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3.240.21 (GSK2606414 and TG+); P 0.0001], but not by AEBSF [6.790.072 (control and TG+) vs. 1 (IRE1) expression and activation of the protein kinase R (PKR)-like ER kinase (PERK) signaling pathway. X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) binding sites were predicted to be located in the MALAT1 gene promoter regions and the expression of MALAT1 was positively associated with XBP1 and ATF4 expression levels in CRC tissue samples. Thus, these findings indicated that ER stress may promote the migration of CRC cells and contribute to the progression of CRC through the activation of the IRE1/XBP1 and PERK/eIF2/ATF4 signaling pathways. In conclusion, to the best of our knowledge, this study is the first report that lncRNA MALAT1 expression is regulated by the IRE1/XBP1 pathway in CRC. strong class=”kwd-title” Keywords: colorectal cancer, endoplasmic reticulum stress, cell migration, thapsigargin, metastasis-associated lung adenocarcinoma transcript 1, unfolded protein response Introduction Colorectal cancer (CRC) is one of the most common cancers in world, ranking third overall in terms of Rabbit monoclonal to IgG (H+L) incidence rates and second in terms of mortality rates, with 1.8 million new cases and 861,663 death cases reported worldwide in 2018 (1). Both the incidence and mortality rates of CRC have increased in China in the past decade; in 2018, the latest epidemiological statistics of Globocan reported that the incidence and mortality rates of CRC were 23.7 and 10.9, respectively, per 100,000 (1). Unfortunately, in PZ-2891 the majority of patients, CRC is PZ-2891 diagnosed at an advanced stage, following the metastasis to adjacent or distant organs (2); however, the mechanisms regulating metastasis in CRC remain largely unknown. Therefore, there is an urgent requirement to identify the molecular mechanisms of CRC metastasis to provide novel therapeutic targets for the treatment of the disease. Endoplasmic reticulum (ER) stress is reportedly involved in CRC metastasis (3). The ER has established unique signaling pathways to combat stress, which are collectively known as the unfolded protein response (UPR) (4); glucose regulated protein 78 (GRP78) initiates the UPR and it has been demonstrated to promote the resistance of CRC cells to oxaliplatin (5). Depending on the status of GRP78, the ER transmembrane sensors, inositol-requiring enzyme 1 (IRE1), protein kinase RNA activated-like ER kinase (PERK) and activating transcription factor 6 (ATF6) are also involved in initiating signaling pathways involved in the UPR (4). IRE1 PZ-2891 catalyzes a unique splicing event that removes 26 nucleotides from X-box-binding protein 1 (XBP1) mRNA, and the activation of the IRE1/XBP1 pathway has been observed to induce CRC cell invasion (3); however, the mechanism underlying the IRE1/XBP1 pathway induction of CRC cell invasion is not fully elucidated. The phosphorylation of PERK activates the downstream signaling molecule, -subunit of eukaryotic initiation factor-2 (eIF2), which effectively inhibits protein synthesis (4), and has been associated with the hypoxia-induced metastasis of cervical cancer (6). Finally, the proteolytic processing of ATF6 activates the ATF6 pathway, and ATF6 activation was reported to be involved in pancreatic cancer stem cell migration (7). However, the roles of the PERK/eIF2 and ATF6 pathway in CRC migration are unknown. In the present study, PZ-2891 thapsigargin (TG) was used as an ER stress inducer to irreversibly inhibit the sarco/ER Ca2+ ATPase and promote rapid ER Ca2+ depletion (8). Long non-coding RNAs (lncRNAs) are non-coding transcripts of 200 nucleotides in length and certain lncRNAs serve important roles in CRC metastasis (9,10). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), also known as nuclear enriched abundant transcript 2 or LINC00047, is a lncRNA (11). MALAT1 is found to be overexpressed in colorectal cancer patients (12) and multiple studies have reported an association between MALAT1 expression and CRC metastasis (9,13). The first study demonstrating the UPR-induced regulation of lncRNA expression was in a study of the flavivirus infection, whereby MALAT1 expression was increased through the PERK pathway of the UPR (14). However, the mechanisms underlying increased MALAT1 expression levels in CRC are not clear, in addition to whether the UPR pathway is involved in upregulating MALAT1 expression in CRC. It is hypothesized that the ER stress pathway regulates MALAT1 expression in CRC; thus, the present PZ-2891 study aimed to identify the association between the ER stress pathway, MALAT1 expression and cell migration in CRC, in addition to elucidating the roles of ER stress in CRC development. Materials and methods Patient studies The present study was approved by the Ethics Committee of The First Hospital of Hebei.