lncRNAs are RNA molecules longer than 200 nucleotides that are critical in various cellular functions, including apoptosis, cell differentiation, development, and invasion. Their abnormal expression has been increasingly identified in cancer, suggesting their potential as biomarkers for early tumor detection, treatment monitoring, and relapse assessment. One such lncRNA, MAGI2-AS3, is widely expressed across different tissues and has been identified as a novel biomarker linked to the progression and prognosis of various malignancies.
Our comprehensive analysis of MAGI2-AS3 expression across diverse cancer types revealed significant variations in 23 different cancers. Particularly, MAGI2-AS3 was overexpressed in several carcinomas like PAAD, SKCM, and THYM and different cell lines such as 22Rv1 (human prostate carcinoma) and 23132/87 (gastric cancer), while it was underexpressed in ACC, BLCA, and BRCA and several cell lines such as YH-13 (glioblastoma) and YMB-1 (breast cancer) cell lines. These findings indicate that MAGI2-AS3 may function as either a tumor suppressor or oncogene, depending on the cancer type. Single-cell expression analysis in CRC showed MAGI2-AS3's presence in monocytes and fibroblasts within the tumor microenvironment. This finding suggests that MAGI2-AS3 may play a role in the regulation of cellular functions within the tumor microenvironment, potentially influencing tumor progression and immune responses in CRC.
Our study also identified significant associations with a various array of genes involved in tumorigenesis and cancer progression. According to the results, MAGI2-AS3 consistently correlated with multiple genes such as ZFPM2, RBMS3, and MAGI2, indicating its broad impact on cancer biology. The oncogene ZFPM2-AS1, an important upstream regulator of the MIF/P53 axis, enhances gastric cancer cell proliferation and inhibits apoptosis. The mechanism of ZFPM2-AS1 involves regulating the expression and subcellular localization of p53, where it inactivates the p53 signaling pathway through physical interaction with MIF. Previous studies have shown that MIF, as a tumor promoter, reduces p53 protein stability and prevents its nuclear translocation 27. Another study showed that MAGI2-AS3 interacts with the single-stranded RNA-binding protein RBMS3 to form the MAGI2-AS3-RBMS3 complex. In PRAD, interactions between this complex have been reported to lead to exon skipping in several genes, which promotes cancer progression and invasion 28. Furthermore, the tumor suppressor mechanism of MAGI2-AS3 operates through its target gene, MAGI2. Mechanistic studies have revealed that MAGI2 can exert tumor-suppressive effects by upregulating the tumor-suppressor protein PTEN, and inhibiting AKT1 expression 29. Additionally, MAGI2 inhibits the migration and invasion of CRC cells by interacting with β-catenin and axin 14. These findings emphasize the potential of MAGI2-AS3 as a biomarker and therapeutic target, warranting further exploration through functional and clinical studies to elucidate its precise molecular mechanisms and clinical implications in different cancer types.
Our comprehensive enrichment analysis of MAGI2-AS3 revealed marked enriched pathways, and biological processes such as cell junction and anchoring junction as well as enriched cellular components such as cytoskeletal protein binding and actin binding. It has demonstrated that MAGI2-AS3 is associated with the epithelial-mesenchymal transition (EMT) process and is co-expressed with key EMT regulators ZEB1 and ZEB2. Given EMT's fundamental role in tumor invasion, lncRNA MAGI2-AS3 may play a role in the migration and invasion of various cancer types like gastric cancer 14. In gastric cancer, MAGI2-AS3, an EMT-associated lncRNA, promotes tumor progression by sponging miR-141/200a and maintaining the overexpression of ZEB1 14. Additionally, Du et al. reported that MAGI2-AS3 acts as a therapeutic target for metastatic breast cancer by functioning as a molecular sponge for miR-374a, thereby inhibiting breast cancer cell migration and invasion through PTEN regulation 30. It has demonstrated that MAGI2-AS3 significantly inhibits breast cancer cell growth while increasing Fas and Fas ligand (FasL) expression 31. Similarly, Zhou et al. found that MAGI2-AS3 inhibits cell proliferation and migration and promotes apoptosis in MCF-7 breast cancer cells by upregulating MAGI2 and inhibiting the Wnt/β-catenin pathway 32. It has been suggested that MAGI2-AS3 plays an anti-tumor role by inhibiting the viability, proliferation, and migration of breast cancer cells and may regulate cell migration through extracellular matrix (ECM)-related proteins. Another study indicates that RAB31 inhibits the progression of CRC cells 33. Recent studies have shown that RAB31 inhibits mitogen-activated protein kinase 6 (MAPK6) degradation, interacts with the epidermal growth factor receptor (EGFR), and engages with mRNA-binding proteins like HuR and GDP/GTP exchange factors (GEFs) 34. Additionally, MAGI2-AS3 is involved in regulating apoptosis, cell growth, and migration in CRC through the miR-3163/TMEM106B axis 35. Increased MAGI2-AS3 manages miR-3163 to elevate TMEM106B expression, promoting proliferation and migration in CRC 36. The dystrophin (DMD) gene, crucial for muscle fiber integrity, is a potential risk factor at the rectum and rectosigmoid junction, regulated by a network including lncRNA MAGI2-AS3. These ncRNAs, which bind to DMD, are also sponged by the tumor-suppressive PCG FOXO1, suggesting a protective role in CRC tumors 36.
