expression-clinical-significance-role-immunotherapy-efficacy

Expression, Clinical Significance, and Role in Immunotherapy Efficacy Evaluation of the Co-stimulatory Molecule LLT1 in Gastric Cancer

LLT1 is a novel immune checkpoint molecule and potential therapeutic target. Immunotherapy has improved outcomes in advanced gastric cancer; however, many ...

The First Affiliated Hospital of Soochow University

Colon adenocarcinoma (COAD) is the most frequently occurring type of colon cancer. Cancer-associated fibroblasts (CAFs) are pivotal in facilitating tumor growth and metastasis; however, their specific role in COAD is not yet fully understood. This research utilizes single-cell RNA sequencing (scRNA-seq) to identify and validate gene markers linked to the malignancy of CAFs.

The malignant signature gene of cancer-associated fibroblasts serves as a potential prognostic biomarker for colon adenocarcinoma patients.

 Colorectal cancer (CRC) is acknowledged as the third leading cause of cancer-related mortality, attributed to its high incidence and fatality rates. Long noncoding RNAs (lncRNAs) have emerged as novel biomarkers for the treatment of colon adenocarcinoma. This study is aimed at investigating the function and underlying mechanisms of the lncRNA fetal-lethal noncoding developmental regulatory RNA (FENDRR) in regulating the malignant phenotype of CRC (COAD) cells.  This investigation examined FENDRR expression patterns and their association with clinical outcomes in 496 COAD and 173 READ patients from The Cancer Genome Atlas (TCGA) dataset. Additionally, 10 clinical COAD specimens were collected to validate FENDRR expression levels. Using lentiviral-mediated gene delivery, we stably upregulated FENDRR in HCT-116 cells, with transcriptional changes quantified via qPCR. The tumor biological behavior was evaluated using in vitro experiments, including CCK-8, colony formation, wound healing, transwell assays, and immunofluorescence staining. Protein-level alterations were subsequently confirmed by Western blot.  Through bioinformatics evaluation, a notable decrease in FENDRR expression levels was observed in both COAD and READ tissues, with a pronounced link between FENDRR expression and tumor T stage classification in COAD cases. Patients exhibiting diminished FENDRR expression showed worse clinical outcomes in COAD. Enrichment analysis demonstrated significant associations between FENDRR and various signaling cascades, particularly the cAMP pathway. Additionally, immune cell infiltration analysis showed a significant association with FENDRR expression levels. In vitro experiments confirmed that FENDRR overexpression hindered the proliferation, migration, and invasion of cells. Mechanistically, FENDRR has been demonstrated to induce the sinking of the DUSP4/CREB/PRKACB signaling pathway and reverse the epithelial-mesenchymal transition (EMT) pathway, thereby inhibiting tumor growth.  We establish FENDRR as a tumor-suppressing gene that plays a significant role in suppressing the advancement and metastatic spread of COAD. These findings underscore its diagnostic and prognostic utility in COAD.

FENDRR Affects COAD Biological Behavior by Inhibiting the DUSP4/CREB/PRKACB Pathway.

IntroductionGastric cancer (GC) is a highly heterogeneous malignancy, necessitating novel therapeutic targets. B7-H3 and CD39, as immune checkpoints, are potential modulators of the tumor microenvironment and may influence the efficacy of immunotherapies.MethodsB7-H3, CD39, and CD8 expression was assessed via immunohistochemistry (IHC) in 268 GC tissues and 80 gastric precancerous lesions. The correlation between B7-H3 and CD39 expression was analyzed using Spearman's correlation. Multiplex immunohistochemistry (m-IHC) was employed to determine the co-localization of B7-H3 and CD39 in GC tissues. Kaplan-Meier survival analysis and Cox regression models were utilized to evaluate clinical outcomes in different patient subgroups.ResultsBoth B7-H3 and CD39 expression showed a stepwise increase during gastric carcinogenesis including chronic superficial gastritis (CSG), chronic atrophic gastritis (CAG), low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN) to GC, with significantly higher expression levels in GC tissues compared to all precancerous lesions ( < .05). A significant positive correlation was observed between B7-H3 and CD39 expression (r = 0.2398,  < .001). Co-localization of B7-H3 and CD39 was detected within tumor nests and peritumoral regions and was significantly correlated with tumor volume ( = .017), tumor stage ( = .001), tumor depth ( = .002), lymph node metastasis ( = .005), lymph node involvement ( = .004) and distant metastasis ( = .028). Kaplan-Meier analysis revealed that patients with co-localized B7-H3 and CD39 expression exhibited significantly poorer prognosis ( = .0055). Cox regression analysis confirmed that this co-localization was a significant predictor of survival ( = .007) and an independent prognostic factor in multivariate analysis ( = .027).ConclusionThe co-localized expression of B7-H3 and CD39 in GC patients is strongly associated with poor prognosis. This dual-target expression pattern provides novel insights and a theoretical foundation for the development of dual-target immune checkpoint inhibitors as potential therapeutic strategies.

B7-H3 and CD39 Co-Localization in Gastric Cancer: A Potential Prognostic Biomarker and Potential Dual-Target for Immunotherapy.

Colon adenocarcinoma (COAD) is a particularly aggressive cancer type, frequently identified at a later stage. Thus, it is crucial to enhance our understanding of the fundamental mechanisms that govern COAD cellular behavior and to perform extensive research into the biological foundations underlying its development, progression, invasion, and metastasis. We initially discovered NOL3 as a significant gene influencing COAD metastasis through the application of the weighted gene coexpression network analysis algorithm using the TCGA-COAD dataset. This was succeeded by an assessment of NOL3's expression levels and prognostic significance. Moreover, we investigated the biological roles of NOL3 utilizing transcriptomic data. Our results demonstrate significant associations between NOL3 and immune infiltration in COAD, as well as sensitivity to chemotherapy. Furthermore, we utilized the tumor immune dysfunction and exclusion (TIDE) algorithm to evaluate how various cohorts responded to immune checkpoint therapies. Ultimately, the influence of NOL3 on the metastasis of COAD cells was confirmed through in vitro experiments. Our results indicate that NOL3 can promote COAD metastasis, and its underlying mechanism may be associated with DNA methylation. In summary, NOL3 has been identified by us as a key biomarker for COAD metastasis.

Article	Year
The malignant signature gene of cancer-associated fibroblasts serves as a potential prognostic biomarker for colon adenocarcinoma patients. Frontiers in immunology\| PubMed ID: 40313961	2025
FENDRR Affects COAD Biological Behavior by Inhibiting the DUSP4/CREB/PRKACB Pathway. International journal of genomics\| PubMed ID: 40630642	2025
B7-H3 and CD39 Co-Localization in Gastric Cancer: A Potential Prognostic Biomarker and Potential Dual-Target for Immunotherapy. Technology in cancer research & treatment\| PubMed ID: 40990627	2025
The Role of NOL3 in Colon Adenocarcinoma Metastasis and Its Association With DNA Methylation. Human mutation\| PubMed ID: 41040951	2025

Ruipeng Wang

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