CircRNAs known as a novel category of non-coding RNAs exist widely in mammalian cells23. They have been considered as ideal biomarkers for disease because of their conservative feature across species. There are a few studies concentrated on the role of circRNAs in hematological malignancies. For instance, circ_0004277 expression had been reported to be down-regulated in AML. And the expression of circ_0004277 tended to up-regulated when the patients got complete remission and down-regulated again when they got relapsed. Circ_0004277 expression changed dynamically with process of AML, which proved that it could be used as AML biological marker24.
According to what we know, this is the first report foused on the expression of circular RNA of PTEN in AML. In this study, circ_0002232 expression in AML was notably down-regulated compared with that in controls. The same results were found in groups of non-APL AML and CN-AML. Accordng to ROC curve analysis, circ_0002232 could act as a valuable marker to identify AML patients and control groups.
Identifying the relation between the expression of circ_0002232 and clinical characteristic, we found that the expression level of circ_0002232 was positively correlated with platelet count. Circ_0002232low group tended to have lower platelet count. There already have several reports focused on the abnormal platelet count and dysfunction in AML25. Low platelet count was associated with poor prognosis and recovery of platelet was concerned with relapse-free survival rate after chemotherapy in AML26,27. Moreover, circ_0002232low group also tended to have lower hemoglobin, and higher percentage of blast compared with circ_0002232 high expression group. This means circ_0002232low group have more severe myelosuppression and more serious infiltration in BM. Hence, low expression of circ_0002232 is an adverse factor of AML.
Unexpectedly, results of Kaplan-Meier analysis revealed that OS of patients with low-expressed circ_00002232 were longer than that of patients with high-expressed circ_00002232 in whole AML. PTEN, parental gene of circ_0002232, plays a role of tumor suppressor in many diseases. At the beginning of our experiment, we proposed that patients with low-expressed circ_0002232 might have shorter overall survival time, which was obviously contract with current results.
However, our study indicated that patients in circ_0002232low group were significantly younger than those in circ_0002232high group. In other words, old patients were liable to have high expression of circ_0002232. Pearson analysis was used to confirm this result, which revealed that the circ_0002232 expression was positively correlated with patients’ age. Age is an important risk factor for AML. Survival time of AML patients tends to decrease with increased age28,29. We suppose that it may help us to understand this conflicting result. The correlation between age and circ_0002232 expression led to this reverse result.
Then according to the expression level of circ_0002232, we divided the patients (age < 40y) into two groups and compared the differences in survival time. The result showed that circ_0002232high group tended to have better OS compared with circ_0002232low group. This result confirmed our conjecture. But due to the limitation of our experiment size, this result wasn’t statistically significant. In the future, additional experiments are needed to enlarge sample size and identify the relationship between circ_0002232 expression and OS in different age subgroups.
Moreover, the phenomenon of circRNAs acting as miRNA sponges in regulating proliferation, metastasis and relapse of gastrointestinal cancer have been reported in some studies5. In this research, prediction websites revealed that there were potential binding sites among circ_0002232, miR-92a-3p, and PTEN. MiR-92a-3p expression has been revealed to be up-regulated in several solid cancers including breast cancer and brain glioma30,31. According to our experiment, miR-92a-3p expression of AML patients was obviously up-regulated compared with controls and was negatively correlated with the expression of circ_0002232.
Furthermore, high-expressed miR-92a have been found to regulate colorectal cell migration and invasion by reducing the expression level of PTEN32. Alteration of miR-92a also promoted its effect on metastatic behavior of nasopharyngeal carcinoma cell by targeting PTEN33. Notably, we found that the expression level of miR-92a-3p was also negatively correlated with PTEN in AML. Hence, we proposed that circ_0002232 might regulate PTEN expression through sponging miR-92a-3p and affect the process of AML. In the future, we plan to design more experiments like knock-out and over-expressed experiments to explore the mechanism of this pathway in AML.