VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR–PI3K–AKT pathway

• Published in: Oncogene 2020-02, Vol.39 (6), p.1213-1230
• Main Authors: Zhangyuan, Guangyan, Wang, Fei, Zhang, Haitian, Jiang, Runqiu, Tao, Xuewen, Yu, Decai, Jin, Kangpeng, Yu, WeiWei, Liu, Yang, Yin, Yin, Shen, Jintao, Xu, Qinfeng, Zhang, Wenjie, Sun, Beicheng
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/109; 13/31; 13/51; 14/1; 14/19; 38/77; 38/91; 45/29; 631/67/2327; 631/67/395; 64/60; 82/58; Acidification; AKT protein; Analysis; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinogenesis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Proliferation; Computed tomography; Development and progression; Disease Progression; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Gene Expression Regulation, Neoplastic; Glycolysis; Health aspects; Hepatocellular carcinoma; Hepatoma; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Malignancy; Mass spectroscopy; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Molecular modelling; Oncology; Oxygen consumption; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Polymerase chain reaction; Positron emission tomography; Prognosis; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Reverse transcription; Ribonucleic acid; RNA; RNA sequencing; Signal Transduction; Survival Rate; Therapeutic applications; Therapeutic targets; Tomography; Tumor Cells, Cultured; Tumors; Versican; Versicans - genetics; Versicans - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-1052-7

Versican has been reported to participate in carcinogenesis in several malignant tumors. However, the accurate role of VersicanV1, a predominant isoform of Versican in liver, remains an enigma in hepatocellular carcinoma (HCC). The expression of VersicanV1 in HCC tissues and adjacent tissues was detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western Blot (WB) and inmumohistochemistry (IHC). Gain and loss of function assays were performed to examine the role of VersicanV1 in proliferation and metastasis of HCC. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in vitro and PET-CT (positron emission tomography/computed tomography) analysis in vivo were applied to evaluate the effects of VersicanV1 on glycolysis. RNA sequencing, Co-IP (Co-immunoprecipitation) and MS (mass spectrometry) were utilized to investigate the molecular mechanisms. Our current study reveals that VersicanV1, regulated by direct interaction with Linc01225, is significantly upregulated in HCC tissues and correlates with poor prognosis. Both in vitro and in vivo experiments show that knockdown of VersicanV1 in HCC cells attenuates cancer cells malignancy. Further studies identify the positive role of VersicanV1 in aerobic glycolysis. Mechanistic investigation discovers the activation of EGFR–PI3K–AKT pathway in HCC cells expressing high VersicanV1. Moreover, EGF-like motif is indispensable for VersicanV1 to promote Warburg effect of HCC cells and subsequently, proliferation, invasion, and metastasis ability via activation of EGFR–PI3K–AKT axis. In sum, our research highlights a novel role of VersicanV1 in the progression of HCC, suggesting that VersicanV1 is an indicator for prognosis and a potential therapeutic target of HCC.