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Cancer Res Treat. 2017 Apr;49(2):387-398. doi: 10.4143/crt.2016.106. Epub 2016 Jul 19.

Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma.

Author information

1
Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
2
Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea.
3
Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
4
Department of Neurosurgery, Ajou University School of Medicine, Suwon, Korea.
5
Department of Neurosurgery, Korea University College of Medicine, Seoul, Korea.
6
Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
7
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
8
Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
9
Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
10
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Abstract

PURPOSE:

Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.

MATERIALS AND METHODS:

The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis.

RESULTS:

The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified.

CONCLUSION:

The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

KEYWORDS:

Glioblastoma; HOXA11; Homeobox genes; Treatment resistance

PMID:
27456940
PMCID:
PMC5398402
DOI:
10.4143/crt.2016.106
[Indexed for MEDLINE]
Free PMC Article

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