DLGAP5 regulates malignancy and lenvatinib sensitivity of hepatocellular carcinoma through AKT/mTOR/NF-κB pathway

BACKGROUND: Lenvatinib is the first-line therapy for advanced hepatocellular carcinoma (HCC). Nevertheless, drug resistance is a challenge for improving the outcomes of these patients. Discs Large Homolog Associated Protein 5 (DLGAP5) belongs to cell-cycle-regulated proteins, associated with poor prognosis in cancer. However, its biological roles and mechanisms in lenvatinib sensitivity of HCC remain unclear. METHODS: We analyzed the expression level of DLGAP5 by public database. A sixty HCC patients' cohort was used to investigate the prognostic potential after lenvatinib treatment. Cell growth, metastasis, apoptosis, and animal experiments were used to explore the specific function of DLGAP5. Differentially expressed genes of DLGAP5-knockdown cells were analyzed by RNA-seq data. RESULTS: DLGAP5 was upregulated in HCC tissues, especially in lesions of patients with metastasis. Overexpression of DLGAP5 correlated with poor prognosis and lower response to lenvatinib treatment. We found that the downregulation of DLGAP5 inhibited malignancy and increased the sensitivity of HCC cells to lenvatinib both in vitro and in vivo. Mechanistically, DLGAP5 might function by regulating AKT/mTOR/NF-κB signaling pathway. CONCLUSIONS: DLGAP5 promotes malignancy of HCC and reduces cell lenvatinib sensitivity by positively regulating the AKT/mTOR/NF-κB pathway, indicating that DLGAP5 functions as a potential biomarker for clinical prognosis and lenvatinib treatment in HCC.