Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells.
OBJECTIVE
This study aimed to identify novel hypoxia-inducible and prognostic markers in vivo from hypoxic tumor cells.


METHODS
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.
Uemura
Mamoru
M
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka, Japan.
Yamamoto
Hirofumi
H
Takemasa
Ichiro
I
Mimori
Koshi
K
Hemmi
Hideyuki
H
Mizushima
Tsunekazu
T
Ikeda
Masataka
M
Sekimoto
Mitsugu
M
Matsuura
Nariaki
N
Doki
Yuichiro
Y
Mori
Masaki
M
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D056485:Retinoblastoma-Binding Protein 2