PLAGL2‐EGFR‐HIF‐1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity

• DOI: 10.1002/hep.31293
• Publication Date: 2020-04-26T03:16:10Z
• Authors: Weiwei Hu; Shufang Zheng; Haixin Guo; Beiying Dai; Jiaping Ni; Yaohong Shi; Hanrui Bian; Lanxin Li; Yumeng Shen; Mo Wu; Zhoutong Tian; Guilai Liu; Md Amir Hossain; Hongbao Yang; Duowei Wang; Qin Zhang; Jun Yu; Lutz Birnbaumer; Jifeng Feng; Decai Yu; Yong Yang
• Keywords: Adult; 0301 basic medicine; Carcinoma, Hepatocellular; PLAGL2-EGFR-HIF1/2A; Kaplan-Meier Estimate; Erlotinib Hydrochloride; 03 medical and health sciences; Cell Movement; https://purl.org/becyt/ford/1.6; Cell Line, Tumor; Basic Helix-Loop-Helix Transcription Factors; Animals; Humans; https://purl.org/becyt/ford/1; Aged; Cell Proliferation; Feedback, Physiological; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; DNA-Binding Proteins; ErbB Receptors; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Disease Progression; Female

Background and Aims 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.

Approach and Results In this study, we demonstrated that PLAGL2 was up‐regulated in HCC compared with that of adjacent nontumorous 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. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2‐EGFR‐HIF1/2A 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.

Conclusions This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.