their downstream target genes was confirmed through experiments such as RNA pull-down, RIP and fluorescence in situ hybridisation. A series of in vitro and in vivo functional experiments were performed to verify the effects of circASAP1 on RCC proliferation and metastasis. Circular RNA sequencing analysis revealed that circASAP1 expression was markedly elevated in ccRCC, with a significant association observed between elevated circASAP1 expression and poor prognosis and metastasis. Actinomycin D, RNase R, as well as fluorescence in situ hybridization (FISH) analyses revealed the ring structure and cytoplasmic localization of circASAP1. High circASAP1 expression was associated with ccRCC cell proliferative viability, invasion, and metastasis in CCK-8, transwell, plate cloning, and EdU experiments. Interaction of circASAP1 with HNRNPC and their downstream target genes was confirmed by RNA pull-down, RNA immunoprecipitation, FISH, silver staining, and mass spectrometry. Experiments using truncated isoforms demonstrated that amino acids 16–87 of HNRNPC bound circASAP1. Proteins altered by circASAP1 were enriched in the ferroptosis pathway on the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The relationship between circRNA and the ASAP1/HNRNPC/GPX4 axis was demonstrated by experimental data, which was further confirmed by rescue experiments. circASAP1 influenced tumor growth and ferroptosis in animal experiments and predicted the prognosis of patients with ccRCC. The circASAP1/HNRNPC/GPX4 axis provides novel directions and potential targets for RCC treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer drivers of metastasis","authors":"Ryan Lusby, Engin Demirdizen, Mohammed Inayatullah, Paramita Kundu, Oscar Maiques, Ziyi Zhang, Mikkel Green Terp, Victoria Sanz-Moreno, Vijay K. Tiwari","doi":"10.1186/s12943-024-02182-w","DOIUrl":"https://doi.org/10.1186/s12943-024-02182-w","url":null,"abstract":"Metastasis remains a leading cause of cancer-related mortality, irrespective of the primary tumour origin. However, the core gene regulatory program governing distinct stages of metastasis across cancers remains poorly understood. We investigate this through single-cell transcriptome analysis encompassing over two hundred patients with metastatic and non-metastatic tumours across six cancer types. Our analysis revealed a prognostic core gene signature that provides insights into the intricate cellular dynamics and gene regulatory networks driving metastasis progression at the pan-cancer and single-cell level. Notably, the dissection of transcription factor networks active across different stages of metastasis, combined with functional perturbation, identified SP1 and KLF5 as key regulators, acting as drivers and suppressors of metastasis, respectively, at critical steps of this transition across multiple cancer types. Through in vivo and in vitro loss of function of SP1 in cancer cells, we revealed its role in driving cancer cell survival, invasive growth, and metastatic colonisation. Furthermore, tumour cells and the microenvironment increasingly engage in communication through WNT signalling as metastasis progresses, driven by SP1. Further validating these observations, a drug repurposing analysis identified distinct FDA-approved drugs with anti-metastasis properties, including inhibitors of WNT signalling across various cancers.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"16 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The miR-23a/27a/24 − 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung cancer","authors":"Hao Luo, Bin Hu, Xiang-Rong Gu, Jing Chen, Xiao-Qing Fan, Wei Zhang, Ren-Tao Wang, Xian-Dong He, Wei Guo, Nan Dai, Dan Jian, Qing Li, Cheng-Xiong Xu, Hua Jin","doi":"10.1186/s12943-024-02201-w","DOIUrl":"https://doi.org/10.1186/s12943-024-02201-w","url":null,"abstract":"Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex I (MHC-I) are key molecules related to tumor immune evasion and resistance to programmed cell death protein 1 (PD-1)/PD-L1 blockade. Here, we demonstrated that the upregulation of all miRNAs in the miR-23a/27a/24 − 2 cluster was correlated with poor survival, immune evasion and PD-1/PD-L1 blockade resistance in patients with non-small cell lung cancer (NSCLC). The overexpression of all miRNAs in the miR-23a/27a/24 − 2 cluster upregulated PD-L1 expression by targeting Cbl proto-oncogene B (CBLB) and downregulated MHC-I expression by increasing the level of eukaryotic initiation factor 3B (eIF3B) via the targeting of microphthalmia-associated transcription factor (MITF). In addition, we demonstrated that the expression of the miR-23a/27a/24 − 2 cluster of miRNAs is maintained in NSCLC through increased Wnt/β-catenin signaling-regulated interaction of transcription factor 4 (TCF4) and the miR-23a/27a/24 − 2 cluster promoter. Notably, pharmacologic targeting of the eIF3B pathway dramatically increased sensitivity to PD-1/PD-L1 blockade in patients with high expression of the miR-23a/27a/24 − 2 cluster in NSCLC. This effect was achieved by increasing MHC-I expression while maintaining high expression of PD-L1 induced by the miR-23a/27a/24 − 2 cluster. In summary, we elucidate the mechanism by which the miR-23a/27a/24 − 2 cluster miRNAs maintain their own expression and the molecular mechanism by which the miR-23a/27a/24 − 2 cluster miRNAs promote tumor immune evasion and PD-1/PD-L1 blockade resistance. In addition, we provide a novel strategy for the treatment of NSCLC expressing high levels of the miR-23a/27a/24 − 2 cluster.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"26 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional landscape and predictive potential of long noncoding RNAs in peritoneal recurrence of gastric cancer","authors":"Xiao-Xia Cai, Guo-Ming Chen, Zi-Qi Zheng, Yi-Xin Yin, Shuang Wang, Li Qiao, Xiao-Jiang Chen, Bai-Wei Zhao, Jin-Ling Duan, Cheng-Cai Liang, Ruo-Peng Zhang, Cheng-Zhi Wei, Fei-Yang Zhang, Bo-Wen Huang, Ze-Xian Liu, Zhi-Wei Zhou, Dan Xie, Mu-Yan Cai, Shu-Qiang Yuan, Yuan-Fang Li, Run-Cong Nie","doi":"10.1186/s12943-024-02196-4","DOIUrl":"https://doi.org/10.1186/s12943-024-02196-4","url":null,"abstract":"Long noncoding RNAs (lncRNAs) play a critical role in gastric cancer (GC) progression and metastasis. However, research comprehensively exploring tissue-derived lncRNAs for predicting peritoneal recurrence in patients with GC remains limited. This study aims to investigate the transcriptional landscape of lncRNAs in GC with peritoneal metastasis (PM) and to develop an integrated lncRNA-based score to predict peritoneal recurrence in patients with GC after radical gastrectomy. We analyzed the transcriptome profile of lncRNAs in paired peritoneal, primary gastric tumor, and normal tissue specimens from 12 patients with GC in the Sun Yat-sen University Cancer Center (SYSUCC) discovery cohort. Key lncRNAs were identified via interactive analysis with the TCGA database and SYSUCC validation cohort. A score model was constructed using the LASSO regression model and nomogram COX regression and evaluated using receiver operating characteristic curves. The role of lncRNAs in the PM of GC was then examined through wound healing, Transwell, 3D multicellular tumor spheroid invasion, and peritoneal cavity xenograft tumorigenicity assays in mice. Five essential lncRNAs were screened and incorporated into the PM risk score to predict peritoneal recurrence-free survival (pRFS). We developed a comprehensive, integrated nomogram score, including the PM risk score, pT, pN, and tumor size, which could effectively predict the 5-year pRFS with an Area under the curve of 0.79 (95% CI: 0.71-0.88). Subsequently, we demonstrated that one of these lncRNAs, CASC15, promoted the invasion and migration of GC cells in vitro and facilitated the PM of GC cells in vivo, initially verifying that lncRNAs contribute to the PM of GC. Mechanistic analysis demonstrated that CASC15 promoted EMT and metastasis by activating the JNK and p38 pathways. A lncRNA-based integrated score was constructed in this study to predict peritoneal recurrence in patients clinically.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"3 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}