SummaryAAA domain-containing 3A (ATAD3A) is a member of the AAA-ATPase family. Three forms of ATAD3 have been identified: ATAD3A, ATAD3B and ATAD3C. In this study, we examined the type and expression of ATAD3 in lung adenocarcinoma (LADC). Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. Our results show that ATAD3A is the major form expressed in LADC. Silencing of ATAD3A expression increased mitochondrial fragmentation and cisplatin sensitivity. Serum deprivation increased ATAD3A expression and drug resistance. These results suggest that ATAD3A could be an anti-apoptotic marker in LADC.
We examined gene expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR), or product of proto-oncogene c-met (c-met), in smokers and nonsmokers with adenocarcinoma (ADC) by suppression subtractive hybridization and microarray techniques. Expression of HGF and c-met was confirmed by RT-PCR. HGF content in the respective tumor mass and nontumor lung tissue was measured by ELISA. HGF in pathologic samples was localized by immunohistochemistry and in situ hybridization. Our results indicate that overexpression of HGFR was frequently detected in ADC cells, whereas overexpression of HGF was detected in alveolar type II (ATII) cells. Overexpression of HGF was correlated with cigarette smoking and tumor stages. In vitro, HGF expression was evaluated in isolated murine ATII cells and in 12 ADC cell lines, and we found that nicotine activated HGF expression in ATII cells and lung cancer cells.
Our previous study had shown that advanced stages of lung adenocarcinomas (ADC) was frequently associated with overexpression of hepatocyte growth factor (HGF), which has multipotent and anti-apoptotic activities. In this study, we examined the effect of HGF on gene expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in lung ADC cells. Expression of AIF was determined by immunocytochemistry and confocal immunofluorescence microscopy. Our data show that addition of HGF suppressed AIF expression and increased cisplatin resistance. The effect could be through HGF receptor and its downstream effector, focal adhesion kinase (FAK). Interestingly, knockout of FAK gene increased AIF expression and drug sensitivity. Re-introduction of FAK gene, on the other hand, restored drug resistance. These results suggested that HGF might induce cisplatin resistance via c-Met to activate FAK and down-regulate AIF expression.
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