Abstract
Background and aimsColorectal cancer (CRC) is a major killer. Host immunity is important in tumorigenesis. Direct comparison among IL-36α, IL-36β and IL-36γ in the prognosis of CRC is unclear.MethodsCRC tissue arrays were generated from colorectostomy samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, IL-36α, IL-36β and IL-36γ were determined, in comparison to non-cancer tissues.ResultsA significant association was observed between colonic IL-36α, IL-36β or IL-36γ and the presence of cancer (with all P < 0.0001). Using ROC curve analysis, specificity and sensitivity of IL-36α, IL-36β or IL-36γ were confirmed, with area under the curve (AUC) values of 0.68, 0.73 and 0.65, respectively. Significant differences in survival were observed between IL-36αhigh and IL-36αlow (P = 0.003) or IL-36γhigh and IL-36γlow (P = 0.03). Survival curves varied significantly when further stratification into sub-groups, on the basis of combined levels of expression of two isotypes of IL-36 was undertaken. A significant difference was observed when levels of IL-36α and IL-36β were combined (P = 0.01), or a combination of IL-36α plus IL-36γ (P = 0.002). The sub-groups with a combination of IL-36αhigh plus IL-36βhigh, or IL-36αhigh plus IL-36γlow exhibited the longest survival time among CRC patients. In contrast, the sub-groups of IL-36αlow plus IL-36βhigh or IL-36αlow plus IL-36γhigh had the shortest overall survival. Using the log-rank test, IL-36αhigh expression significantly improved survival in patients with an invasion depth of T4 (P < 0.0001), lymph node metastasis (P = 0.04), TNM III-IV (P = 0.03) or with a right-sided colon tumour (P = 0.02). Similarly, IL-36γlow expression was significantly associated with improved survival in patients with no lymph node metastasis (P = 0.008), TNM I-II (P = 0.03) or with a left-sided colon tumour (P = 0.05). Multivariate analysis demonstrated that among IL-36α, IL-36β and IL-36γ, only IL-36α (HR, 0.37; 95% CI, 0.16–0.87; P = 0.02) was an independent factor in survival, using Cox proportional hazards regression analysis.ConclusionIL-36α or IL-36γ are reliable biomarkers in predicting the prognosis of CRC during the later or early stages of the disease, respectively. Combining IL-36α plus IL-36γ appears to more accurately predict the postoperative prognosis of CRC patients. Our data may be useful in the management of CRC.
Highlights
IntroductionColorectal cancer (CRC) is still the third most common cancer, in Western society, despite decades of extensive clinical and basic research [1]
Background and aimsColorectal cancer (CRC) is a major killer
IL-36α, β and γ are IL-1 family members that signal through the IL-1 receptor, i.e. IL-1Rrp2 (IL-1RL2) and IL-1RAcP [6], via activating the nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPKs), Jun N-terminal kinases (JNK), and ERK1/2 kinase cascades [7], which are key signalling pathways for intestinal tumorigenesis [8] [9]
Summary
Colorectal cancer (CRC) is still the third most common cancer, in Western society, despite decades of extensive clinical and basic research [1]. The largest clinical challenge is the delay in early detection [3], compromising the outcomes of CRC patients who may have to be managed with palliative care [4]. It is well known that host immunity is critical in the development of cancer(s), for example, the discovery of cancer therapy by inhibition of negative immune regulation [5]. IL-36α, β and γ (formerly IL-1F6, IL-1F8, and IL-1F9) are IL-1 family members that signal through the IL-1 receptor, i.e. IL-1Rrp (IL-1RL2) and IL-1RAcP [6], via activating the nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPKs), Jun N-terminal kinases (JNK), and ERK1/2 kinase cascades [7], which are key signalling pathways for intestinal tumorigenesis [8] [9]. IL-36 gene therapy may mediate a therapeutic effect in a fibrosarcoma mouse model [12]
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