{"title":"Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and therapy resistance.","authors":"Rudong Li, Zhipeng Zhao, Xudong Wang","doi":"10.1080/15384047.2026.2710413","DOIUrl":null,"url":null,"abstract":"<p><p>14-3-3 proteins are phosphoserine- and phosphothreonine-binding adaptors that regulate client localization, stability and activity under cellular stress. This narrative review synthesizes stress-specific 14-3-3-client modules in gastric, colorectal, pancreatic, hepatocellular and biliary cancers. Modules were classified as high, moderate, early/context-dependent or background according to mechanistic evidence, functional perturbation, client mapping, treatment-state validation and clinical association. In gastric cancer, G3BP stress granule assembly factor 1 (G3BP1) cooperates with YWHAZ-encoded 14-3-3ζ to retain pro-apoptotic Bax in the cytoplasm. In colorectal cancer, SFN-encoded 14-3-3σ restricts Yin Yang 1 (YY1), sustaining the unfolded protein response and chemotherapy tolerance. In pancreatic cancer, SFN-encoded 14-3-3σ interacts with Yes-associated protein 1 (YAP1) to promote ribonucleotide reductase expression and gemcitabine resistance. In hepatobiliary cancers, SFN-related modules support anoikis resistance but remain context dependent. Clinically relevant units are stress-specific 14-3-3-client complexes rather than total 14-3-3 expression.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2710413"},"PeriodicalIF":5.7000,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418467/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biology & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/15384047.2026.2710413","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/7/27 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
14-3-3 proteins are phosphoserine- and phosphothreonine-binding adaptors that regulate client localization, stability and activity under cellular stress. This narrative review synthesizes stress-specific 14-3-3-client modules in gastric, colorectal, pancreatic, hepatocellular and biliary cancers. Modules were classified as high, moderate, early/context-dependent or background according to mechanistic evidence, functional perturbation, client mapping, treatment-state validation and clinical association. In gastric cancer, G3BP stress granule assembly factor 1 (G3BP1) cooperates with YWHAZ-encoded 14-3-3ζ to retain pro-apoptotic Bax in the cytoplasm. In colorectal cancer, SFN-encoded 14-3-3σ restricts Yin Yang 1 (YY1), sustaining the unfolded protein response and chemotherapy tolerance. In pancreatic cancer, SFN-encoded 14-3-3σ interacts with Yes-associated protein 1 (YAP1) to promote ribonucleotide reductase expression and gemcitabine resistance. In hepatobiliary cancers, SFN-related modules support anoikis resistance but remain context dependent. Clinically relevant units are stress-specific 14-3-3-client complexes rather than total 14-3-3 expression.
期刊介绍：
Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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