Background: The morbidity and mortality of lung cancer in Xuanwei (LCXW) is among the highest in China for both males and females and increases constantly. The underlying molecular changes associated with LCXW are still unclear. The purpose of this study was to screen out potential cancer-related genes which may become promising biomarkers of LCXW. Methods: Differentially expressed genes (DEGs) were detected by the expression microarrays in 29 paired LCXW tissues (tumor tissue and matched adjacent non-cancerous lung tissues). Integrated with bioinformatic analyses, a literature review was applied for screening out important cancer-related genes. An additional 44 paired LCXW samples were collected to verify the transcription and expression levels of the candidate gene by qRT-PCR and Western blotting. The relationship between the candidate genes and clinical pathological features were evaluated using Fisher's test. Results: mRNA expression microarrays revealed that the LCXW patients harbored 2,424 differentially expressed genes (fold change >= 2.0). Of these genes, 1,636 were up-regulated while the other 788 genes were down-regulated. Forty previously reported DNA repair genes associated with PAHs exposure were identified by microarrays. Bioinformatic analyses indicated down-regulated ANXA3 in LCXW patients which was closely related to pathological stage and involved in the regulation of a variety of biological responses. Review of the literature on ANXA3 found its down-regulation was a distinct expression pattern compared with lung cancer occurring in other geographic areas. qRT-PCR and Western blotting confirmed the down-regulation of ANXA3 was associated with LCXW. The correlation analysis of clinical features showed down-regulated ANXA3 was correlated to the progression of pathological stage. Conclusions: The LCXW patients harbored more DEGs, and these DEGs were involved in a wide range of pathways and biological function damage. We preliminarily suggested ANXA3 may be a potential LCXW related gene. ANXA3 may serve as a promising biomarker for diagnosis of LCXW.