The role of HOXA11 gene in the treatment resistance

Abstract

Purpose. Homeobox (HOX) genes are essential developmental regulators and should normally be in the silenced state in the adult brain.Aberrant expression of HOX genes has been associated with prognosis in many cancer types including glioblastoma (GBM). In this study, the identity and role of HOX genes affecting GBM prognosis and treatment resistance were investigated. Materials and Methods. By performing microarray analysis of 5 pairs of initial and recurrent human GBM samples, we screened the full series of HOX genes for the most plausible candidate responsible for GBM prognosis. We used another 20 newly diagnosed GBM samples for prognostic validation. In vitro experiments were performed to confirm the HOX role in treatment resistance. Mediators involved in HOX gene regulation were searched by using differentially expressed gene analysis, gene set enrichment tests, and network analysis. Results. Underexpression of HOXA11 was identified as a consistent signature for poor prognosis among HOX genes. Overall survival of GBM patients indicated significantly favorable prognoses in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in those with low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in GBM cell lines, anticancer effect of radiotherapy and/or temozolomide was declined. In addition, we identified five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) which may confer oncologic effect after HOXA11 suppression. Conclusion. Treatment resistance induced by underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation is needed to confirm the value of HOXA11 as a potential target for overcoming treatment resistance by developing chemo- or radio-sensitizers.