Kaplan-Meier analysis in our study indicated that increased MAGI2-AS3 expression is associated with shorter OS in several cancers such as LUSC, and BLCA, and with longer OS in Pancreatic adenocarcinoma (PAAD), LUAD, and KIRC. It has been reported that MAGI2-AS3 expression is significantly reduced in bladder cancer, indicating a poor prognosis. This study confirmed that MAGI2-AS3 acts as a tumor suppressor in bladder cancer by inhibiting cell proliferation, migration, and invasion by negatively regulating the miR-15b-5p/CCDC19 signaling axis 37.
Our heatmap analyses demonstrated significant correlations between MAGI2-AS3 expression and various immune cells and immunomodulators across all cohorts (FDR < 0.05). These results highlight the complex interplay between MAGI2-AS3 expression and the tumor microenvironment (TME), suggesting its capacity to influence cancer progression by modulating specific immune cell populations. The consistent correlation with cytokine and cytokine receptor pathways across multiple cancers highlights its potential influence on inflammation and immune signaling.
In CRC, our findings emphasize the intricate interactions of MAGI2-AS3 with various immunomodulators within the TME. Positive correlations with chemokines and antigen presentation molecules suggest MAGI2-AS3 may promote immune cell recruitment and enhance tumor antigen presentation. Conversely, associations with immunoinhibitors such as CTLA4 and PD-1 indicate MAGI2-AS3's potential involvement in immune evasion mechanisms, enabling tumors to evade immune surveillance. It can be suggested that patients with higher MAGI2-AS3 levels may derive less benefit from anti-PD-1/CTLA-4 or anti-PD-L1 therapies, whereas those with lower expression levels could potentially experience greater therapeutic benefit. These findings position MAGI2-AS3 as a promising therapeutic target and underscore its potential as a predictive marker for guiding personalized immunotherapy strategies, not only in CRC but also across other cancer types.
Loss of E-cadherin protein function, a hallmark of EMT, leads to loss of cellular polarity and tissue organization. This process is regulated by several factors including EMT transcription factors (EMT-TFs) such as ZEB family members. It has revealed that MAGI2-AS3 binds miR-141/200a, known negative regulators of ZEB1 and the EMT pathway, thereby maintaining elevated ZEB1 expression and promoting tumor metastasis 14. Additionally, some studies have implicated the lncRNA MAGI2-AS3 in the progression of CRC. The increased risk of CRC is associated with the presence of the SNP rs7783388 in lncRNA MAGI2-AS3, which affects the glucocorticoid receptor (GR) binding capacity to the MAGI2-AS3 promoter 38. Moreover, MAGI2-AS3 regulates tumor growth, cell motility, and invasiveness by enhancing the expression of cleaved PARP and cleaved caspase-3 38.
Resistance to radiotherapy remains a significant challenge in cancer treatment, despite the involvement of lncRNAs in influencing this resistance 39. Our study, utilizing heatmap analyses, has revealed a strong correlation between MAGI2-AS3 expression and the sensitivity to various chemotherapeutic agents across different cancer types. These findings suggest that MAGI2-AS3 could potentially serve as a predictive biomarker for optimizing chemotherapy strategies. Additionally, the DNA methylation pattern of MAGI2-AS3 across multiple cancers indicates hypermethylation, which correlates with its reduced expression in these cancer types.
It has shown that MAGI2-AS3 plays significant roles in drug resistance with clinical implications in colon cancer. The biological functions of MAGI2-AS3 present promising opportunities as a target for cancer therapy. For instance, increasing MAGI2-AS3 expression can sensitize esophageal cancer cells to radiotherapy in vivo and in vitro 12, whereas its depletion in NPC inhibits disease progression and reduces cisplatin resistance 40. Identification of MAGI2-AS3 as a potential biomarker for radioresistance in some cancers, suggests that gene therapy to restore MAGI2-AS3 could improve treatments by overcoming radioresistance in these malignancies. Similar observations have been reported in breast and bladder cancers, where reduced MAGI2-AS3 expression correlates with cancer progression, and restoration of MAGI2-AS3 suppresses tumor growth 31,41. It inhibits breast cancer progression by suppressing DNA methylation of the MAGI2 promoter, suggesting potential therapeutic strategies involving MAGI2-AS3 DNA methylation inhibition 32. Additionally, MAGI2-AS3 shows prognostic significance in glioma and influences pathways linked to chemoresistance 42. Epigenetic modifiers like AZA, currently being clinically evaluated for ovarian cancer therapy 43, could potentially modulate MAGI2-AS3 expression to suppress tumor growth.
Moreover, Samadi et al. have shown that in their study on colorectal cancer (CRC), the lncRNA MAGI2-AS3 exhibits a strong correlation with genes involved in TNM staging, suggesting its potential role in CRC progression. Their construction of a lncRNA–mRNA interaction network revealed that MAGI2-AS3, among other lncRNAs such as HAND2-AS1, MIR100HG, and LINC00578, shares a significant number of edges with differentially expressed genes (DEGs). Specifically, MAGI2-AS3 was identified with 220 node interactions, indicating its substantial connectivity and potential importance in CRC carcinogenesis. The study emphasizes the complexity and significance of these interactions, highlighting the necessity to explore these pivotal lncRNAs further for their role in CRC development and staging. The high connectivity of MAGI2-AS3 in the network underscores its relevance, aligning with the study's objective to identify key lncRNAs that could serve as biomarkers or therapeutic targets in CRC 44.