Increased protein expression of interleukin-10 and its signalling molecules in colon cancer progression: potential prognostic and therapeutic targets.

Background: Interleukin-10 (IL-10) regulates immune responses in solid tumours, but its role in colorectal cancer (CRC) is unclear due to inconsistent findings. Tumour location is a critical prognostic factor, with proximal tumours often linked to worse outcomes. However, the relationship between IL-10 expression and tumour site is poorly understood.

Methods: Protein expression of IL-10, its α-receptor (IL10Rα), and intracellular signal transducer (STAT3) was measured by immunohistochemistry in archived paired non-cancerous and cancerous colonic specimens collected from the same patients (n = 120). The data were then stratified according to clinical stages (early-stage I/II vs. late-stage III/IV) and tumour sites (right-sided cancers; RSCs vs. left-sided cancers; LSCs). Functional effects of biologically active IL-10 protein (0.1, 1, and 40 ng/ml), anti-IL10Rα monoclonal antibody (0.1, 1, and 40 ng/ml), and a single concentration of a specific STAT3 inhibitor (2 µM) on cell cycle and apoptosis were assessed in HT29 and SW620 CRC cell lines, along with the expression of key regulatory molecules.

Results: Overall, protein expression of IL-10, IL10Rα, and STAT3 was significantly higher in malignant tissues compared to non-malignant tissues. Early and late-stage RSCs exhibited markedly increased expression of these proteins relative to LSCs, with the highest levels observed in late-stage RSCs. Elevated protein levels of all molecules correlated with high-grade tumours, mucinous histology, lymph node metastasis, and advanced cancer stage. While IL-10 treatment showed minimal effects, IL-10Rα blockade or STAT3 inhibition led to cell cycle arrest and apoptosis in HT29 and SW620 cells, associated with increased p21, p27, and Caspase-3, and decreased CCND1, CCND3, PCNA, and survivin gene and protein expression.

Conclusions: IL-10 and its signalling molecules increased in CRC progression, particularly in RSCs, suggesting their potential oncogenic roles and prognostic significance. Furthermore, targeting IL-10 signalling pathways could offer a promising avenue for CRC treatment. However, further studies are required to explore the IL-10 system in relation to tumour consensus molecular subtypes to better elucidate its biological functions and prognostic values in CRC.