Identification and Validation of SLC9A2 as A Potential Tumor Suppressor in Colorectal Cancer: Integrating Bioinformatics Analysis with Experimental Confirmation.

Autor: Liu YM; Department of Gastroenterology, the Central Hospital of Wuhan, Key Laboratory for Molecular Diagnosis of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China., Yang TC; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Fang XC; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Yang LJ; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Shi LW; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Wang HQ; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Dou TT; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Shu L; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Chen TL; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China., Hu J; Department of General Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China., Yu XM; Department of Gastrointestinal Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Wuhan, 435001, China. yuxiaoming@163.com., Li XF; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. lxf8591@163.com.; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, 430071, China. lxf8591@163.com.; Hubei Provincial Clinical Research Center for Cancer, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan, 430071, China. lxf8591@163.com.
Jazyk: angličtina
Zdroj: Current medical science [Curr Med Sci] 2024 Jun; Vol. 44 (3), pp. 529-544. Date of Electronic Publication: 2024 May 29.
DOI: 10.1007/s11596-024-2871-5
Abstrakt: Objective: To uncover the mechanisms underlying the development of colorectal cancer (CRC), we applied bioinformatic analyses to identify key genes and experimentally validated their possible roles in CRC onset and progression.
Methods: We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on differentially expressed genes (DEGs), constructed a protein-protein interaction (PPI) network to find the top 10 hub genes, and analyzed their expression in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). We also studied the correlation between these genes and immune cell infiltration and prognosis and validated the expression of SLC9A2 in CRC tissues and cell lines using qRT-PCR and Western blotting. Functional experiments were conducted in vitro to investigate the effects of SLC9A2 on tumor growth and metastasis.
Results: We found 130 DEGs, with 45 up-regulated and 85 down-regulated in CRC. GO analysis indicated that these DEGs were primarily enriched in functions related to the regulation of cellular pH, zymogen granules, and transmembrane transporter activity. KEGG pathway analysis revealed that the DEGs played pivotal roles in pancreatic secretion, rheumatoid arthritis, and the IL-17 signaling pathway. We identified 10 hub genes: CXCL1, SLC26A3, CXCL2, MMP7, MMP1, SLC9A2, SLC4A4, CLCA1, CLCA4, and ZG16. GO enrichment analysis showed that these hub genes were predominantly involved in the positive regulation of transcription. Gene expression analysis revealed that CXCL1, CXCL2, MMP1, and MMP7 were highly expressed in CRC, whereas CLCA1, CLCA4, SLC4A4, SLC9A2, SLC26A3, and ZG16 were expressed at lower levels. Survival analysis revealed that 5 key genes were significantly associated with the prognosis of CRC. Both mRNA and protein expression levels of SLC9A2 were markedly reduced in CRC tissues and cell lines. Importantly, SLC9A2 overexpression in SW480 cells led to a notable inhibition of cell proliferation, migration, and invasion. Western blotting analysis revealed that the expression levels of phosphorylated ERK (p-ERK) and phosphorylated JNK (p-JNK) proteins were significantly increased, whereas there were no significant changes in the expression levels of ERK and JNK following SLC9A2 overexpression. Correlation analysis indicated a potential link between SLC9A2 expression and the MAPK signaling pathway.
Conclusion: Our study suggests that SLC9A2 acts as a tumor suppressor through the MAPK pathway and could be a potential target for CRC diagnosis and therapy.
(© 2024. Huazhong University of Science and Technology.)
Databáze: MEDLINE
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