ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer

• Published in: British journal of cancer 2011-02, Vol.104 (4), p.700-706
• Main Authors: Tasaki, M, Shimada, K, Kimura, H, Tsujikawa, K, Konishi, N
• Format: Article
• Language: English
• Subjects: 692/53/2421; 692/699/67/1612/1350; Aged; Aged, 80 and over; AlkB Homolog 1, Histone H2a Dioxygenase; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Dioxygenases - genetics; Dioxygenases - physiology; DNA Repair Enzymes - genetics; DNA Repair Enzymes - physiology; Drug Resistance; Epidemiology; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - physiology; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Molecular Diagnostics; Molecular Medicine; Oncology; Pneumology; RNA, Small Interfering - pharmacology; Sequence Homology; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6606012

Background: We have demonstrated for the first time that a novel human AlkB homologue, ALKBH3, contributes to prostate cancer development, but its clinical and biological roles in lung cancer remain unclear. Methods: Expression of both mRNA and protein of PCA-1 was examined by RT–PCR and western blotting. We also assessed association with senescence and in vivo ALKBH3 treatment on orthotopic tumour cell inoculation, and analysed it clinicopathologically. Results: We have since found novel biological roles for ALKBH3 in human lung cancers, particularly in adenocarcinoma. Our immunohistochemical analysis of human adenocarcinomas and squamous cell carcinomas of the lung not only showed overexpression of ALKBH3 in these tumours but the percentage of cells positive for ALKBH3 also correlated statistically to recurrence-free survival in adenocarcinoma. Knockdown of ALKBH3 by siRNA transfection induced expression of p21 WAF1/Cip1 and p27 Kip1 in the human lung adenocarcinoma cell line A549, resulting in cell cycle arrest, senescence and strong suppression of cell growth in vitro . In vivo , peritoneal tumour growth and dissemination was inhibited in nude mice, previously inoculated with the A549 cell line, by intraperitoneal injection of ALKBH3 siRNA + atelocollagen, as demonstrated by the reduction in both number and diameter of tumours developing in the peritoneum. Conclusion: We suggest that ALKBH3 contributes significantly to cancer cell survival and may be a therapeutic target for human adenocarcinoma of the lung.