Activation of WD repeat and high-mobility group box DNA binding protein 1 in pulmonary and esophageal carcinogenesis.
OBJECTIVE
We attempted to identify novel biomarkers and therapeutic targets for lung and esophageal cancers.


METHODS
We screened for genes that were overexpressed in a large proportion of lung and esophageal carcinomas using a cDNA microarray representing 27,648 genes or expressed sequence tags. A gene encoding WDHD1, a WD repeat and high-mobility group box DNA binding protein 1, was selected as a candidate. Tumor tissue microarray containing 267 archival non-small cell lung cancers and 283 esophageal squamous cell carcinomas (ESCC) was used to investigate the clinicopathologic significance of WDHD1 expression. The role of WDHD1 in cancer cell growth and/or survival was examined by small interfering RNA experiments and cell growth assays. The mechanism of WDHD1 activation through its phosphorylation in cancer cells was examined by immunoprecipitation and kinase assays.


RESULTS
Positive WDHD1 immunostaining was associated with a poor prognosis for patients with non-small cell lung cancer (P = 0.0403) as well as ESCC (P = 0.0426). Multivariate analysis indicated it to be an independent prognostic factor for ESCC (P = 0.0104). Suppression of WDHD1 expression with small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of the exogenous expression of WDHD1 promoted the growth of mammalian cells. AKT1 kinase seemed to phosphorylate and stabilize the WDHD1 protein in cancer cells.


CONCLUSIONS
WDHD1 expression is likely to play an important role in lung and esophageal carcinogenesis as a cell cycle regulator and a downstream molecule in the phosphoinositide 3-kinase/AKT pathway, and that WDHD1 is a candidate biomarker and a promising therapeutic target for cancer.
Sato
Nagato
N
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Koinuma
Junkichi
J
Fujita
Masahiro
M
Hosokawa
Masao
M
Ito
Tomoo
T
Tsuchiya
Eiju
E
Kondo
Satoshi
S
Nakamura
Yusuke
Y
Daigo
Yataro
Y
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000175:diagnosis*; D005260:Female; D024243:HMGB1 Protein / Q000032:analysis*; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt