Overexpression of long noncoding RNA HOXA-AS2 predicts an adverse prognosis and promotes tumorigenesis via SOX4/PI3K/AKT pathway in acute myeloid leukemia.

Long noncoding RNAs (lncRNAs) play important roles in diverse cellular processes and carcinogenesis. Homeobox A cluster antisense RNA 2 (HOXA-AS2) is a 1,048-basepairs lncRNA located between human HOXA3 and HOXA4 genes, whose overactivation was previously found to promote the proliferation and invasion of solid tumors. However, its clinical and biological roles in acute myeloid leukemia (AML) remain unclear. This study showed that HOXA-AS2 was overexpressed in AML patients. In addition, the increased HOXA-AS2 expression was correlated with higher white blood cell and bone marrow blast counts, unfavorable karyotype classification, more measurable residual disease positivity, and earlier death. There was also a tendency toward inferior survival in patients with high HOXA-AS2 expression, and HOXA-AS2 was an independent prognostic factor among the normal-karyotype AMLs. Furthermore, the results of in vitro study showed that silencing HOXA-AS2 significantly inhibited the growth of leukemic cells by inducing G1/G0-phase arrest and apoptosis. Further analysis demonstrated that silencing HOXA-AS2 suppressed the phosphorylation level of PI3K and AKT, which thereafter promoted the expression of P21 and P27. Moreover, it was suggested that the sex-determining region Y-box 4 (SOX4), which is closely involved in the PI3K/AKT pathway, might be one of the major downstream targets of HOXA-AS2. Silencing HOXA-AS2 decreased the expression of SOX4, whereas the upregulation of SOX4 partially abrogated the inhibitory effect of silencing HOXA-AS2 on leukemic cells. In conclusion, these findings suggest that HOXA-AS2 probably functions as an oncogene via SOX4/PI3K/AKT pathway and might be a useful biomarker for the prognostic prediction in AML patients, providing a potential therapeutic target for AML.

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