Abstract 4157: DACH1 Inhibited proliferation and tumor growth of lung adenocarcinoma cells

Abstract

Abstract Lung cancer is the leading cause of cancer death worldwide. A key driver to the proliferation of lung cancer includes increased activity of the gene encoding the epidermal growth factor receptor (EGFR) and mutation of K-ras oncogene. Target therapies through small molecules to inhibit the tyrosine kinase domain of EGFR (Gefitinib) or monoclonal antibody to EGFR (Cetuximab) have demonstrated clinical benefit. Unfortunately, development of resistance to those treatments occurs in most patients within one year. Studies of the hyperactive EGFR in drosophila identified a genetic inhibitor of EGFR signaling, known as dachshund (dac). Activate ras inhibits DACH1 expression in malignant peripheral nerve sheath tumor. Dachshund can activate or represses transcription, and regulates cell proliferation and differentiation in multiple context-dependent manners. Our studies have proved that DACH1, human homolog of dac, functions as a potential tumor suppressor of breast and prostate cancer. Expression of DACH1 is lost during cancer progression and re-expression of DACH1 gene inhibited cellular proliferation, migration and tumor formation. The expression levels and the role of DACH1 in lung cancer are largely unknown. As both EGFR and Ras signaling interact with DACH1, we hypotheses that loss of endogenous DACH1 may contribute to the lung tumorigenesis. The mRNA expression of DACH1 was decreased in lung adenocarcinoma compared with normal lung tissues. Ectopic expression of DACH1 by stably transduction inhibited cellular proliferation of lung cancer cell lines A549 and SKLU, cell cycle progression and clone formation rate in contact-dependent and -independent growth. ELISA using conditional medium from A549 cells expressing vector control or DACH1 demonstrated remarkable inhibition of secreting factors, such as CXCL1, CXCL2, CXCL5 and CXCL8. Those chemokines have already been proved to positively regulating angiogenesis and proliferation. To test in vivo tumorigenesis, 2x106 A549 cells expressing DACH1 or vector control were injected subcutaneously into nude mouse and tumor size was monitored weekly. Tumor growth was dramatically blocked by DACH1. Tumor weight was 297.8 ± 38.6mg for vector control and 31 ± 6.1mg for cells expressing DACH1(p value <0.001). Importantly, over-expression of CXCL5 can partly rescue tumor growth inhibition by DACH1 in A549 cells. Together, our study demonstrated that DACH1 is a potentially tumor suppressor of lung cancer though repression of chemokines secretion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4157. doi:1538-7445.AM2012-4157