High expression of SMPD4 promotes liver cancer and is associated with poor prognosis

Abstract Background and objective: The expression of sphingomyelin phosphodiesterase 4 (SMPD4), a neutral sphingomyelin enzyme, is intricately associated with tumorigenesis and progression. However, its function in hepatocellular carcinoma (HCC) and its pathogenic mechanism remain largely unclear. We investigated the correlation between SMPD4 in HCC and its prognostic significance and functions in HCC cell proliferation, invasion, and migration. Methods The expression of SMPD4 was detected in different tumor types, such as HCC, using the database from The Cancer Genome Atlas (TCGA). The diagnostic significance of SMPD4 was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). The Kaplan–Meier curve analysis was conducted to assess the ability of SMPD4 to predict HCC prognosis. The relationship between SMPD4 expression and the degree of immune cell infiltration in HCC was examined using the Tumor Immune Estimation Resource (TIMER) database. In addition, we performed quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to verify SMPD4 expression in 20 frozen liver cancer tissue samples and paired non-carcinoma liver tissues. Small interfering RNA (siRNA) was performed to silence SMPD4 in cancer cells. The effect of SMPD4 expression in liver cancer cells was measured through qRT-PCR and western blotting. The function of SMPD4 in the proliferation, invasion, and migration of Hep3B and HepG2 cells was validated using the CCK-8, EdU, wound healing, and Transwell assays. Finally, the relationship between SMPD4 and drug sensitivity was examined. Results Elevated expression of SMPD4 was recorded in 22 cancer types, including HCC. SMPD4 expression was related to gender, T stage, N stage, clinical stage, and pathological grade. The area under the ROC curve was 0.952, indicating the excellent diagnostic value of SMPD4. The Kaplan–Meier analysis demonstrated that SMPD4 upregulation was related to poor overall survival (OS) in patients with HCC. The functional enrichment analysis revealed the critical effect of SMPD4 on the cell cycle. Moreover, SMPD4 expression exhibited a positive relationship between the infiltration levels of B cells, CD8 T+ cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Knocking down SMPD4 significantly inhibited HCC cell growth, invasion, and migration. Finally, SMPD4 expression was related to drug sensitivity. Conclusions SMPD4 is upregulated in HCC, indicating poor prognosis. It could be used as a diagnostic and prognostic biomarker for HCC. Knocking down SMPD4 affects the ability of proliferation, migration, and invasion by regulating the expression of cell cycle genes.