Circular RNAs, distinct from linear RNA molecules, form covalently closed loop structures without 5’ to 3’ polarity, conferring them notable stability and unique biological functions. Their capacity to act as molecular sponges for microRNAs (miRNAs) positions them as critical regulators of gene expression, influencing a broad spectrum of cellular processes including proliferation, differentiation, and apoptosis. Researchers have increasingly recognized circRNAs as pivotal modulators of tumorigenesis across multiple cancer types; however, their precise roles in gastric cancer remain insufficiently characterized. This latest investigation offers the first comprehensive genome-wide insight into the alteration of circRNA landscapes within extracellular vesicles (EVs) circulating in patient plasma.

Utilizing state-of-the-art high-throughput RNA sequencing of plasma-derived extracellular vesicles from gastric cancer patients, the researchers identified a marked downregulation of circMORC1. Extracellular vesicles, nanoscale membranous structures secreted into the bloodstream, serve as intercellular messengers carrying nucleic acids and proteins, thereby influencing tumor microenvironment remodeling and systemic disease progression. The decreased abundance of circMORC1 in plasma EVs was paradoxical given its observed upregulation within malignant gastric epithelial cells, underscoring a complex compartmentalized expression pattern reflective of dynamic tumor-host interactions.

To resolve this apparent contradiction, functional characterization of circMORC1 was undertaken using cultured gastric cancer cell lines AGS and SGC-7901. Manipulation of circMORC1 levels revealed a robust promotion of tumorigenic phenotypes: increased cell proliferation, enhanced viability, accelerated migration, and significant inhibition of programmed cell death pathways. These phenotypic effects firmly establish circMORC1 as an oncogenic effector at the cellular level, suggesting its elevated intracellular presence actively drives malignancy progression.

Delving into the mechanistic basis of circMORC1’s oncogenic function, the study employed luciferase reporter and RNA pull-down assays to identify direct molecular interactions. A critical finding emerged demonstrating that circMORC1 binds and sequesters miR-103a-1-5p, a microRNA that ordinarily exerts tumor-suppressive effects by negatively regulating downstream signaling pathways. This interaction exemplifies the “sponge” model, where circRNAs attenuate miRNA availability, thereby modulating post-transcriptional gene silencing. Such a relationship corroborates the emerging paradigm where competing endogenous RNAs (ceRNAs) orchestrate complex gene expression networks in cancer.

Further transcriptomic profiling via RNA-sequencing and quantitative PCR assays implicated the Wnt signaling pathway as the principal downstream effector modulated by the circMORC1/miR-103a-1-5p axis. The Wnt pathway, a well-established driver of cellular proliferation, survival, and metastasis across multiple carcinomas, was found to be relieved from miRNA-mediated inhibition through circMORC1 sequestration of miR-103a-1-5p. This derepression catalyzes aberrant Wnt pathway activation, reinforcing oncogenic signaling cascades that facilitate gastric tumor growth and invasive potential.

Critically, this work delineates a novel regulatory feedback loop wherein circMORC1 acts as an oncogenic RNA sponge to counteract the suppressive effects of miR-103a-1-5p on the Wnt pathway, thereby stimulating tumorigenesis. This mechanistic insight not only enriches current models of gastric cancer molecular biology but also highlights circMORC1 as a compelling biomarker. Its differential abundance in circulatory EVs versus tumor cells offers a dual-faceted diagnostic angle—potentially improving early detection accuracy and monitoring disease progression or therapeutic response.

The clinical implications of these findings are profound. Given gastric cancer’s often late diagnosis and suboptimal prognoses, identifying stable, sensitive biomarkers in plasma EVs introduces a minimally invasive avenue for screening high-risk populations. Moreover, targeting the circMORC1/miR-103a-1-5p/Wnt signaling nexus opens new therapeutic strategies tailored to disrupt the oncogenic RNA interactome. Pharmacological approaches could involve diminishing circMORC1 expression or restoring miR-103a-1-5p functionality, thus reinstating tumor-suppressive pathways and curtailing malignant phenotypes.

This study is emblematic of a broader shift in cancer research emphasizing the non-coding genome’s regulatory capacity. While protein-coding genes have dominated therapeutic targeting historically, the emerging appreciation of circRNAs heralds a future where RNA-based diagnostics and interventions become integral to oncology practice. The stability of circRNAs in biofluids, coupled with their specificity and functional versatility, underscores their translational potential far beyond gastric cancer.

