Abstract
Distant metastatic colorectal cancer (CRC) is present in approximately 25% of patients at initial diagnosis, and eventually half of CRC patients will develop metastatic disease. The 5-year survival rate for patients with metastatic CRC is a mere 12.5%; thus, there is an urgent need to investigate the molecular mechanisms of cancer progression in CRC. High expression of human high-mobility group A2 (HMGA2) is related to tumor progression, a poor prognosis, and a poor response to therapy for CRC. Therefore, HMGA2 is an attractive target for cancer therapy. In this study, we identified aspirin and sulindac sulfide as novel potential inhibitors of HMGA2 using a genome-wide mRNA signature-based approach. In addition, aspirin and sulindac sulfide induced cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration. Moreover, a gene set enrichment analysis (GSEA) revealed that gene sets related to inflammation were positively correlated with HMGA2 and that the main molecular function of these genes was categorized as a G-protein-coupled receptor (GPCR) activity event. Collectively, this is the first study to report that aspirin and sulindac sulfide are novel potential inhibitors of HMGA2, which can induce cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration through influencing inflammatory-response genes, the majority of which are involved in GPCR signaling.
Highlights
Around a quarter of colorectal cancer (CRC) patients are incurable at diagnosis, and half of the patients who undergo potentially curative surgery will develop metastatic disease [1].Distant metastatic disease of CRC is present in approximately 25% of patients at initial diagnosis, and half of CRC patients will develop metastatic disease [2]
This is the first report to describe aspirin and sulindac sulfide as novel potential inhibitors of high-mobility group A2 (HMGA2), which can induce cytotoxicity in CRC cells overexpressing HMGA2 by inhibiting cell proliferation and migration through influencing inflammatory-response genes, the majority of which are involved in
Our study showed that HMGA2 overexpression was positively correlated with an increased rate of migration of DLD-1 cells with stable expression of HMGA2, which was consistent with previous findings
Summary
Around a quarter of colorectal cancer (CRC) patients are incurable at diagnosis, and half of the patients who undergo potentially curative surgery will develop metastatic disease [1]. It was demonstrated that overexpression of the HMGA2 protein occurs in various types of cancer, including CRC [7]. Bioinformatics methodologies have become a crucial part of drug discovery [10] This is mostly because they can impact the entire drug development trajectory, by identifying and discovering potential new drugs with a significant reduction in the traditionally high costs and long periods required for new drug development [11]. An urgent need remains to discover and develop potential therapeutic drugs to suppress the overexpression of HMGA2 in cancer patients
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