Long non-coding RNAs (lncRNAs) play crucial roles in regulating gene expression and tumor progression. Growth arrest specific 6-antisense RNA 1 (GAS6-AS1), a novel lncRNA located antisense to the GAS6 gene, has been increasingly recognized as an important regulator in multiple cancers. Emerging evidence demonstrates that GAS6-AS1 participates in tumor initiation and progression by functioning as a competitive endogenous RNA that modulates microRNA activity, regulates downstream target genes, and influences key signaling pathways, including Wnt/β-catenin and AXL signaling. Through these mechanisms, GAS6-AS1 affects cancer cell proliferation, migration, invasion, apoptosis, metabolic reprogramming and chemoresistance.
GAS6-AS1 exhibits context-dependent functions across different cancer types. GAS6-AS1 predominantly functions as an oncogenic lncRNA in multiple cancers, including colorectal cancer, breast cancer, hepatocellular carcinoma, ovarian cancer, glioma, gastric cancer, renal cell carcinoma and acute myeloid leukemia. In contrast, GAS6-AS1 has been reported to exert tumor-suppressive effects in lung adenocarcinoma. Abnormal expression of GAS6-AS1 is closely associated with tumor progression, metastasis and patient prognosis, highlighting its potential as a diagnostic and prognostic biomarker as well as a therapeutic target.
Overall, GAS6-AS1 represents a promising molecule for understanding cancer pathogenesis and developing novel strategies for precision cancer diagnosis and treatment, although further clinical validation and mechanistic studies are still required.
Increasing evidence indicates that long non-coding RNAs (lncRNAs) play diverse roles in multiple stages of normal cellular biology and pathological processes ([1]). LncRNAs are transcripts exceeding 200 nucleotides in length that cannot encode proteins due to the absence of open reading frames ([2]). Unlike traditional messenger RNAs, lncRNAs do not primarily function through protein translation, but instead regulate gene expression and cellular behavior through diverse molecular mechanisms. It has been shown that lncRNAs participate in chromatin remodeling, transcriptional regulation, post-transcriptional processing, RNA stability and protein modification, thereby influencing multiple physiological and pathological processes ([3]). In recent years, with the rapid development of high-throughput sequencing technologies and bioinformatics analysis, researchers have identified numerous lncRNAs associated with human diseases, especially malignant tumors. Cancer remains one of the leading causes of death worldwide, and despite considerable progress in diagnosis and treatment, the prognosis of numerous advanced malignancies remains unsatisfactory. Tumor initiation and progression involve complex interactions among oncogenes, tumor suppressor genes, signaling pathways and the tumor microenvironment. Increasing studies have confirmed that lncRNAs are deeply involved in tumorigenesis, metastasis, therapeutic resistance, immune escape and metabolic reprogramming. Therefore, lncRNAs have attracted extensive attention as novel biomarkers and therapeutic targets.
Growth arrest-specific 6 antisense RNA 1 (GAS6-AS1) is an lncRNA located on chromosome 13q34 and transcribed antisense to the GAS6 gene. It comprises five exons and produces a transcript of ~902 nucleotides. As an antisense transcript, GAS6-AS1 can regulate its cognate sense gene GAS6 by forming an RNA-RNA duplex, thereby modulating GAS6 expression and downstream AXL signaling in a context-dependent manner. In addition to this GAS6-dependent mechanism, GAS6-AS1 can also function independently through competitive endogenous (ce)RNA networks and interactions with RNA-binding proteins or transcription factors ([4]). Emerging evidence indicates that GAS6-AS1 participates in regulating proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), glycolysis and drug resistance in various tumors ([4-8]). Furthermore, GAS6-AS1 exhibits cancer-type-specific biological functions. In most malignancies, GAS6-AS1 functions as an oncogenic lncRNA that promotes tumor progression, whereas in lung adenocarcinoma (LUAD), it may exhibit tumor-suppressive properties. In addition, abnormal expression of GAS6-AS1 is significantly associated with clinicopathological characteristics, including tumor stage, lymph node metastasis, recurrence and overall survival. Therefore, GAS6-AS1 may serve not only as a molecular biomarker for early tumor diagnosis and prognosis prediction, but also as a promising target for precision therapy. Currently, the mechanisms underlying GAS6-AS1-mediated tumor progression are being gradually elucidated. GAS6-AS1 can function as a ceRNA by sponging tumor-suppressive micro (mi)RNAs and regulating downstream target genes. It can also interact with RNA-binding proteins and transcription factors to modulate signaling pathways involved in tumor development. These pathways include Wnt/β-catenin signaling, AXL signaling and glucose metabolic pathways. Through these mechanisms, GAS6-AS1 influences multiple malignant phenotypes of tumor cells. In particular, studies have revealed additional roles of GAS6-AS1 in chemoresistance and complex ceRNA- and RNA-binding protein-mediated regulatory networks, further highlighting the need for an updated and focused synthesis of this lncRNA ([4],[9]). Therefore, this review specifically summarizes current evidence regarding the aberrant expression, biological functions, molecular regulatory networks and clinical significance of GAS6-AS1 across different cancers. Its potential value as a diagnostic and prognostic biomarker and therapeutic target were also discussed, as well as current challenges and future directions for its clinical translation.
