1. Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
3. Department of Gastroenterology, Beilun Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Ningbo 315800, China
#These authors contributed equally to this work.
Background: Increasing evidence has implicated that lncRNAs (long non-coding RNAs) play significant roles in carcinogenesis and progression of HCC (hepatocellular carcinoma). LINC01503 is a new lncRNA related to several tumors. Nonetheless, its role in HCC still remains unclear.
Methods: The expression levels of LINC01503 in HCC, normal liver tissues as well as HCC cell lines were evaluated by TCGA (The Cancer Genome Atlas) and real-time PCR assay, respectively. The relationship between LINC01503 levels and the prognosis of patients with HCC was evaluated using Kaplan‐Meier survival analysis. Then the potential biological functions and pathways related to LINC01503 were investigated by GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, and GSEA v4.0.1 software was employed. Furthermore, the influence of LINC01503 on the proliferation and apoptosis of HCC cells was confirmed using CCK8 assay, flow cytometry, and clone formation assay in cell experiments. Also the pro-tumor effect of LINC01503 was verified by mice xenograft experiment in vivo. In addition, the functional pathway of LINC01503 was proved by western blot and rescue experiments.
Results: LINC01503 was highly expressed in HCC and positively correlated with large tumor size, high tumor grade, advanced tumor stage, and poor prognosis of HCC patients. Silencing LINC01503 with shRNA significantly restrained the proliferation of MHCC-97H HCC cells and strengthened the apoptosis, while up-regulation of LINC01503 in Huh7 HCC cells contributed to the contrary effects. Besides, LINC01503 promoted tumor growth of nude mice transplanted with liver cancer cells. Mechanistically, MAPK/ERK signaling pathway was activated by LINC01503, inhibition of which could alleviate the pro-tumor effect of LINC01503, consistent with the forecast of GSEA (Gene Set Enrichment Analysis).
Conclusion: LINC01503 is highly expressed in HCC and promotes the progression of HCC via MAPK/ERK pathway, which maybe a new potential biomarker and therapeutic target for HCC.
Keywords: hepatocellular carcinoma, LINC01503, MAPK/ERK pathway, proliferation, apoptosis