Jumonji Domain Containing 1A Is a Novel Prognostic Marker for Colorectal Cancer: In vivo Identification from Hypoxic Tumor Cells

Purpose: This study aimed to identify novel hypoxia-inducible and prognostic markers in vivo from hypoxic tumor cells. Experimental Design: Using carbonic anhydrase 9 and CD34 as a guide for hypoxic tumor cells, laser capture microdissection was used to isolate colorectal cancer (CRC) liver metastases. The samples were analyzed by microarray analysis, in parallel with five CRC cell lines cultured under hypoxic conditions. To evaluate the prognostic impact of the expression of certain genes, samples from a total of 356 CRC patients were analyzed by microarray or quantitative reverse transcription-PCR. In vitro mechanistic studies and in vivo therapeutic experiments were also done about a histone H3 Lys(9) demethylase, Jumonji domain containing 1A (JMJD1A). Results: Several candidate genes were identified by microarray analysis of liver metastases and culturing of CRC cells under hypoxic conditions. Among them, we found that JMJD1A was a novel independent prognostic factor for CRC (P = 0.013). In vitro assays revealed that loss of JMJD1A by small interfering RNA treatment was associated with a reduction of proliferative activity and decrease in invasion of CRC cell lines. Furthermore, treatment with an adenovirus system for antisense JMJD1A construct displayed prominent therapeutic effects when injected into established tumor xenografts of the CRC cell lines HCT116 and DLD1. Conclusions: JMJD1A is a useful biomarker for hypoxic tumor cells and a prognostic marker that could be a promising therapeutic target against CRC. Clin Cancer Res; 16(18); 4636-46. (c) 2010 AACR.