Abstract
BackgroundGolgi phosphoprotein 3 (GOLPH3) has been frequently reported as an oncoprotein in a variety of tumors. However, its role in the cancer-associated intercellular signaling communication has not yet been explored. This study aimed at exploring whether GOLPH3 regulates angiogenesis and sorafenib resistance via exosomal mechanisms in hepatocellular carcinoma (HCC).MethodsIn vivo assays were performed to elucidate the function of GOLPH3 in HCC. Exosomes of HCC cells were isolated by differential centrifugation, and then measured and quantified using nanoparticle tracking analysis (NTA), BCA assay, western blot (WB), and transmission electron microscopy (TEM). Differentially expressed miRNAs in exosome were analyzed and verified through small RNA sequencing (sRNA-seq) and reverse-transcription polymerase chain reaction (RT-PCR). In addition, a series of in vitro assays were performed to determine the function of exosomes and miR-494-3p in HCC. The candidate target gene of miR-494-3p was identified by bioinformatics prediction and dual-luciferase reporter assay.ResultsDownregulation of GOLPH3 expression could suppress angiogenesis and enhance sorafenib sensitivity in HCC. Exosomes derived from GOLPH3 overexpression HCC cells promoted the angiogenesis ability of HUVECs and induced sorafenib resistance in HCC cells. A total of 13 differentially expressed miRNAs between negative control and GOLPH3 knockdown group were found in exosomes. However, GOLPH3 was only associated with miR-494-3p expression level in exosomes derived from HCC cells without affecting total cellular miR-494-3p content. Results confirmed that exosomal miR-494-3p promotes angiogenesis of HUVECs and sorafenib resistance in HCC cells through directly targeting PTEN.ConclusionsHCC cells with high expression levels of GOLPH3 could promote angiogenesis and sorafenib resistance by enhancing exosomal miR-494-3p secretion to recipient HUVECs and HCC cells, respectively.
Highlights
Golgi phosphoprotein 3 (GOLPH3) has been frequently reported as an oncoprotein in a variety of tumors
Eight hepatocellular carcinoma (HCC) cell lines were used to explore the expression of GOLPH3 in HCC cells and appropriate cell lines were selected for further investigation
GOLPH3 mRNA and protein levels were analyzed by real-time quantitative (RT-qPCR) and western blot (WB)
Summary
Golgi phosphoprotein 3 (GOLPH3) has been frequently reported as an oncoprotein in a variety of tumors. This study aimed at exploring whether GOLPH3 regulates angiogenesis and sorafenib resistance via exosomal mechanisms in hepatocellular carcinoma (HCC). Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality worldwide [1,2,3]. Most HCC patients are diagnosed at an advanced stage, leading to poor prognosis with an average median survival time of 6 months and an. Sorafenib exhibits significant efficacy to placebo in improving overall survival (OS) of advanced HCC patients [5]. In the past 10 years, sorafenib has been the only available conventional therapy for advanced-stage HCC [4, 6]. Studies should explore potential strategies to enhance efficacy of anti-angiogenic therapy and reduce sorafenib resistance improving clinical outcome of advance HCC patients
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