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Background <p>Extracellular vesicle (EV)-based liquid biopsy is increasingly recognized as a promising strategy for cancer diagnosis and prognosis, as EVs carry abundant, stable biomolecular cargo. N6-methyladenosine (m6A), the most prevalent modification in eukaryotic intracellular RNA, plays a critical role in regulating diverse cellular processes and has been implicated in tumor initiation and progression. However, the potential of EV-associated m6A-modified RNA (EV-m6A RNA) as a clinically useful biomarker for cancer detection remains unclear.</p> Methods <p>EV-RNA was isolated from tumor tissues and matched serum samples collected from 76 colorectal cancer (CRC) patients. Serum samples from 30 healthy donors were included as controls. Serum EVs were prepared using the ExoQuick™ precipitation reagent. EV-RNA was extracted using Trizol reagent, and EV-m6A RNA levels were quantified using an enzyme-linked immunosorbent assay (ELISA).</p> Results <p>Precipitation-enriched serum particles (PESPs) isolated from CRC patients and healthy donors were identified as CD9(+)/CD63(+)/ALIX(+) small particles, with a mean particle diameter of 60–70&#xa0;nm. The ApoB expression was detectable in PESPs. The mean PESP concentration and PESP-RNA yield were significantly higher in CRC patients than in healthy controls (PESP concentration: 11 ± 8 × 10<sup>12</sup>/mL vs. 5 ± 2 × 10<sup>12</sup>/mL, <i>p</i> &lt; 0.001; PESP-RNA yield: 57 ± 52 ng/µL vs. 22 ± 15 ng/µL, <i>p</i> &lt; 0.001). Through m6A modification-specific ELISA quantification, receiver operating characteristic (ROC) curve analysis demonstrated good discriminatory performance of normalized PESP-m6A RNA levels for CRC detection (AUC, 0.8346; 95% CI, 0.7583–0.9110; <i>p</i> &lt; 0.0001). PESP-m6A RNA levels were noted to be higher in late-stage (III/IV) CRC patients than in those with early-stage (I/II) disease (0.015 ± 0.001% vs. 0.009 ± 0.005%, <i>p</i> &lt; 0.001) with no significant correlation with intratumoral METTL3 expression, a m6A writer. Increased PESP-m6A RNA abundance further predicted a worse overall survival (OS) in CRC patients (<i>p</i> = 0.0107; HR, 3.938), while m6A RNA levels in tumor tissues showed no significant prognostic value (<i>p</i> = 0.7765; HR, 1.153).</p> Conclusion <p>These findings support circulating PESP-m6A RNA levels as a feasible and noninvasive biomarker for CRC diagnosis, with additional potential for liquid biopsy-based prognostication and longitudinal disease monitoring.</p>

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Circulating N6-methyladenosine RNA as a diagnostic and a stage-associated prognostic biomarker in colorectal cancer

  • 期刊论文

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  • 发表日期：

    2026年6月15日

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  • You-Tong Lin,
  • An-Chen Chang,
  • Chian-Shiu Chien,
  • Chun-Chi Lin,
  • Hsin-Yi Lan,
  • Hao-Wei Teng,
  • Wei-Lun Hwang

摘要

Background

Extracellular vesicle (EV)-based liquid biopsy is increasingly recognized as a promising strategy for cancer diagnosis and prognosis, as EVs carry abundant, stable biomolecular cargo. N6-methyladenosine (m6A), the most prevalent modification in eukaryotic intracellular RNA, plays a critical role in regulating diverse cellular processes and has been implicated in tumor initiation and progression. However, the potential of EV-associated m6A-modified RNA (EV-m6A RNA) as a clinically useful biomarker for cancer detection remains unclear.

Methods

EV-RNA was isolated from tumor tissues and matched serum samples collected from 76 colorectal cancer (CRC) patients. Serum samples from 30 healthy donors were included as controls. Serum EVs were prepared using the ExoQuick™ precipitation reagent. EV-RNA was extracted using Trizol reagent, and EV-m6A RNA levels were quantified using an enzyme-linked immunosorbent assay (ELISA).

Results

Precipitation-enriched serum particles (PESPs) isolated from CRC patients and healthy donors were identified as CD9(+)/CD63(+)/ALIX(+) small particles, with a mean particle diameter of 60–70 nm. The ApoB expression was detectable in PESPs. The mean PESP concentration and PESP-RNA yield were significantly higher in CRC patients than in healthy controls (PESP concentration: 11 ± 8 × 1012/mL vs. 5 ± 2 × 1012/mL, p < 0.001; PESP-RNA yield: 57 ± 52 ng/µL vs. 22 ± 15 ng/µL, p < 0.001). Through m6A modification-specific ELISA quantification, receiver operating characteristic (ROC) curve analysis demonstrated good discriminatory performance of normalized PESP-m6A RNA levels for CRC detection (AUC, 0.8346; 95% CI, 0.7583–0.9110; p < 0.0001). PESP-m6A RNA levels were noted to be higher in late-stage (III/IV) CRC patients than in those with early-stage (I/II) disease (0.015 ± 0.001% vs. 0.009 ± 0.005%, p < 0.001) with no significant correlation with intratumoral METTL3 expression, a m6A writer. Increased PESP-m6A RNA abundance further predicted a worse overall survival (OS) in CRC patients (p = 0.0107; HR, 3.938), while m6A RNA levels in tumor tissues showed no significant prognostic value (p = 0.7765; HR, 1.153).

Conclusion

These findings support circulating PESP-m6A RNA levels as a feasible and noninvasive biomarker for CRC diagnosis, with additional potential for liquid biopsy-based prognostication and longitudinal disease monitoring.