Golgi phosphoprotein 3 promotes angiogenesis and sorafenib resistance in hepatocellular carcinoma via upregulating exosomal miR-494-3p

Abstract

Background Golgi 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). Methods In 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. Results Downregulation 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. Conclusions HCC 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.

Deepening the knowledge of rare diseases dependent on angiogenesis through semantic similarity clustering and network analysis

“…Another more specific function such as ‘phosphoprotein binding’ is shared in clusters 10, 4, 5, 3 and 8. There are proteins with this function that have been related to angiogenesis stimulation in pathogenic processes [ 9 ]. Clusters 1, 2 and 8 are those with a greater number of associated functional categories, being mostly related to the mitochondrial transport chain in clusters 1 and 8, while cluster 2 has functions mostly related to protein synthesis and cellular communication.…”

Microvesicles: the functional mediators in sorafenib resistance

“…Conversely, TMVs have been shown to activate CAFs to improve the mobility of tumor cells, while the activated fibroblasts could secret MVs and in turn facilitate tumor progression [12,85] . Moreover, small GTPases and RHO-associated protein kinase, key factors in the biogenesis of MVs [73] , were found to be highly expressed in both CAFs and cancer cells [86] , which indicates the possible role of CAFs in the alteration of MVs secretion.…”

Extracellular Vesicles as Delivery Shippers for Noncoding RNA‐Based Modulation of Angiogenesis: Insights from Ischemic Stroke and Cancer

“…Seventy‐six publications were found in this section, from Iran, Japan, China, Korea, and India, performed between 2013 and 2022. [ 127,174–248 ] Of these ncRNAs, 3 circRNAs, 14 lncRNAs, and 45 microRNAs were differentially expressed between healthy individuals and various cancers. Concerning circRNAs (namely, circHIPK3, circFNDC3B, and circCMTM3 derived from EVs) are upregulated and shown to regulate metatherian, tissue inhibitor of metalloproteinase 3, SOX9 through miR‐124‐3p, miR‐937‐5p, miR‐3619‐5p in breast cancer, colorectal cancer, and hepatocellular carcinoma, respectively, which enhance EC viability, migration and tube formation except in colorectal cancer to drive the process of carcinogenesis.…”

“…EV‐miR‐494‐3p, which is upregulated in hepatocellular and lung cancer, can accelerate cancer angiogenesis by directly targeting phosphatase and tensin homolog (PTEN) and tyrosine‐protein phosphatase nonreceptor type 12. [ 235 ] Likewise, EV‐miR‐10a‐5p overexpression enhanced the viability and migration of ECs in gastric and cervical cancer by targeting ZMYND11 and TBX5. [ 191,245 ] More details and the associated main effect of EV‐ncRNAs on angiogenesis regulation under cancer conditions are summarized in Table 2 and Figure .…”