PABPC1-induced stabilization of IFI27 mRNA promotes angiogenesis and malignant progression in esophageal squamous cell carcinoma through exosomal miRNA-21-5p

Abstract

Background Emerging evidence has demonstrated that RNA-binding protein dysregulation is involved in esophageal squamous cell carcinoma (ESCC) progression. However, the role of poly (A) binding protein cytoplasmic 1 (PABPC1) in ESCC is unclear. We therefore aimed to explore the functions and potential mechanisms of PABPC1 in ESCC progression. Methods PABPC1 expression was characterized using immunohistochemistry and qRT-PCR in ESCC tissues and cell lines. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to detect histone acetylation in the promoter region of PABPC1. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of PABPC1 in ESCC angiogenesis and malignant procession. Results PABPC1 expression was upregulated in ESCC tissues compared with in normal esophageal epithelial tissues. Elevated PABPC1 expression was correlated with tumor cell differentiation and poor prognosis in patients. Sp1 and p300 cooperated to increase the level of H2K37ac in the PABPC1 promoter. Functionally, PABPC1 overexpression enhanced esophageal squamous cell proliferation and invasion by activating the IFN/IFI27 signaling pathway. PABPC1 interacted with eIF4G to increase the stability of IFI27 mRNA by competing with RNA exosomes in ESCC. Furthermore, PABPC1/IFI27 could increase miR-21-5p expression to enable exosomal delivery of miR-21-5p to human umbilical vein endothelial cells to increase angiogenesis via inhibiting CXCL10. Conclusion PABPC1 plays a critical role in ESCC malignant progression by interacting with eIF4G to regulate IFI27 mRNA stability and promote angiogenesis via exosomal miR-21-5p/CXCL10. Taken together, our results suggest that PABPC1 is a promising therapeutic target for ESCC.

PABPC1——mRNA stability, protein translation and tumorigenesis

“…EXOSC2 is an important catalytic part of the RNA exosome complex, and EXOSC2 knockdown severely reduced RNA exosome function ( 171 , 172 ). The investigators rescued the decrease in IFI27mRNA stability by EXOSC2 knockdown and EXOSC2 knockdown increased PABPC1 binding to IFI27mRNA, similar to how PABPC1 knockdown increased the binding affinity of EXOSC2 to IFI27mRNA, all suggesting that PABPC1 competes with the RNA exosome to prevent degradation of IFI27mRNA ( 167 ). Various miRNAs from exosomes are major inducers of angiogenesis by activating signal transduction pathways that trigger the promotion of endothelial cell growth and migration.…”

“…Most past studies on PABPC1 in tumors have focused on detecting gene copy number and/or protein expression of PABPC1 in different types of tumor tissues or cells, and its high expression in some solid tumors is associated with poorer patient prognosis ( 23 – 30 , 142 , 161 , 183 , 185 – 190 ). PABPC1 selectively regulates transcripts by interacting with non-coding RNAs such as long-stranded non-coding RNAs, microRNAs specific translation and expression of specific oncogenic proteomes, enhancing cancer cell plasticity and thus promoting therapeutic evasion of cancer progression ( 24 , 28 – 30 , 167 , 186 ).…”

“…Zhang et al. used their own cohort and public database TCGA sample analysis to conclude that PABPC1 expression is upregulated in esophageal squamous cancer tissues and its elevated expression is associated with tumor cell differentiation and poor prognosis in patients ( 167 ). Pabpc1 promotes esophageal squamous cancer cell proliferation, migration and invasion and inhibits apoptosis.…”

Insulin‐like growth factor‐2 mRNA‐binding protein 3 promotes cell migration, invasion, and epithelial−mesenchymal transition of esophageal squamous cell carcinoma cells by targeting zinc finger E‐box‐binding homeobox 1 mRNA

“…Histone modification is an important epigenetic mechanism that can deregulate cancer‐related gene expression in tumors. Several studies 20,21 have reported the effects of histone H3 lysine 27 acetylation (H3K27Ac) in ESCC. To investigate whether the increased expression of IGF2BP3 in our ESCC cell lines was associated with aberrant histone modifications, we performed a genome bioinformatics analysis using the data from http://genome.ucsc.edu/, found that the promoter region of IGF2BP3 was enriched by H3K27Ac (Figure 7A and Supporting Information: Figure ).…”

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.…”