The CELF gene family is a group of genes that encode conserved RNA binding proteins that are frequently involved in posttranscriptional regulation. Some of CELFs have been reported to be dysregulated in cancers, for example, CELF1 in lung cancer and liver cancer and CELF2 in breast cancer [24–26]. To the best of our knowledge, bioinformatics analysis of the relationships between CELF gene family members and glioma remains elusive. Our study is the first to explore the mRNA expression levels and prognostic values of CELF gene family members in glioma.
In the CELF gene family, CELF1 has undergone the most research. Bernd et al. revealed that CELF1 participates in regulation of the cell cycle, apoptosis and cell motility and is a proto-oncogene[27, 28]. Dysregulation of CELF1 plays an important role in the development of cancers, including glioma. CDKN1B is a crucial gene that regulates the cell cycle and prevents cell division[29]. It has been reported that overexpression of CELF1 in brain tissues can promote glioma cell proliferation by suppressing CDKN1B expression and that silencing CELF1 gene expression can promote CDKN1B expression and thus stimulate p27 IRES activity[9, 30]. According to one study, miR-330-3p can suppress glioma cell proliferation and metastasis by targeting CELF1[31]. This finding is consistent with our findings, as analysis of the GEPIA and Human Protein Atlas databases revealed that the expression level of CELF1 was higher in glioma cells than that in normal cells. However no dataset in Oncomine showed was related to overexpression of CELF1 in glioma. Notably, patients with LGG had poor OS when the expression of CELF1 was high.
CELF2 is an RNA binding protein that regulates mRNA stability and translation[32]. CELF2 was discovered in neuroblastoma cells that had been induced to undergo apoptosis with colchicine[33]. It has been reported that CELF2 expression is decreased in non-small cell lung carcinoma[34], breast cancer[35] and ovarian cancer[36]. MicroRNA-20a modulates glioma cell reproduction, metastasis and apoptosis by targeting CELF2[8]. Interestingly, it has been reported that downregulation of miR‑95‑3p can suppress the growth of glioma cells by targeting CELF2[37]. In our study, we revealed that the expression level of CELF2 was higher in glioma tissues than in normal tissues and that CELF2 expression was weakly correlated with tumour grade in patients with low-grade glioma. Moreover, marked relationships between CELF2 expression and the clinical characteristics of patients with glioma were observed. In GEPIA, we determined the prognostic value of CELF2 in patients with glioma; however, the results showed that in all of the patients with glioma, the expression of CLEF2 was not significantly related to OS and DFS.
Currently, research on the expression and role of CELF3 in glioma remains rare. Zhou et al. revealed that CELF3 was differentially expressed in patients with colorectal cancer metastases, and at the genomic level, the copy number variation of CELF3 showed a significant differential distribution between patients with and without metastasis[38]. In our report, the expression of CELF3 in glioma tissues was lower than that in normal tissues and was associated with tumour grade in glioma patients. In all patients with LGG, low CELF3 expression was significantly correlated with poor OS and DFS.
CELF4 is mainly expressed in the neural system, and its expression levels in muscle, heart, etc, are minimal[39]. In addition, a decreased copy number of CELF4 was observed in gastric cancer cells, and CELF4 copy number loss was identified as an independent prognostic indicator for colorectal cancer[40, 41]. In our study, we compared the level of CELF4 expression in glioma tissues and normal brain tissues in Oncomine and GEPIA, and the results showed that CELF4 expression was lower in the former than in the latter and was associated with tumour stage in LGG in UALCAN. In addition, the survival curve revealed that lower expression of CELF4 in patients with LGG was associated with worse OS and DFS.
CELF5 regulates gene transcription and function through involvement in posttranscriptional modifications, including mRNA editing and pre-mRNA alternative splicing[3]. Katarzyna et al. reported that CELF5 was a promising candidate biomarker for the detection of populations with hepatocellular carcinoma[42]. It has been reported that CELF5 could regulate the synthesis of human cytomegalovirus (HCMV) genomic DNA, which participates in tumour cell migration, invasion and apoptosis[43, 44]. According to our study, significantly lower expression in glioma tissues compared to normal tissues was observed not only in Oncomine but also in GEPIA and HPA. CELF5 expression was linked to tumour grade in glioma patients. Furthermore, LGG patients with low CELF4 expression had poor OS and DFS.
CELF6 can regulate p21 stability and then modulate the cell cycle and cell division[45]. While Yang et al. identified CELF6 as a tumour suppressor gene, as its overexpression could inhibit tumour development[7]. CELF6 gene expression was found to be significantly downregulated in glioma tissues in the current study, and its expression level was related to tumour grade in patients with glioma. However, we can easily see from the figure that GBM patients with high expression of CELF6 have poor OS, which was inconsistent with our previous results. In addition, the mechanisms involved have yet to be studied.