Academic Journal
Senescence-circadian interplay stratifies patient prognosis and reveals immune remodeling heterogeneity in colorectal cancer.
| Τίτλος: | Senescence-circadian interplay stratifies patient prognosis and reveals immune remodeling heterogeneity in colorectal cancer. |
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| Συγγραφείς: | Luo LZ; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China., Zhan Y; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.; Department of Bioinformatics, Sun Yat-sen University Cancer Center, Guangzhou, China., Bao RX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.; Department of Bioinformatics, Sun Yat-sen University Cancer Center, Guangzhou, China., Zheng YQ; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China., Wu QN; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China., Xi SY; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China., Liu ZX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.; Department of Bioinformatics, Sun Yat-sen University Cancer Center, Guangzhou, China., Li T; Department of Gastroenterology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China., Zhao Q; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.; Department of Bioinformatics, Sun Yat-sen University Cancer Center, Guangzhou, China. |
| Πηγή: | Frontiers in immunology [Front Immunol] 2026 Jun 03; Vol. 17, pp. 1804974. Date of Electronic Publication: 2026 Jun 03 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Ιατρικοί όροι (MeSH): | Colorectal Neoplasms*/immunology , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/mortality , Colorectal Neoplasms*/pathology , Cellular Senescence*/genetics , Cellular Senescence*/immunology , Circadian Rhythm*/genetics , Circadian Rhythm*/immunology, NADPH Oxidase 4/genetics ; NADPH Oxidase 4/metabolism ; Biomarkers, Tumor/genetics ; Tumor Microenvironment/immunology ; Tumor Microenvironment/genetics ; Lymphocytes, Tumor-Infiltrating/immunology ; Humans ; Prognosis ; Gene Expression Regulation, Neoplastic ; Gene Expression Profiling ; Transcriptome ; Female |
| Περίληψη: | Background: Colorectal cancer (CRC) exhibits substantial biological and prognostic heterogeneity that is not fully captured by conventional clinicopathological staging, and the interplay between the cellular senescence and circadian dysregulation in CRC remains insufficiently defined. Methods: We integrated bulk transcriptomic and clinical data from public CRC cohorts to construct a senescence-circadian interplay score (SCore). Senescence-related and circadian-related gene sets were intersected with CRC differentially expressed genes to identify candidate genes, from which a four-gene random survival forest model was established. The model was evaluated in the TCGA-COAD/READ training cohort and externally validated in GSE12945 and GSE39582. We further characterized clinicopathological associations, prognostic independence, nomogram performance, pathway enrichment, consensus molecular subtype distribution, immune landscape features, and predicted drug sensitivity. Single-cell RNA sequencing dataset was used to localize SCore-associated programs and to examine T-cell communication and differentiation dynamics. In addition, RT-qPCR in CRC cell lines, immunohistochemical validation in 120 paired CRC and adjacent non-tumor tissues, and NOX4-centered knockdown experiments were performed to provide orthogonal experimental support. Results: A higher SCore was consistently associated with poorer overall survival across cohorts and retained prognostic value when integrated with clinicopathological variables. High-SCore tumors were characterized by enrichment of oxidative stress, extracellular matrix remodeling, focal adhesion, and invasion-related programs, together with computationally inferred immune dysfunction/exclusion-associated features. Single-cell analyses localized SCore-associated signals to a T-cell-centered context, where cell-cell communication, pseudotime dynamics, and functional-state remodeling converged. Notably, MIF-(CD74+CXCR4) signaling emerged as a prominent interaction axis. Consistent with the transcriptomic findings, immunohistochemistry confirmed higher expression of NOX4, CXCL1, CDKN2A, and SIX1 in CRC tissues than in paired adjacent non-tumor tissues. Functionally, NOX4 knockdown reduced intracellular ROS, attenuated multiple inflammatory/immunoregulatory mediators, lowered PD-L1 protein expression, and suppressed migratory capacity, supporting a NOX4-associated redox/inflammatory component within the broader SCore-linked state. Conclusion: SCore provides biologically interpretable transcriptomic framework for CRC risk stratification. The NOX4-centered data provide functional support for one component of this state, whereas the broader immune and circadian implications remain hypothesis-generating. (Copyright © 2026 Luo, Zhan, Bao, Zheng, Wu, Xi, Liu, Li and Zhao.) |
| Competing Interests: | The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
| Contributed Indexing: | Keywords: NOX4; cellular senescence; circadian rhythm; colorectal cancer; immune heterogeneity; prognostic risk score; single-cell RNA sequencing |
| Substance Nomenclature: | EC 1.6.3.- (NADPH Oxidase 4) EC 1.6.3.- (NOX4 protein, human) 0 (Biomarkers, Tumor) |
| Entry Date(s): | Date Created: 20260619 Date Completed: 20260619 Latest Revision: 20260619 |
| Update Code: | 20260619 |
| PubMed Central ID: | PMC13272428 |
| DOI: | 10.3389/fimmu.2026.1804974 |
| PMID: | 42317343 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2026.1804974 |