In addition, the compartmentalized expression pattern observed—circMORC1’s increase inside gastric cancer cells but decrease in circulating EVs—raises compelling biological questions regarding nucleic acid trafficking and intercellular communication. The selective packaging or clearance of circRNAs via EVs might constitute a tumor cell mechanism to modulate local versus systemic environments, possibly influencing immune evasion or metastatic niche conditioning. Further exploration of these dynamics may unravel novel facets of tumor biology and systemic regulation.

Furthermore, this research exemplifies the power of integrative multi-omics techniques combining RNA sequencing, biochemical assays, and functional cellular analyses to decode intricate molecular interplays. Such an approach not only strengthens the validity of discovered mechanisms but also accelerates the translation from molecular findings to clinical application, underscoring the vital role of interdisciplinary collaboration within biomedical sciences.

In conclusion, the revelation of circMORC1’s oncogenic role through miR-103a-1-5p sponging and subsequent Wnt pathway activation represents a significant leap forward in gastric cancer research. By defining a previously unappreciated RNA-based regulatory axis, this work opens novel avenues for biomarker development and targeted therapeutics. As research continues to unravel the expansive regulatory universe of circRNAs, their integration into precision oncology frameworks promises to transform gastric cancer management and improve patient outcomes worldwide.

Subject of Research: Regulation of gastric cancer progression by circMORC1 via miR-103a-1-5p sponging and Wnt signaling pathway modulation.

Article Title: CircMORC1 downregulated in plasma EVs promotes gastric cancer cell proliferation and invasion via miR-103a-1-5p sponging.

Article References:
Zhai, XM., Yang, YQ., Lin, L. et al. CircMORC1 downregulated in plasma EVs promotes gastric cancer cell proliferation and invasion via miR-103a-1-5p sponging. BMC Cancer 25, 1313 (2025). https://doi.org/10.1186/s12885-025-14688-7

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14688-7

Esophageal squamous cell carcinoma accounts for a significant proportion of esophageal cancer cases globally, with high mortality attributed to its late detection and rapid dissemination. Precision oncology demands a thorough understanding of the molecular underpinnings behind ESCC’s malignancy. Within this context, non-coding RNAs, particularly circular RNAs (circRNAs), have emerged as crucial regulators in cancer biology. Unlike linear RNAs, circRNAs possess a covalently closed loop structure that confers exceptional stability, enabling them to participate in post-transcriptional regulatory networks. However, the exact roles of many circRNAs in esophageal cancer remained elusive until now.

The researchers employed a multifaceted approach combining transcriptome sequencing and quantitative PCR to systematically profile circSLC22A3 expression in ESCC tissues and cell lines. Their findings revealed a pronounced downregulation of circSLC22A3 in cancerous samples compared to normal esophageal tissues. Through rigorous validation techniques including Sanger sequencing, RNase R digestion assays, and fluorescence in situ hybridization, the circular nature and subcellular localization of circSLC22A3 were confirmed, setting the stage for functional characterization.

Functional assays both in vitro and in vivo painted a compelling picture: restoring circSLC22A3 expression notably curtailed the migratory and invasive capacities of ESCC cells, hallmarks of metastatic potential. This suppression of malignant phenotype underscores circSLC22A3’s potential as a tumor suppressor. To dissect the mechanisms underpinning this effect, the team delved into identifying the molecular interactors and regulatory partners of circSLC22A3.

One pathway unveiled involves circSLC22A3 acting as a molecular sponge for miR-19b-3p, a microRNA known previously to facilitate carcinogenic processes. By sequestering miR-19b-3p, circSLC22A3 alleviates its inhibitory control over trafficking kinesin protein 2 (TRAK2), thus promoting TRAK2 expression. TRAK2 plays a crucial role in intracellular transport systems, and its upregulation contributes to limiting cancer cell dissemination. This circSLC22A3/miR-19b-3p/TRAK2 axis delineates a novel molecular cascade impinging directly on ESCC metastatic behavior.

