Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma

Keren Li; Yi Niu; Kai Li; Chengrui Zhong; Zhiyu Qiu; Yichuan Yuan; Yunxing Shi; Zhu Lin; Zhenkun Huang; Dinglan Zuo; Yunfei Yuan; Binkui Li

doi:10.14218/JCTH.2022.00401

Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma

J Clin Transl Hepatol. 2023 Oct 28;11(5):1094-1105. doi: 10.14218/JCTH.2022.00401. Epub 2023 Apr 21.

Authors

Keren Li^{1

2}, Yi Niu¹, Kai Li^{1

2}, Chengrui Zhong^{1

2}, Zhiyu Qiu^{1

2}, Yichuan Yuan^{1

2}, Yunxing Shi^{1

2}, Zhu Lin^{1

2}, Zhenkun Huang^{1

2}, Dinglan Zuo¹, Yunfei Yuan^{1

2}, Binkui Li^{1

2}

Affiliations

¹ State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
² Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.

Abstract

Background and aims: Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma (HCC) patients while the underlying mechanism of metastasis remains elusive. In our study, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was shown to be involved in the process of metastasis in HCC.

Methods: The Cancer Genome Atlas (TCGA) database and HCC tissue microarrays were used to evaluate the expression of genes. In vitro migration, invasion, in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC. RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells. A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and interferon regulatory factor 5 (IRF5).

Results: The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues, and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients. In vitro experiments, knockdown of PLOD2 reduced the migration and invasion of human HCC cells. Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model. Baculoviral IAP repeat containing 3 (BIRC3) was proven to be the downstream factor of PLOD2 in human HCC cells. In addition, PLOD2 was transcriptionally regulated by IRF5 in HCC cells.

Conclusions: High expression of PLOD2 was regulated by IRF5, which was correlated with the poor survival of HCC patients. PLOD2 enhanced HCC metastasis via BIRC3, suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment.

Keywords: Hepatocellular carcinoma; Invasion; Metastasis; PLOD2; Proliferation.