miR-155 shows context-dependent links to cancer treatment outcomes

A systematic review of 19 clinical studies found that microRNA-155, or miR-155, was associated with cancer treatment outcomes in several settings, but the direction of the association varied substantially by cancer type, molecular subtype, treatment regimen and biological sample. Elevated miR-155 most often accompanied treatment resistance, yet selected studies linked higher expression to improved response or survival. The review identified clinical evidence in eight cancers: breast cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, pediatric acute lymphoblastic leukemia, cutaneous melanoma, non-muscle-invasive bladder cancer, papillary thyroid cancer and pancreatic ductal adenocarcinoma. Its authors concluded that the prognostic and predictive significance of miR-155 requires further evaluation.

The systematic review followed PRISMA 2020 guidelines and searched PubMed, ProQuest and Google Scholar for English-language research published from January 2019 through December 2024. The protocol was registered in PROSPERO in January 2025 under CRD42025632573. Three reviewers independently selected studies, extracted data and assessed the evidence against predefined inclusion criteria, while a fourth reviewer verified their assessments and resolved discrepancies. Eligible studies examined miR-155 expression in patients with cancer who received radiation, chemotherapy, multidrug treatment or combination treatment and reported relevant clinical outcomes. Laboratory, animal, computational, simulation and other preclinical studies were excluded, as were articles without patient data. Studies also had to report survival outcomes according to the therapeutic regimen, narrowing the review to evidence connecting expression with care delivered to patients rather than an assessment of miR-155 as a treatment itself.

The initial search returned 248,057 records: 169,989 from Google Scholar, 77,918 from ProQuest and 150 from PubMed. The reviewers removed 426 duplicates and screened the remaining records by title and abstract, after which 97 articles were assessed in full text. Seventy-eight were excluded, including 32 without validation of miR-155, 26 without therapy-based analyses in patients, 18 without clinical outcomes linked to miR-155 or with insufficient data, and two simulation or machine-learning papers without patient data. Nineteen studies were eligible. Together, the reports comprised 1,640 patient samples, 230 healthy controls and data from 701 patients in two Gene Expression Omnibus datasets. Two publications analyzed the same underlying diffuse large B-cell lymphoma cohort, so they did not provide independent replication. Eleven studies were classified as high quality on the Newcastle-Ottawa Scale, seven were rated moderate to high, and one was rated moderate; none was classified as low quality.

MiR-155 is encoded by the miR-155 host gene, or miR-155HG, and belongs to a precursor family that produces mature miRNAs known as miR-155-5p and miR-155-3p. The clinical studies reviewed focused on measuring miR-155 expression rather than administering a miR-155-directed treatment. Investigators used quantitative real-time polymerase chain reaction to assess expression in tumor tissue, peripheral blood, serum, plasma, exosomal fractions and bone marrow, with one study examining both tissue and blood. These materials do not necessarily represent the same biological state: tissue measurements reflect the local tumor environment, whereas circulating and exosomal measurements capture systemic or extracellular pools. The lack of consistent reporting further complicated interpretation. Sixteen of the 19 studies referred only to “miR-155” without identifying the mature strand, while three explicitly evaluated miR-155-5p.

Four studies reported higher miR-155 expression in treatment-resistant patients. In pediatric acute lymphoblastic leukemia, elevated bone-marrow expression was associated with poor response to induction chemotherapy, residual disease and relapse-related clinical characteristics. In HER2-positive breast cancer, increased miR-155 in serum exosomes was associated with resistance to trastuzumab-containing neoadjuvant therapy, poorer treatment outcomes, shorter progression-free survival and shorter event-free survival. In diffuse large B-cell lymphoma, exosomal miR-155 distinguished patients with refractory or relapsed disease from those who responded to R-CHOP treatment, although the same study did not find an equivalent association in plasma. In gastric diffuse large B-cell lymphoma, higher tissue expression was associated with resistance to Helicobacter pylori eradication therapy. These resistance-associated findings spanned bone marrow, serum, exosomes and tumor tissue, but no resistance association was reported for radiotherapy or immunotherapy in the reviewed evidence. The pattern was therefore concentrated mainly in chemotherapy, targeted-therapy and immunochemotherapy settings rather than being uniform across treatment modalities.

