Circular RNAs, or circRNAs, are unusual RNA molecules produced when a stretch of RNA is spliced head-to-tail, creating a closed loop with a distinctive back-spliced junction. For decades they were dismissed as transcriptional noise, but researchers now know that some circRNAs are far from inert: they can sponge microRNAs, interact with proteins, and, remarkably, serve as templates for protein synthesis. The coding potential of circRNAs comes from short open reading frames, abbreviated sORFs, which are brief sequences that ribosomes can translate into micropeptides typically fewer than 100 amino acids long. Because these sequences are short and circRNAs are often expressed at low levels, identifying which circular RNAs actually encode functional peptides has been a major technical challenge in the field.

The research team approached this problem with integrative transcriptomic profiling, comparing the circular RNA landscape of KRAS-mutant colorectal cancer tumors with that of other samples to find circRNAs that are dysregulated specifically in the KRAS-mutant setting. Their search pinpointed circRAB6A, a circular RNA derived from the RAB6A gene, as highly expressed in KRAS-mutant colorectal cancer. Clinical data added weight to the observation: patients whose tumors carried elevated circRAB6A abundance had poorer clinical outcomes, linking this molecule to aggressive disease. The association suggests that circRAB6A is not merely a passenger alteration but a contributor to tumor progression.

To determine whether circRAB6A could actually produce a protein, the investigators combined bioinformatic prediction with laboratory validation. They identified a short open reading frame within the circular sequence and tested whether ribosomes could initiate translation on a circular RNA, which normally lacks the cap structure that standard translation requires. Internal ribosome entry site, or IRES, reporter assays demonstrated that the circRAB6A sequence contains elements allowing cap-independent translation initiation. Mass spectrometry then provided direct evidence that the predicted micropeptide is produced in cells, confirming that circRAB6A encodes a previously uncharacterized micropeptide, which the team designated KAPEP.

With the micropeptide confirmed, the researchers assessed its functional effects. In vitro assays showed that KAPEP promotes colorectal cancer cell proliferation, migration, and invasion, the three hallmark behaviors that drive tumor expansion and metastasis. The team then moved to animal models, using orthotopic models, in which tumors are implanted in the location where colorectal cancer naturally arises, and patient-derived xenograft, or PDX, models, in which tumor tissue from actual patients is transplanted into mice. In both systems, KAPEP accelerated tumor growth in vivo, demonstrating that its effects extend beyond isolated cells to genuine tumor environments.

The mechanistic core of the study explains how KAPEP exerts these effects. Using RNA sequencing, co-immunoprecipitation, bio-layer interferometry, and molecular dynamics simulations, the investigators showed that KAPEP directly binds PTPN6, a protein tyrosine phosphatase. PTPN6, also known as SHP1, normally acts as a brake on signaling pathways by removing phosphate groups from target proteins. When KAPEP binds PTPN6, it inhibits the enzyme’s phosphatase activity, relieving the PTPN6-mediated restraint on JAK-STAT signaling. The JAK-STAT pathway, which transmits signals from cell surface receptors to the nucleus, becomes sustained in its activation, fueling the proliferative and invasive behaviors that KAPEP promotes.

The technical rigor of the binding studies deserves particular attention. Co-immunoprecipitation demonstrated that KAPEP and PTPN6 associate within cells, while bio-layer interferometry, a technique that measures real-time binding between molecules, quantified the direct physical interaction. Molecular dynamics simulations then provided atomic-level insight into how the micropeptide engages the phosphatase, supporting the conclusion that binding disrupts the enzyme’s catalytic function. Together, these complementary approaches establish a coherent mechanistic chain from a circular RNA to a micropeptide to a specific enzyme to a signaling pathway to tumor behavior.

The clinical implications are significant because KRAS-mutant colorectal cancer remains challenging to treat despite advances in targeted therapy. While antibodies against EGFR, the epidermal growth factor receptor, benefit some colorectal cancer patients, tumors carrying KRAS mutations are typically resistant to these agents, leaving limited options for this subgroup. The identification of the KAPEP/PTPN6 interaction as a potential therapeutic vulnerability offers a new angle: rather than targeting the KRAS mutation itself, which has proven notoriously difficult, clinicians could aim to disrupt the downstream mechanism that KAPEP uses to sustain JAK-STAT activation.

The study also highlights the broader significance of circRNA-encoded micropeptides in cancer biology. Although circular RNAs have emerged as important regulators of tumorigenesis, the functional significance of circRNA-encoded micropeptides in KRAS-mutant colorectal cancer was poorly understood before this work. By demonstrating that a specific circular RNA produces a micropeptide with a defined molecular target and a measurable effect on tumor progression, the research provides a template for investigating other circular RNAs that may encode functional peptides in different cancer types.

The work, published open access in Molecular Cancer, was conducted by Haitao Yuan, Jiaxin Lin, Kexin Chen, Hongming Li, Liaonan Zou, Xinquan Lu and colleagues, with Yuan, Lin, and Chen contributing equally. All experiments involving human tissues were approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine, and animal studies were reviewed by the Institutional Animal Care and Use Committee of Guangzhou University of Chinese Medicine. The authors declare no competing interests. As the field moves forward, the KAPEP/PTPN6 axis stands out as a concrete molecular interaction that researchers can now pursue as a target in a cancer subgroup that urgently needs better options.

Subject of Research: circRAB6A-encoded KAPEP relieves PTPN6-mediated restraint on JAK-STAT signaling to drive KRAS-mutant colorectal cancer progression

Article Title: circRAB6A-encoded KAPEP relieves PTPN6-mediated restraint on JAK-STAT signaling to drive KRAS-mutant colorectal cancer progression

Article References: Yuan, H., Lin, J., Chen, K., Li, H., Zou, L., & Lu, X. (2026). circRAB6A-encoded KAPEP relieves PTPN6-mediated restraint on JAK-STAT signaling to drive KRAS-mutant colorectal cancer progression. Molecular Cancer. https://doi.org/10.1186/s12943-026-02818-z

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02818-z

Keywords: circRAB6A-encoded, KAPEP, relieves, PTPN6-mediated, restraint, JAK-STAT, signaling, drive, KRAS-mutant, colorectal, cancer, progression