Beyond miRNA sponging, circSLC22A3 exhibits another sophisticated mode of action through RNA-protein interactions. The study identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as a primary circSLC22A3-associated protein. IGF2BP1 is recognized for its role as an m^6A “reader” protein, binding mRNAs modified by N6-methyladenosine, a widespread epigenetic mark influencing mRNA stability and translation. The circSLC22A3/IGF2BP1 interaction perturbs the stabilization of acyl-CoA synthetase bubblegum family member 1 (ACSBG1) mRNA, which bears m^6A modifications.

ACSBG1 has been implicated in lipid metabolism pathways relevant to cancer cell energy dynamics and proliferation. The study’s use of methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that IGF2BP1 recognizes m^6A-modified ACSBG1 mRNA, promoting its stability. However, circSLC22A3’s binding to IGF2BP1 appears to disrupt this process, reducing ACSBG1 mRNA half-life as demonstrated by actinomycin D transcriptional shutoff assays. This post-transcriptional control leads to decreased ACSBG1 protein levels, attenuating ESCC invasive properties.

Integrating these molecular insights, the research delineates a dual-axis tumor suppressive mechanism: on one front, the circSLC22A3/miR-19b-3p/TRAK2 axis enhances intracellular trafficking constraints on malignant cells; on the other, the circSLC22A3/IGF2BP1/ACSBG1 axis diminishes pro-metastatic lipid metabolic signaling via targeted mRNA destabilization. The synergy of these pathways orchestrates a robust blockade against tumor progression.

Crucially, tissue microarray analyses underscored clinical relevance by correlating low circSLC22A3 levels with aggressive tumor phenotypes and poor patient prognosis. Such findings elevate circSLC22A3 from a molecular curiosity to a promising biomarker candidate. Furthermore, restoring circSLC22A3 expression or targeting its downstream effectors could inspire novel therapeutic modalities aimed at curbing ESCC metastasis.

This revelation of circSLC22A3’s multifaceted tumor suppressor role invites deeper exploration into circular RNA biology within oncology. The study exemplifies how circRNAs, beyond mere miRNA sponges, engage in intricate RNA-protein interactions modulating epigenetic mRNA modifications, a frontier area in cancer research. The interplay between circRNAs, m^6A machinery, and mRNA stability unveils additional layers of post-transcriptional regulation with therapeutic implications.

Moreover, the identification of TRAK2 as a functional effector through miR-19b-3p modulation links intracellular trafficking pathways to cancer invasiveness, suggesting that targeting motor proteins may offer unexplored anti-metastatic strategies. Similarly, ACSBG1’s involvement bridges metabolic regulation with oncogenic signaling, supporting the growing recognition of metabolic reprogramming in cancer aggressiveness.

As the landscape of ESCC treatment remains bleak with limited targeted options, the discovery of circSLC22A3-mediated signaling axes provides hope for precision medicine approaches. Future research will need to address how circSLC22A3 expression can be modulated clinically and whether synthetic circRNA mimetics or small molecules interfering with miR-19b-3p or IGF2BP1 interactions can be developed.

The study’s comprehensive methodology, integrating transcriptomics, molecular biology, and clinical correlations, sets a benchmark for investigating circRNAs in cancer. This work not only advances esophageal cancer biology but also exemplifies the power of epigenetic and post-transcriptional networks in malignancy.

In summary, circSLC22A3 emerges as a multifaceted suppressor of ESCC invasion and metastasis by concurrently mitigating oncogenic miRNA effects and destabilizing pro-metastatic mRNAs through m^6A-dependent mechanisms. These insights offer fertile ground for novel anti-cancer strategies and underscore the indispensable roles of non-coding RNA species in tumor regulation.

Subject of Research: The role of circSLC22A3 in inhibiting invasion and metastasis in esophageal squamous cell carcinoma via miRNA sponging and m^6A-mediated mRNA regulation.

Article Title: CircSLC22A3 inhibits the invasion and metastasis of ESCC via the miR-19b-3p/TRAK2 axis and by reducing the stability of m^6A-modified ACSBG1 mRNA.

Article References:
Pan, Y., Yang, H., Zhang, J. et al. CircSLC22A3 inhibits the invasion and metastasis of ESCC via the miR-19b-3p/TRAK2 axis and by reducing the stability of m^6A-modified ACSBG1 mRNA. BMC Cancer 25, 971 (2025). https://doi.org/10.1186/s12885-025-14390-8

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14390-8