Other studies pointed in the opposite direction. Analyses of patient-derived samples and public lymphoma datasets linked elevated miR-155 after R-CHOP treatment to favorable response and improved survival in germinal center B-cell-like diffuse large B-cell lymphoma, but not consistently in the activated B-cell-like subtype. In pediatric acute lymphoblastic leukemia, one study reported an association between miR-155-5p and favorable early prednisone response, while another associated elevated expression with suboptimal response. These contrasting results indicate that the same expression pattern may carry different clinical meanings in different diseases and treatment settings. The DLBCL findings provide the clearest example of molecular-subtype dependence: higher tissue miR-155 was linked to a favorable outcome in germinal center B-cell-like disease, while elevated exosomal miR-155 was associated with refractory or relapsed disease in another cohort. Neither the direction of the association nor the choice of biological specimen can therefore be assumed to transfer directly from one clinical context to another.

Survival results were also divided. Four studies reported favorable survival associations, four reported adverse associations, one produced mixed or endpoint-dependent findings, and one found no significant difference in overall or progression-free survival. Nine did not perform a miR-155-specific survival analysis. Higher expression was associated with longer overall or progression-free survival in selected germinal center B-cell-like lymphoma and breast cancer cohorts, including triple-negative breast cancer, and with longer disease-free survival in a breast cancer study. Conversely, adverse associations with shorter progression-free, event-free or overall survival appeared in selected lymphoma, lung cancer and breast cancer settings, particularly during chemotherapy or targeted treatment. The same study did not always produce the same relationship across endpoints. In HER2-positive breast cancer, for example, elevated exosomal miR-155 was associated with poorer event-free and progression-free survival but not a statistically significant difference in overall survival. In non-small cell lung cancer treated with platinum-based chemotherapy, higher circulating miR-155 was associated with poorer overall survival, although it was not significantly associated with treatment response or progression-free survival.

Clinical and methodological heterogeneity complicates the interpretation of the evidence. The studies differed in cancer and disease subtype, patient characteristics, therapy, sample type, timing of collection, endpoint definitions and follow-up duration. Six of the 19 studies enrolled 55 or fewer participants, including one with only 10 patients, which can reduce statistical precision and make results more susceptible to random variation. Most of the evidence was observational, and adjustment for potential confounding was inconsistent: nine studies received the maximum comparability score on the Newcastle-Ottawa Scale, eight received one star and two received none. Prospectively collected clinical samples were also mixed with secondary analyses of public molecular datasets. Several studies used a cross-sectional design or collected specimens at different stages of care, limiting the ability to determine whether altered miR-155 preceded or followed response, resistance or progression. Treatment resistance, early response, progression-free survival, event-free survival, disease-free survival and overall survival were treated as distinct endpoints, and differences in follow-up further limited direct comparisons. Most treatment-linked associations also rested on a single study rather than independent replication.

The review does not establish miR-155 as either a clinically usable biomarker or a therapeutic target. No included study evaluated the efficacy of a miR-155-directed intervention in patients, and the available evidence was insufficient to support a universal predictive or prognostic role across cancers. The authors argue for larger prospective multicenter studies with clearly defined patient subgroups, consistent treatment and response criteria, sequential sampling and independent validation. Standardizing specimen collection, RNA extraction, normalization and quantification is also essential, as is explicitly distinguishing miR-155-5p or miR-155-3p from measurements reported only as miR-155. The evidence supports further study of miR-155 as a potentially useful, context-specific marker, but not routine clinical interpretation or treatment decisions based on its expression. Important limitations remain, including the restricted five-year publication window, the use of only three bibliographic sources, the small number of studies for several cancers and the absence of clinical efficacy evidence for interventions directed at miR-155.

Subject of Research: Clinical associations between miR-155 expression and cancer treatment outcomes

Article Title: A systematic review on the possible role of microRNA-155 in cancer treatment

Article References: Ravichandran, S. N., Banerjee, A., Parnigotto, P. P., Pathak, S., & Barbon, S. (2026). A systematic review on the possible role of microRNA-155 in cancer treatment. Frontiers in Pharmacology, 17, Article 1885427. https://doi.org/10.3389/fphar.2026.1885427

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1885427

Keywords: microRNA-155, cancer biomarkers, treatment resistance, treatment response, survival outcomes, systematic review, clinical studies, cancer biology, systematic, review, possible, role