AKR1B1 Expression in the Colorectal Tumor Microenvironment Contributes Towards Its Prognostic Significance.

Publisher: John Wiley & Sons Ltd Country of Publication: United States NLM ID: 101595310 Publication Model: Print Cited Medium: Internet ISSN: 2045-7634 (Electronic) Linking ISSN: 20457634 NLM ISO Abbreviation: Cancer Med Subsets: MEDLINE

Original Publication: [Malden, MA] : John Wiley & Sons Ltd., c2012-

Colorectal Neoplasms*/pathology ; Colorectal Neoplasms*/genetics ; Colorectal Neoplasms*/mortality ; Colorectal Neoplasms*/metabolism ; Tumor Microenvironment*/genetics ; Biomarkers, Tumor*/metabolism ; Biomarkers, Tumor*/genetics ; Aldehyde Reductase*/metabolism; Antigens, Differentiation, Myelomonocytic/metabolism ; Receptors, Cell Surface/metabolism ; Antigens, CD/metabolism ; Stromal Cells/metabolism ; Humans ; Prognosis ; Female ; Male ; CD163 Antigen ; Middle Aged ; Gene Expression Regulation, Neoplastic ; Aged

Background: AKR1B1, a member of the aldo-keto reductase enzyme family involved in the polyol pathway of aldehyde metabolism, is aberrantly expressed in colorectal cancer (CRC). Our previous studies demonstrated that AKR1B1 knockdown reduced the motility and proliferation of CRC cell lines, and its elevated expression was correlated with increased mesenchymal marker expression, inflammation, and poor prognosis in CRC patient cohorts. However, whether stromal cells also express AKR1B1 and whether stromal expression can affect clinical outcomes has not been examined.
Objectives: To evaluate the expression of AKR1B1 within the tumor microenvironment (TME) of CRC, with a paticular focus on stromal cells, and to assess its association with clinical outcomes.
Methods: We assessed AKR1B1 expression in colorectal tumors utilizing publicly available transcriptomic data from CRC tumors. Single-cell RNA-sequencing data from CRC samples were analyzed to determine cell type-specific expression. Immunohistochemistry based assessment of AKR1B1 expression was performed in Turkish and Serbian cohorts. Co-localization of AKR1B1 and CD163 (M2 macrophage marker) was evaluated by immunoflourescence.
Results: AKR1B1 was expressed in both the epithelial and stromal components of colorectal tumors, with higher expression observed in the stroma. Single-cell transcriptomic analysis revealed AKR1B1 expression in myeloid cells, T and NK cells, B cells, dendritic cells, fibroblasts, and epithelial cells. Notably, AKR1B1-expressing macrophages were predominantly of the M2 phenotype, and AKR1B1 expression and M2 marker expression showed strong positive correlation in bulk transcriptomic data. Immunofluorescence confirmed the colocalization of CD163 and AKR1B1 in stromal macrophages. Moreover, immunohistochemical analysis of AKR1B1 expression in tumor stroma from a cohort of Turkish patients revealed that its expression was associated with favorable overall survival, particularly in tumors with higher stromal infiltration.
Conclusions: Overall, our findings underscore the significant influence of the TME composition on the relationship between AKR1B1 expression and clinical outcomes.
(© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

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220N427 Türkiye Bilimsel ve Teknolojik Araştırma Kurumu; ÇDAP-108-2020-10197 ODTÜ BAP; 451-03-136/2025-03/200007 Technological Development and Innovations of the Republic of Serbia; 451-03-136/2025-03/200042 Technological Development and Innovations of the Republic of Serbia

Keywords: AKR1B1; colorectal cancer; gene expression; prognosis; stroma; tissue microenvironment

EC 1.1.1.21 (AKR1B1 protein, human)
0 (Biomarkers, Tumor)
0 (CD163 Antigen)
0 (Antigens, Differentiation, Myelomonocytic)
0 (Receptors, Cell Surface)
0 (Antigens, CD)
EC 1.1.1.21 (Aldehyde Reductase)

Date Created: 20250521 Date Completed: 20250521 Latest Revision: 20250605

20260130

PMC12093151

10.1002/cam4.70974

40396420