Abstract
Toll-like receptors (TLRs) not only form an important part of the innate immune system but also serve to activate the adaptive immune system in response to cancer. Real-time PCR; immunohistochemical stain and Western blotting analyses were performed to clarify molecular alterations in colorectal cancer (CRC) patients. We identified Toll-like receptor 1 (TLR1), TLR2, TLR4 and TLR8 gene expression levels and downstream gene, i.e., interleukin-6 (IL-6), IL-8, interferon-α (IFN-α) and myeloid differentiation primary-response protein-88 (MyD88), expression levels in CRC patients and in cancer cell lines. CRC tissues have higher TLR1, TLR2, TLR4, TLR8, IL-6 and IL-8 gene expression levels than do the normal colon mucosa (p < 0.05). TLR2 expression varied in different cell types (mucosa and lymphocytes). There was no difference in the MyD88 and IFN-α gene expression levels between cancerous and normal colon mucosa. CRC patients had higher levels of IL-6 (p = 0.002) and IL-8 (p = 0.038) expression than healthy volunteers did; and higher IL-6 and IL-8 expression was also found to signify a higher risk of recurrence. CL075 (3M002) treatments can reduce the production of IL-8 in different cancer cell lines. The signaling pathway of TLRs in cancer tissue is different from that in normal cells; and is MyD88-independent. Higher expression levels of TLR1, TLR2, TLR 4 and TLR 8 mRNA were related to upregulation inflammatory cytokines IL-6 and IL-8 gene expression in tissue and to the upregulation of IL-6 in blood. The concentration of IL-6 in serum can be used as an indicator of the possibility of CRC recurrence. Treatment with 3M002 can reduce IL-6 production in vitro and may prevent CRC recurrence. Our findings provide evidence that TLR1, TLR2, TLR4 and TLR8 gene expression induce downstream IL-6 and IL-8 gene expression; detection of these expression levels can serve as a CRC marker.
Highlights
Colorectal cancer (CRC) is the third most common type of cancer and the fourth leading cause of cancer-related death worldwide [1]
Protein expression of Toll-like receptors (TLRs) examined in colorectal cancer tissues from patients showed unexpectedly differential results from gene expression assay
TLR-mediated signaling components such as myeloid differentiation primary-response protein-88 (MyD88) may promote the development of colorectal cancer (CRC); the proinflammatory cytokine IL-1β uses MyD88 to signal downstream of its receptor [22]
Summary
Colorectal cancer (CRC) is the third most common type of cancer and the fourth leading cause of cancer-related death worldwide [1]. In animal models [2,3] and in human patients [4], bacteria are associated with inducing chronic inflammation (or inflammatory bowel disease (IBD)) and colitis-associated colon cancer. The cellular and humoral immune systems have been implicated in the response to tumor antigens in CRC cell lines. The discovery of Toll-like receptors (TLRs) reveals the molecular level of the adjuvants’ role in effective immune potentiation [5,6]. Ten members of the toll-like receptor family have been identified in humans. TLR2 and TLR4 are known to recognize peptidoglycan and lipopolysaccharide (LPS) on the surface of bacteria. The extracellular domain of TLR4 forms a homodimer complex with the MD-2 protein, and it plays a critical role in LPS recognition [8,9]. Among the TLRs, TLR7, TLR8 and TLR9 function inside the endosome [12]
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