Expression of inositol-requiring enzyme 1β is downregulated in colorectal cancer

Abstract

The endoplasmic reticulum stress inositol-requiring enzyme (IRE) 1α/X-box binding protein (XBP) 1 signaling pathway is involved in the tumorigenesis of breast and prostate cancer. Mucin 2 (MUC2) protects colon tissues from the formation of tumors. In human colorectal cancer (CRC) the role of IRE1α, and its analogue, IRE1β, has yet to be elucidated. In the present study, the expression levels of IRE1α, IRE1β, un-spliced XBP1u, spliced XBP1s and MUC2 in surgically resected cancerous and adjacent non-cancerous tissues from patients with CRC were investigated. The IRE1α, IRE1β, XBP1u, XBP1s and MUC2 mRNA expression levels were determined using reverse transcription-quantitative polymerase chain reaction, and the protein expression levels were detected using immunohistochemistry and western blotting. The association between the expression levels of IRE1α, IRE1β and MUC2 and the clinicopathological features of patients with CRC was subsequently analyzed. The mRNA expression levels of IRE1β and MUC2 were decreased by ~2.1 and ~4.5-fold in CRC tissues, respectively, as compared with the adjacent normal tissues. The protein expression levels of IRE1β and MUC2 were decreased by ~8.0 and ~2.0-fold in the CRC tissues, respectively. IRE1β mRNA expression levels were positively correlated with MUC2 mRNA expression levels. IRE1β expression levels were revealed to be significantly associated with lymph node metastasis, tumor stage and histological differentiation. However, IRE1α, XBP1u and XBP1s mRNA and IRE1α protein expression levels were not observed to significantly differ between cancerous tissues and the adjacent normal tissues. The results indicated that the expression of IRE1β, but not IRE1α, may protect colon tissue from developing CRC by inducing MUC2 expression. Therefore, decreased IRE1β expression levels may be associated with the development of CRC through the inhibition of MUC2 expression.

Role of the unfolded protein response in determining the fate of tumor cells and the promise of multi-targeted therapies

“…Failing to move the C-terminal peptide of mucin-2 during posttranslation may interefere with the mobility of mucin-2, which could be the reason of the overaccumulation of aberrant mucin-2 in the ER lumen (Tsuru et al 2013). Consistently, it has been found that there was downregulated IRE1β expression in colorectal adenocarcinomas compared with normal colon (Jiang et al 2017). Clinical studies based on archived tumor tissues demonstrate that the levels of expression of specific ER stress markers can work as predictors of cancer (summarized in Table 1).…”

Expression of inositol‑requiring enzyme 1β is downregulated in azoxymethane/dextran sulfate sodium‑induced mouse colonic tumors

“…IRE1β has been revealed to be involved in cell apoptosis (27). In a previous study, it was reported that IRE1β and MUC2 expression are downregulated in human colonic tissues (44). These results indicated that IRE1β serves an important role in the pathogenesis of colitis and tumors.…”

“…IRE1α serves a protective role against ER stress and colitis (24,40). The IRE1-XBP1 signaling pathway serves a pivotal role in cell survival under conditions of ER stress and is associated with tumorigenesis of various cancer types (41)(42)(43)(44). In the current study, mRNA expression of IRE1α, XBP1u and XBP1s and IRE1α protein expression were compared in tumor and normal tissues.…”

“…During the RIDD process, IRE1 promotes the degradation of mRNAs that predominately encode ER-targeting proteins (52), which may be the mechanism for the involvement of the IRE1α-XBP1 signaling pathway in the pathogenesis of inflammation-mediated CRC. It was previously reported that IRE1α and XBP1 protein expression levels were unchanged in human CRC tissue compared with adjacent normal tissue (44). Therefore, the role of the IRE1-XBP1 signaling pathway in the pathogenesis of colonic tumors may be discrepant between humans and mice.…”

Unique expression of the xbp1 gene correlates with human prostate cancer

“…31 A more recent study showed no significant differences in XBP1 (U) and XBP1(S) gene and protein expression between human colorectal cancerous tissues and the adjacent normal tissues. 32 Only one study has shown low expression of XBP1 in human prostate cancer. 33 However, the study did not differentiate between XBP1 (S) and XBP1 (U) mRNA expression levels.…”