Introduction: Hepatocellular carcinoma (HCC) is characterized by the complex pathogenesis, limited therapeutic methods, and poor prognosis. Endoplasmic reticulum stress (ERS) plays an important role in the development of HCC, therefore, we still need further study of molecular mechanism of HCC and ERS for early diagnosis and promising treatment targets.
Methods: In this study, differential analysis was used to find differential ERS-related genes (ERSRGs) associated with HCC. An artificial neural network (ANN) prediction model was constructed based on Random Forest (RF) and Support Vector Machine (SVM). The ESTIMATE algorithm was used to analyze the correlation between ERSRGs and the immune micro-environment. Single-cell sequencing was used to evaluate the role of ERSRGs in the tumor micro-environment. The effect of ERS-related core gene, the protein phosphatase 1 regulatory subunit 16A (PPP1R16A) on hepatoma cells was verified through cytological experiments.
Results: An ANN related to the ERS model was constructed based on SRPX, THBS4, CTH, PPP1R16A, CLGN, and THBS1. The area under the curve (AUC) value of this model in the training set was 0.979, and the AUC values in the three validation sets were 0.958, 0.936, and 0.970 respectively. Among the six ERSRGs, the mutation rate of PPP1R16A was the highest, characterized by gene copy amplification. The expression levels of the six ERSRGs were highly correlated with immune cell infiltration and immune-related pathways. The intercellular interactions showed that PPP1R16A could remodel the tumor micro-environment through signals pathway such as macrophage migration inhibitory factor (MIF)/CD74+CXCR4. Functional experiments showed that the expression of PPP1R16A was down-regulated after siRNA knockdown, which suppressed the proliferation, migration, and invasion abilities of HCCLM3 and Hep3B cells in vitro.
Conclusion: This manuscript explored function and main molecular mechanism of ERS in HCC, and found that PPP1R16A probably paly an important role in the development of HCC. These findings may provide a new direction for the diagnosis and treatment of HCC.