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LncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis.

ABSTRACT: Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy.

SUBMITTER: Wu H

PROVIDER: S-EPMC7139143 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis.

Wu Hailu H Wei Ming M Jiang Xinglu X Tan Jiacheng J Xu Wei W Fan Xiaobo X Zhang Rui R Ding Chenbo C Zhao Fengfeng F Shao Xiangyu X Zhang Zhigang Z Shi Ruihua R Zhang Weijia W Wu Guoqiu G

Molecular therapy. Nucleic acids 20200319

Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferati ...[more]

PMID: 32276209

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Project description:BackgroundLong-non-coding RNA PVT1 (lncRNA PVT1) can be used as an oncogenic regulatory non-coding RNA (ncRNA) for many cancers. However, its function and mechanism in breast cancer (BRCA) are still not clearly elucidated.ObjectiveWe attempt to explain the mechanism of PVT1's role in breast cancer from different perspectives.MethodsWe analyzed the expression of PVT1 and its correlation with the breast cancer related clinical data in the The Cancer Genome Atlas (TCGA) database. We used PVT1 overexpression and knockdown lentivirus to infect breast cancer MDA-MB-231 cell line for cell function verification, in vitro using CCK-8 to measure proliferation, flow cytometry to measure apoptosis, transwell test to measure invasion and migration ability, detecting cell extracellular acidification rate (ECAR) to assess glycolysis metabolism and explore the biological functions of PVT1 in breast cancer cells. Transcriptome sequencing was used to analyze the changes of related genes in cells after overexpression of PVT1. In vivo we used a xenograft model to study the effect of PVT1 on breast cancer.ResultsPVT1 was up-regulated in breast cancer tissues and was positively correlated with the clinical stage of breast cancer patients. Overexpression of PVT1 in vitro promoted cell proliferation, migration and invasion, and promoted tumor growth in vivo. Knockdown of PVT1 led to the opposite biological consequence. Further bioinformatics analysis showed that PVT1 changes the glycolysis metabolism of tumors through regulation of glycolysis-related genes. In addition, the expression of miR-145-5p is negatively correlated with PVT1. We consider the possibility of PVT1 promoting cell proliferation and metastasis by regulating the aerobic glucose metabolism in breast cancer cells through sponging the miR-145-5p.ConclusionOur results reveal a potential pathway for competing endogenous RNA to regulate breast cancer glucose metabolism. PVT1 regulates glycolysis related genes expression by competitively binding to endogenous miR-145-5p in breast cancer cells to change the metabolic phenotype. This may Provide new ideas for precise molecular therapy targets for breast cancer.

Project description:BackgroundTreating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear.MethodsComputational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)).ResultsThe in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated.ConclusionExosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

Project description:Glioma is the most common malignant tumor in the central nervous system. Altered long noncoding RNAs (lncRNAs) are playing regulatory roles in physiological and pathogenic processes in cancer. Here, we uncovered a differentially expressed lncRNA called brain cytoplasmic RNA 1 (BCYRN1), and elucidated its function and molecular mechanism in the progression and development of glioma. Three fresh tumor tissues from glioma patients and three normal brain tissues from craniocerebral trauma patients were prepared for high-throughput RNA sequencing. Differential RNA transcripts and BCYRN1 were identified by RT-qPCR in glioma samples and controls. CCK-8, colony formation assays, flow cytometry, TUNEL assays, cell migration assays, wound-healing assays, and xenograft model were established to investigate the biological function of BCYRN1 both in vitro and in vivo. Various bioinformatics analysis, dual-luciferase reporter assays, biotinylated RNA pulldown assays, and rescue experiments were conducted to reveal the underlying mechanisms of competitive endogenous RNAs (ceRNAs). 183 lncRNAs were identified with significant dysregulation in glioma and randomly selected differential RNAs were further confirmed by RT-qPCR. Among them, BCYRN1 was the most downregulated lncRNA, and its low expression positively correlated with glioma progression. Functionally, BCYRN1 overexpression inhibited cell proliferation, migration in glioma cell lines, whereas BCYRN1 depletion resulted in the opposite way. MiR-619-5p was further confirmed as the direct target of BCYRN1. Mechanistically, miR-619-5p specifically targeted the CUE domain containing protein 2 (CUEDC2), and BCYRN1/miR-619-5p suppressed glioma tumorigenesis by inactivating PTEN/AKT/p21 pathway in a CUEDC2-dependent manner. Overall, our data presented that the reduced expression of BCYRN1 was associated with poor patient outcome in glioma. BCYRN1 functioned as a ceRNA to inhibit glioma progression by sponging miR-619-5p to regulate CUEDC2 expression and PTEN/AKT/p21 pathway. Our results indicated that BCYRN1 exerted tumor suppressor potential and might be a candidate in the diagnosis and treatment of glioma.

Dataset Information

LncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis.

Publications

lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis.

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