Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

Abstract

Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti–apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC.

New Activities of the Nuclear Pore Complexes

“…For instance, we provided several lines of evidence that the phosphorylation of the cohesin subunit, SMC1, stimulates binding to mitotic Rae1 [27,28], a phenomenon recently confirmed by others to form part of a mechanism of antimitotic catastrophe in early tumorigenesis [29]. Indeed, Rae1 is highly overexpressed in colon cancer [30]. We and others also showed NPCs and nuclear transport proteins play critical roles in various cancers [31][32][33][34], especially leukemia [35,36].…”

RAE1 is a prognostic biomarker and is correlated with clinicopathological characteristics of patients with hepatocellular carcinoma

“…RAE1 overexpression could facilitate EMT to lead to an invasive ductal histology and a high histological grade in breast cancer. RAE1 also promoted colorectal tumor growth through inhibiting apoptosis and promoting cell cycle progression in part by stabilization of spindle bipolarity [ 13 , 19 ]. To date, the role of RAE1 in HCC has not been investigated.…”

“…An elevated RAE1 expression level was correlated with a higher T stage, pathologic stage, tumor status, histologic grade, and AFP level. A high expression level of RAE1 was also significantly associated with distant metastasis [ 13 ]. Importantly, RAE1 expression level was correlated with AFP level in the present study.…”

“…Microtubules are essential components of the cytoskeleton, and they are an important molecular target for novel therapeutics in cancer [ 13 ]. Microtubules are involved in a variety of biological processes, including cell division, apoptosis, proliferation, and angiogenesis, because they constitute the mitotic spindle, which is a complex structure that coordinates the accurate segregation of chromosomes during cell division.…”

“…Moreover, RAE1 was found to be positively correlated with gene copy number, which promoted a more aggressive phenotype and induced epithelial-mesenchymal transition (EMT). Furthermore, RAE1 overexpression was positively correlated with the histologic grade and a poor prognosis in patients with breast cancer and colorectal cancer [ 13 , 19 – 22 ]. However, the detailed mechanisms of RAE1 in HCC have still remained elusive.…”