PLAGL2‐EGFR‐HIF‐1/2α signaling loop promotes HCC progression and Erlotinib insensitivity

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. In this study, we demonstrated that PLAGL2 was upregulated in HCC compared to that of adjacent non-tumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Besides, hypoxia was found to significantly induce high expression of PLAGL2, which promoted HIF1/2alpha expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF-1/2alpha signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib. Conclusion: This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential novel therapeutic target of HCC.