Abstract
The global morbidity and mortality of colorectal cancer (CRC) are ranked the third among gastrointestinal tumors in the world. MiR-451a is associated with several types of cancer, including CRC. However, the roles and mechanisms of miR-451a in CRC have not been elucidated. BAP31 is a predicted target gene of miR-451a in our suppression subtractive hybridization library. Its relationship with miR-451a and function in CRC are unclear. We hypothesized that miR-451a could induce apoptosis through suppressing BAP31 in CRC. Immunohistochemistry and real-time PCR were used to measure BAP31 expressions in CRC tissues and pericarcinous tissues from 57 CRC patients and CRC cell lines. Dual-luciferase reporter assay was used to detect the binding of miR-451a to BAP31. The expression of BAP31 protein in CRC tissues was significantly higher than that in pericarcinous tissues, which was correlated with distant metastasis and advanced clinical stages of CRC patients. The expression of BAP31 was higher in HCT116, HT29, SW620, and DLD cells than that in the normal colonic epithelial cell line NCM460. The expression of BAP31 was absolutely down-regulated when over-expressing miR-451a in HCT116 and SW620 cells compared with control cells. Mir-451a inhibited the expression of BAP31 by binding to its 5’-UTR. Over-expressing miR-451a or silencing BAP31 suppressed the proliferation and apoptosis of CRC cells by increasing the expressions of endoplasmic reticulum stress (ERS)-associated proteins, including GRP78/BIP, BAX, and PERK/elF2α/ATF4/CHOP, which resulted in increased ERS, cytoplasmic calcium ion flowing, and apoptosis of CRC cells. These changes resulting from over-expressing miR-451a were reversed by over-expressing BAP31 with mutated miR-451a-binding sites. Over-expressing miR-451a or silencing BAP31 inhibited tumor growth by inducing ERS. The present study demonstrated that miR-451a can inhibit proliferation and increase apoptosis through inducing ERS by binding to the 5’-UTR of BAP31 in CRC.
Highlights
Colorectal cancer (CRC) is the third most common malignant gastrointestinal tumor in the world
Our results showed that the expression of BAP31 in CRC tissues was significantly increased, while the expression of miR-451a in CRC tissues was obviously down-regulated
We found that BAP31 relative expression levels were correlated with advanced clinical stage and distant metastasis of CRC
Summary
Colorectal cancer (CRC) is the third most common malignant gastrointestinal tumor in the world. Its mortality has increased from 694,000 in 2012 to 774,000 in 2015, with the increased death ratio being 11.53%1. With the improvement of people’s living standards, the incidence and the mortality of CRC in China were both increased to the fifth among all cancers in 20112. The current treatments for CRC include resection, Official journal of the Cell Death Differentiation Association. Xu et al Cell Death and Disease (2019)10:152. Page 2 of 16 152 radiotherapy, and chemotherapy. Chemotherapy can be used for patients at different clinical stages, but is not recommended for patients with poor general or organ functions. There is an urgent need to explore new therapeutic targets for CRC to improve clinical efficacy
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