2. Characteristics of lncRNA GAS6-AS1
LncRNAs play crucial roles in regulating gene expression at both the transcriptional and post-transcriptional levels ([9],[10]). Previous studies have demonstrated that lncRNAs can exert either tumor-suppressive or oncogenic effects through diverse mechanisms, including molecular sponging and post-transcriptional regulation ([11-16]). Importantly, their tissue- and context-specific expression patterns make lncRNAs attractive candidates for cancer diagnosis and prognosis evaluation. GAS6-AS1 is a recently identified cancer-associated lncRNA that plays important roles in malignant tumors and may serve as a potential biomarker for cancer diagnosis and prognosis ([5]). GAS6-AS1 is located on chromosome 13q34 and transcribed antisense to the GAS6 gene. It has five exons and generates one variant transcript, which is composed of a 902-nt lncRNA (Fig. 1) ([4]). To investigate the secondary structure of lncRNA GAS6-AS1 in depth, this study utilized the ViennaRNA Web Services (http://rna.tbi.univie.ac.at/forna/) to visualize it using RNA secondary structure prediction and visualization analysis (Fig. 2). Subcellular localization analysis revealed an apparent discrepancy among different prediction platforms. lncLocator (http://www.csbio.sjtu.edu.cn/bioinfo/lnclocator/) predicted that GAS6-AS1 is preferentially localized in the cytoplasm (score: 0.688; Table I), whereas lncATLAS (http://lncatlas.crg.eu/) analysis based on RNA-sequencing data from multiple human cell lines indicated relative nuclear enrichment. This inconsistency may arise from differences in the underlying analytical strategies. lncLocator is an integrated machine-learning prediction tool based on sequence-derived features, whereas lncATLAS reflects experimentally generated RNA-sequencing profiles from specific cellular contexts. Therefore, the predicted localization of GAS6-AS1 may not represent a universal characteristic but rather a context-dependent pattern influenced by cell type, tumor origin, differentiation state and intracellular regulatory environment. Consistent with this concept, experimental studies have reported diverse subcellular distributions of GAS6-AS1. In LUAD cells, GAS6-AS1 was predominantly detected in the nucleus, where it interacted with the transcription factor E2F1 to regulate glucose transporter 1 (GLUT1) transcription ([6]). By contrast, studies in colorectal cancer (CRC) and acute myeloid leukemia (AML) demonstrated that GAS6-AS1 was distributed in both nuclear and cytoplasmic compartments, enabling distinct regulatory mechanisms, including miRNA sponging and RNA-binding protein-mediated regulation ([5],[7]). These findings suggest that GAS6-AS1 does not possess a fixed subcellular localization; instead, its intracellular distribution may determine its functional mode in different tumor contexts (Fig. 3). Cytoplasmic enrichment may facilitate ceRNA-mediated post-transcriptional regulation, whereas nuclear localization may support transcriptional regulation or interactions with nuclear RNA-binding proteins. Further experimental validation using cell-type-specific fractionation and imaging approaches is required to fully define the dynamic localization landscape of GAS6-AS1. Structural analysis of lncRNAs is important because their biological functions are closely associated with their secondary and tertiary structures, which influence their interactions with RNA-binding proteins and other nucleic acids. GAS6-AS1 regulates GAS6 levels at the transcriptional or translational level, thereby increasing AXL expression in a tumor-context-dependent manner and activating the AXL signaling pathway. GAS6 is a vitamin K-dependent protein and a high-affinity ligand for the AXL receptor tyrosine kinase ([17]). Structurally, GAS6 comprises a γ-carboxyglutamic acid domain, four epidermal growth factor-like domains and two laminin G-like domains ([18]). The GAS6/AXL signaling axis regulates multiple cancer-related processes, including cell proliferation, migration, apoptosis, angiogenesis, immune regulation and drug resistance ([19]), suggesting that GAS6-AS1 may influence tumor progression through modulation of GAS6. Current evidence indicates that GAS6-AS1 participates in cancer pathogenesis through both GAS6-dependent and GAS6-independent mechanisms ([20]). In GAS6-dependent mechanisms, GAS6-AS1 regulates the expression and activity of GAS6 and subsequently activates downstream signaling pathways. By contrast, GAS6-independent mechanisms involve the ceRNA network, transcriptional regulation and interactions with RNA-binding proteins. These diverse mechanisms explain the broad functional spectrum of GAS6-AS1 in different tumor types. An analysis using the Gene Expression Profiling Interactive Analysis (GEPIA) online database (http://gepia.cancer-pku.cn/) revealed that the expression of GAS6-AS1 varies significantly across several cancers (Fig. 4). LncRNA GAS6-AS1 is overexpressed in numerous human cancers and represents a promising candidate among tumor-associated lncRNAs. Its expression pattern varies across tumor tissues and cell lines, suggesting that GAS6-AS1 may have context-dependent biological functions. Furthermore, the association between GAS6-AS1 expression and clinicopathological characteristics indicates that it may serve as a clinically valuable biomarker.
