In recent years, diseases caused by bacteria, viruses, and protozoa have severely limited the development of the sea cucumber () aquaculture industry. Among such diseases, skin ulceration syndrome (SUS) has become the most universal and serious, owing to its high mortality rates. Therefore, the identification and analysis of key genes associated with "skin ulceration" and corresponding signal pathways are important for establishing the molecular mechanism of SUS. We previously analyzed the gene expression and transcriptome of three-stage SUS progression (SUS-I, SUS-Ⅱ, SUS-Ⅲ) in . Here, we further investigated the occurrence of differentially expressed genes (DEGs) among ulcerative and normal body wall (BW) samples from the same individuals at three stages of SUS progression. The R-Bioconductor package (R-2.15.3) was used to perform principal component analysis and Venn diagrams of these DEGs. KEGG enrichment analysis was carried out based on an algorithm (refer to materials and methods 1.2), using the entire transcriptome set as the background and a cutoff value of Q ≤ 0.05. The regulatory network for SUS progression in PCA analysis indicated that the number of DEGs among the ulcerative and normal BW samples was smallest at SUS stage Ⅱ and that the gene expression profiles at SUS stages I and Ⅲ were similar. Venn diagram analysis indicated that the 497, 59, and 433 unique DEGs were expressed at stage I, Ⅱ and Ⅲ of SUS progression, respectively. Only 28 DEGs were co-expressed in all three stages. KEGG enrichment analysis indicated that the "Complement and coagulation cascades" and "ECM-receptor interaction" pathways were significantly enriched throughout all three stages of SUS progression. The important SUS-related DEGs, including the FcGBP and TN family genes, were identified by constructing a regulatory network. Using qRT-PCR, five representative DEGs were selected to validate the sequencing results. The Pearson's correlation coefficient () was 0.7714, which confirmed the consistency and accuracy of the two approaches.In sea cucumbers, SUS is characterized by apparent white skin ulcers, as well as by complicated molecular regulation. The significantly affected signal pathways detected among the ulcerative and normal BW in the same individuals at three stages of SUS progression, such as the "Focal adhesion" and "ECM-receptor interaction" pathways, have also been observed in the ulcerative BW of SUS-affected individuals (including SUS stages I, Ⅱ, and Ⅲ), when compared to healthy individuals in our previous studies. The FcGBP gene involved in these two pathways was worthy of further exploration. FcGBP is an Fc fragment of the IgG binding protein in fluids secreted by cells of the stomach and intestinal mucosa layer and might play a role in cell protection and anti-inflammation. FcGBP was up-regulated in crypts of early stage ulcerative colitis in human. In addition, Tenascins are extracellular matrix glycoproteins which can regulate cell adhesion, migration, proliferation and differentiation. The expression of the Aj-TN gene changed significantly during the process of extracellular matrix remodeling during sea cucumber regeneration. In human disease studies, TN proteins are associated with tumor metastasis, skin wound healing, and ulcer healing. The expression of TN-family genes in ulcerative and normal BW was significantly different during SUS progression, which suggests that these genes play important roles in the onset and development of SUS in sea cucumber. These results will be useful in developing strategies for preventing bacterial SUS in sea cucumber.