MicroRNA‐3064‐5p sponged by MALAT1 suppresses angiogenesis in human hepatocellular carcinoma by targeting the FOXA1/CD24/Src pathway

Abstract

Abbreviations: CLSM, confocal laser scanning microscopy; Co-IP, co-immunoprecipitation; FISH, fluorescence in situ hybridization; FOXA1, forkhead box protein A1; HCC, hepatocellular carcinoma; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; MMP12, macrophage metalloelastase; MVD, microvessel density; OS, overall survival; RFS, recurrence-free survival; RIP, RNA binding protein immunoprecipitation; TNM, tumor node metastasis; VEGFA, vascular endothelial growth factor A. AbstractAngiogenesis is critical for the development, progression, and metastasis of hepatocellular carcinoma (HCC), but the roles of miR-3064-5p in HCC angiogenesis are still unknown. In this study, the roles of miR-3064-5p in HCC angiogenesis were studied in 192 HCC patients, xenograft mouse models, and HCC cell lines. The results showed that miR-3064-5p expression was significantly decreased in HCC tissues and cells, and downregulated miR-3064-5p was associated with upregulated angiogenic potential of HCC. MiR-3064-5p inhibited proangiogenic VEGFA and angiogenin expressions but induced antiangiogenic endostatin and MMP12 expressions, finally leading to suppression of HCC angiogenesis, as shown by the decline in intratumoral microvessel density (MVD). Moreover, miR-3064-5p was inversely correlated with lncRNA MALAT1 and FOXA1. FOXA1 bound to and interacted with CD24 and then regulated Src phosphorylation. MiR-3064-5p played an antiangiogenic role by inhibiting the FOXA1/CD24/Src pathway, whereas oncogenic MALAT1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-3064-5p to alleviate the suppressive effect on the FOXA1 pathway. HCC patients with high miR-3064-5p, low MALAT1, or low FOXA1 expression had a better prognosis with longer overall survival and recurrence-free survival. In univariate and multivariate analyses, miR-3064-5p was identified as the independent prognostic predicator for HCC progression and patient survival. Taken together, miR-3064-5p exerts an antiangiogenic role by targeting the FOXA1/CD24/Src pathway but oncogenic lncRNA MALAT1 acts as a ceRNA to sponge miR-3064-5p. MiR-3064-5p is of great clinical significance and is a novel prognostic indicator and an attractive therapeutic target for HCC. K E Y W O R D SceRNA, FOXA1/CD24/Src pathway, HCC angiogenesis, lncRNA MALAT1, miR-3064-5p | 67 ZHANG et Al.

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

“…MALAT1 acted as a sponge of miRNAs, leading to downregulation of miR-NAs and subsequently abnormal expression of targeted genes. [25][26][27] Here, we made a comprehensive search using the public database miRcode and Starbase, and miR-22-3p was identified to be a target gene of MALAT1, as well as an upstream gene of XIAP in cancer. Therefore, we hypothesized that MALAT1 may compete for miR-22-3p, attenuating the regulatory effect of miR-22-3p on IAPs.…”

“…23,24 They were demonstrated to act as sponges of miRNAs, leading to the dysregulation of miR-NAs and subsequently the abnormal expression of corresponding target genes. [25][26][27][28] BA has been reported to induce cell death through apoptosis in a variety of cancer cells. 29,30 Nevertheless, the role of autophagy in BA-induced cell death in HCC is unknown.…”

Exosomal CircPRRX1 Enhances Doxorubicin Resistance in Gastric Cancer by Regulating MiR-3064-5p/PTPN14 Signaling

“…In hepatocellular carcinoma, miR-3064-5p blocked angiogenesis by binding to MALAT1 and regulating the FOXA1 pathway. 26 In GC, circCOL6A3 was found to facilitate tumor progression by acting as a sponge for miR-3064-5p and activating COL6A3. 27 In our research, miR-3064-5p was down-regulated in doxorubicin-resistant cells.…”

Role of long noncoding RNA-mediated competing endogenous RNA regulatory network in hepatocellular carcinoma

“…A study found that the lncRNA HULC promotes angiogenesis by upregulating SPHK1 in HCC; HULC acts as a ceRNA to increase the expression of transcription factor E2F1 by competitively binding to miR-107 and subsequently results in the activation of the SPHK1 promoter, thus promoting HCC angiogenesis in vivo [ 52 ]. In addition, the lncRNA MALAT1 can promote HCC angiogenesis by sponging miR-3064-5p to activate the forkhead box A1 (FOXA1)/CD24/Src pathway[ 53 ] or by functioning as a miR-140 sponge to enhance vascular endothelial growth factor A expression[ 54 ]. Similarly, LINC00488 , another lncRNA, upregulates the expression of talin 1 to facilitate HCC angiogenesis by sponging miR-330-5p[ 55 ].…”