3. Mechanism of action of lncRNA GAS6-AS1 in tumors
LncRNA GAS6-AS1 regulates tumor initiation and progression primarily through functioning as a ceRNA that modulates miRNA activity and downstream signaling pathways. According to the ceRNA hypothesis, lncRNAs can competitively bind miRNAs through miRNA response elements, thereby preventing miRNAs from suppressing their target mRNAs. Through this mechanism, GAS6-AS1 indirectly regulates the expression of multiple oncogenes and tumor suppressor genes. In multiple malignancies, GAS6-AS1 promotes cancer cell proliferation, migration, invasion, EMT and tumor growth by sponging tumor-suppressive miRNAs, including miR-370-3p, miR-1296-5p, miR-215-5p, miR-585 and miR-324-3p, thereby upregulating target genes such as tripartite motif-containing 14 (TRIM14), SRY-box transcription factor 9 (SOX9), eukaryotic translation initiation factor 5A2 (EIF5A2), tetraspanin 3 (TSPAN3) and spermatogenesis associated 2 (SPATA2). By contrast, in LUAD, GAS6-AS1 functions as a tumor suppressor through the GAS6-AS1/miR-24-3p/GTPase of the immune-associated nucleotide-binding protein family member 6 (GIMAP6) axis, where GAS6-AS1 sponges miR-24-3p and increases GIMAP6 expression, thereby suppressing tumor progression ([21]). Additionally, GAS6-AS1 can interact with RNA-binding proteins to enhance mRNA stability and activate oncogenic signaling pathways, such as the Wnt/β-catenin pathway. Notably, the biological effects of GAS6-AS1 are highly context dependent and are determined by the specific downstream regulatory networks engaged in different tumor settings. This functional diversity highlights the complexity of GAS6-AS1-mediated regulation in cancer biology. This dual role highlights the complexity of lncRNA-mediated regulation in cancer biology. Collectively, GAS6-AS1 influences tumor progression through miRNA-mediated regulatory networks and represents a potential biomarker and therapeutic target across diverse cancers (Fig. 5, Table II).
ceRNA-dependent networks of GAS6-AS1. GAS6-AS1 and CRC
CRC is among the most commonly diagnosed malignancies worldwide and represents a major cause of cancer-related mortality according to GLOBOCAN 2022([22]). The incidence of CRC has been increasing steadily in recent decades due to changes in dietary habits, lifestyle, obesity and population aging. CRC lacks distinct clinical manifestations, so most patients are diagnosed at an advanced stage, resulting in poor survival outcomes, particularly among patients diagnosed at advanced stages ([23]). Therefore, identifying novel molecular biomarkers and therapeutic targets is particularly important for improving patient outcomes. Chen et al ([5]) found that GAS6-AS1 is upregulated in CRC and positively correlates with tumor progression and poor prognosis. High GAS6-AS1 expression is associated with larger tumor size, lymph node metastasis, advanced TNM stage and shorter survival time. Functional studies demonstrated that GAS6-AS1 regulates the proliferation, migration, invasion and EMT of CRC cells in vitro, while inducing the growth and metastasis of CRC in vivo (5). EMT is a crucial biological process during tumor metastasis, and GAS6-AS1 appears to contribute significantly to this process. Experimental validation confirms that GAS6-AS1 exerts its oncogenic function by competitively binding to miR-370-3p and miR-1296-5p, thereby elevating TRIM14 expression. TRIM14 is an important regulator involved in innate immunity, cell proliferation and tumor progression. Both GAS6-AS1 and TRIM14 interact with fused in sarcoma (FUS), and GAS6-AS1 stabilizes TRIM14 mRNA by recruiting FUS. These findings suggest that GAS6-AS1 not only regulates gene expression through ceRNA mechanisms but also modulates mRNA stability through RNA-binding proteins. Overall, the GAS6-AS1/miR-370-3p/miR-1296-5p/TRIM14 regulatory network plays a crucial role in CRC progression. These findings suggest that GAS6-AS1 may serve as a novel biomarker and therapeutic target for CRC.
GAS6-AS1 and LUAD. Lung cancer represents a major global cancer burden and was the most frequently diagnosed cancer and the leading cause of cancer-related death worldwide in 2022, with ~2.5 million new cases and 1.8 million deaths ([22]). Non-small cell lung cancer (NSCLC) can be further classified into LUAD and lung squamous cell carcinoma ([24]). In recent years, the incidence of LUAD has been on the rise. Although advances in surgery, targeted therapy, immunotherapy, radiotherapy and chemotherapy have improved clinical outcomes, the overall survival rate remains
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