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J. Chen
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-074 - ITPKA Expression in Lung and Other Cancers, Regulated via Gene Body Methylation, Functions as an Oncogene (ID 1026)
09:30 - 17:00 | Author(s): J. Chen
- Abstract
Background:
Lung cancer is the leading cause of cancer mortality and accounts for 1.6 million deaths annually in the world. Lung cancers may be classified into non-small cell (NSCLC) and small cell (SCLC) lung cancers, which individually account for approximately 85% and 15%, respectively, of lung cancer cases. Despite recent advances in cancer therapy, the overall 5-year survival rate of lung cancer remains low. There remains an urgent need for discovery of novel approaches for early diagnosis and therapy. Inositol-trisphosphate 3-kinase A (ITPKA) regulates inositol phosphate metabolism and calcium signaling by phosphorylation of the second messenger inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) to inositol-1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) (1). ITPKA has a very limited tissue expression, mainly in brain and testis. ITPKA, previously known as a neuron-specific F-actin bundling protein, has recently been shown to be overexpressed in lung adenocarcinoma and associated with increased metastatic potential (2). However, our understanding of the role and regulation of ITPKA in cancers is limited. Reference: 1. Shears SB. How versatile are inositol phosphate kinases? The Biochemical journal. 2004; 377:265-80. 2. Windhorst S, Kalinina T, Schmid K, Blechner C, Kriebitzsch N, Hinsch R, et al. Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells. International journal of cancer Journal international du cancer. 2011;129:1300-9.
Methods:
To identify potential oncogenes that are involved in the pathogenesis of lung cancer, cDNA microarray analysis was performed to search for up-regulated genes in primary lung adenocarcinomas. Inositol-trisphosphate 3-kinase A (ITPKA) was found to be overexpressed in lung ADC.
Results:
Using gain-of-function and loss-of-function approaches, we demonstrated that ITPKA contributes to cancer development. We also showed that methylation level in the ITPKA gene body is highly tumor-specific, and is positively correlated with its expression. Furthermore, DNMT3B-mediated methylation of the CpG island in ITPKA gene body regulates its expression via modulation of the binding of transcription activator SP1 to the ITPKA promoter. ITPKA gene body methylation first appeared at the in situ carcinoma stage and progressively increased during the multistage pathogenesis of lung carcinoma. Figure 1
Conclusion:
Altogether, deregulation of ITPKA may promote oncogenic transformation and function as a universal or near universal hallmark of malignancy. A novel regulatory mechanism of oncogene expression was demonstrated via gene body methylation which manipulates the binding of transcriptional factor(s) to its promoter and controls gene expression.
