Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long‐standing recognition of the crosstalk between carcinoma‐associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer‐associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA‐ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β‐catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β‐catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.

Excessive reactive oxygen species (ROS) are closely associated with the initiation and progression of cancers. As the most abundant intracellular antioxidant, glutathione (GSH) plays a critical role in regulating cellular ROS levels, modulating physiological processes, and is intricately linked to tumor progression and drug resistance. However, the underlying mechanisms remain not fully elucidated. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of GSH levels. Different ncRNAs modulate various pathways involved in GSH metabolism, and these regulatory targets have the potential to serve as therapeutic targets for enhancing cancer treatment. In this review, we summarize the functions of GSH metabolism and highlight the significance of ncRNA-mediated regulation of GSH in cancer progression, drug resistance, and clinical applications.

Acquired resistance poses a significant obstacle to the effectiveness of platinum-based treatment for cancers. As the most abundant antioxidant, glutathione (GSH) enables cancer cell survival and chemoresistance, by scavenging excessive reactive oxygen species (ROS) induced by platinum. Therapeutic strategy targeting GSH synthesis has been developed, however, failed to produce desirable effects in preventing cancer progression. Thus, uncovering mechanisms of rewired GSH metabolism may aid in the development of additional therapeutic strategies to overcome or delay resistance. Here, we identify upregulation of long noncoding RNA (lncRNA) GDIL (GSH Degradation Inhibiting LncRNA) in platinum resistant colorectal cancer (CRC) and ovarian cancer cells compared with parental ones. High expression of GDIL in resistant CRC is associated with poor survival and hyposensitivity to chemotherapy. We demonstrate that GDIL boosted GSH levels and enhances clearance of ROS induced by platinum. Metabolomic and metabolic flux analysis further reveals that GDIL promotes GSH accumulation by inhibiting GSH degradation. This is attributed by downregulation of CHAC1, an enzyme that specifically degrades intracellular GSH. Mechanistically, GDIL binds and re-localizes the nuclear protein XRN2 to the cytoplasm, where GDIL further serve as a scaffold for XRN2 to identify and degrade CHAC1 mRNA. Suppression of GDIL with selective antisense oligonucleotide, restored drug sensitivity in platinum resistant cell lines and delayed drug resistance in cell line- and patient-derived xenografts. Thus, lncRNA GDIL is a novel target to promote GSH degradation and augment platinum therapy.

Background: Studies highlight the role of migrasomes as mediators of intercellular communication and signaling, critical in influencing tumorigenesis and progression. Yet migrasome-related genes and their potential role in colorectal cancer prognosis remain unexplored. Methods: Differentially expressed gene set A (DEG set A) was identified in the TCGA-CRC dataset, and Weighted Gene Co-expression Network Analysis (WGCNA) was performed to identify the most important modules associated with migrasome-related gene (MRG) scores. Single-cell RNA-seq dataset GSE231559 DEG set B was determined. Candidate migrasome-related genes were filtered by intersecting DGE set A, key module genes, and DEG set B. Prognostic genes were subsequently screened through regression analysis, and a risk model was developed. Patients with CRC in the TCGA cohort were stratified into high- and low-risk groups based on the optimal cutoff of the risk score. Immunotherapy response-related analyses were then performed. Finally, cell-to-cell communication analysis was carried out for key cells identified based on prognostic gene expression analysis in annotated cells. Results: The six candidate migrasome-related genes were identified through the overlap of 5158 DEG set A, 1960 key module genes, and 146 DEG set B. Further screening led to the selection of T1MP1, CXCL8, and MGP as potential prognostic biomarkers. Immune-related analysis indicated that the high-risk group exhibited a better response to immunotherapy. Notably, the prognostic genes showed elevated expression levels in monocytes and tissue stem cells, thereby designating them as key cell types. Conclusions: We conducted bioinformatic analysis of migrasome-related genes and identified significant involvement of T1MP1, CXCL8, and MGP in influencing CRC prognosis and immunotherapy response. Our research provides novel insights into the role of migrasomes in CRC biology.