ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features
Hirotaka Osada1, Yoshio Tatematsu, Yasushi Yatabe
1Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa, Nagoya, Japan. hosada@aichi-cc.jp
Abstract:
Lung cancers with neuroendocrine features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined. The basic helix-loop-helix protein, achaete-scute complex-like 1/achaete-scute homologue 1 (ASH1), is expressed in normal fetal pulmonary neuroendocrine cells and lung cancers with neuroendocrine elements and is suggested to be involved in lung carcinogenesis. In the present study, we show inhibition of ASH1 expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASH1 expression through G2-M cell cycle arrest and accumulation of sub-G1 populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASH1 expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASH1 clearly induced rescue from G2-M arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established and significantly inhibited not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASH1-RNAi adenovirus. The present study therefore suggests that ASH1 plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features.
Insights
Achaete-scute homologue 1 (ASH1) drives aggressive lung cancer growth. Inhibiting ASH1 with RNA interference suppressed tumor cell proliferation and induced apoptosis, suggesting ASH1 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung cancers with neuroendocrine features are aggressive, with poorly understood molecular drivers.
- Achaete-scute complex-like 1/achaete-scute homologue 1 (ASH1) is implicated in lung carcinogenesis and expressed in neuroendocrine lung cells and tumors.
Purpose of the Study:
- To investigate the role of ASH1 in lung cancer development.
- To evaluate the therapeutic potential of targeting ASH1 in lung cancers with neuroendocrine features.
Main Methods:
- Plasmid-based RNA interference (RNAi) was used to inhibit ASH1 expression in lung cancer cell lines.
- ASH1-RNAi adenovirus was employed for both in vitro and in vivo studies, including xenograft models.
- Cell cycle analysis, apoptosis assays, and xenograft growth inhibition were assessed.
Main Results:
- ASH1 inhibition via RNAi significantly suppressed the growth of ASH1-expressing lung cancer cells by inducing G2-M cell cycle arrest and apoptosis.
- ASH1 knockdown specifically affected cancer cells, leaving normal bronchial epithelial cells and ASH1-negative cancer cells unaffected.
- ASH1-RNAi adenovirus demonstrated efficacy in inhibiting both in vitro proliferation and in vivo xenograft growth, with increased apoptosis observed in tumors.
Conclusions:
- ASH1 plays a critical role in the development and progression of lung cancers with neuroendocrine features.
- Targeting ASH1 represents a promising therapeutic strategy for these aggressive lung cancers.
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