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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.

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
The Role of NOL3 in Colon Adenocarcinoma Metastasis and Its Association With DNA Methylation. Human mutation\| PubMed ID: 41040951	2025

Jinjing Xu

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