Abstract
Patients with mismatch repair (MMR)-deficient colorectal cancer (CRC) have a more favorable prognosis than patients with tumors with intact MMR. In order to obtain further insights on the reasons for this different outcome, we investigated the interplay between MMR genes and TLR4/MyD88 signaling. The cancer genome atlas (TCGA) databases were selected to predict the differential expression of TLR4 in colon cancer and its correlation with MMR genes. Moreover, the expression of MMR genes and TLR4 was evaluated by immunohistochemistry in 113 CRC samples and a cohort of 63 patients was used to assess TLR4 mRNA expression and MLH1 epigenetic silencing status. In vitro, the effect of MLH1 knockdown on TLR4 expression was quantified by Real Time PCR. TLR4 expression resulted dependent on MMR status and directly correlated to MLH1 expression. In vitro, MLH1 silencing decreased TLR4 expression. These observations may reflect the better prognosis and the chemoresistance of patients with CRC and MMR defects.
Highlights
3–5% of colorectal cancers occur in the setting of a heritable syndrome, such as hereditary non polyposis colon cancer (HNPCC) syndrome (Barzi et al, 2015)
These results suggest that mismatch repair genes (MMR) genes deficiency in colon adenocarcinoma is associated to decreased Toll-like receptor-4 (TLR4) expression
In this study we investigated for the first time the relationship between MMR genes deficiency and innate immunity in colorectal cancer (CRC), and provided evidence for a direct role of MLH1 in the regulation of TLR4 expression
Summary
3–5% of colorectal cancers occur in the setting of a heritable syndrome, such as hereditary non polyposis colon cancer (HNPCC) syndrome (Barzi et al, 2015). Defects in DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) lead to microsatellite instability (MSIH), which is a hallmark of HNPCC (Ait Ouakrim et al, 2015). High-frequency MSI occurs in approximately 15% of sporadic colorectal cancers (CRC) and other tumors (Peltomäki, 2001), wherein the mismatch repair genes (MMR) defect develops because of epigenetic inactivation of the MLH1 gene by DNA methylation (Cunningham et al, 1998; Poynter et al, 2008; Sinicrope et al, 2010). MLH1 and TLR4 Interplay in CRC among the approximately 150,000 new CRC cases diagnosed in the United States in 2008 (Jemal et al, 2008), at least 20,000 patients were expected to have sporadic MMR-deficient tumors (Sinicrope et al, 2010)
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