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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 258-265

ZNF561 antisense RNA 1 contributes to angiogenesis in hepatocellular carcinoma through upregulation of platelet-derived growth Factor-D


1 Department of Hepatological Surgery, Changshu Second People's Hospital, Suzhou, Jiangsu Province, China
2 Department of Hepatological Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China

Date of Submission05-Jun-2022
Date of Decision19-Jul-2022
Date of Acceptance25-Aug-2022
Date of Web Publication27-Oct-2022

Correspondence Address:
Dr. Jihu Zheng
Department of Hepatological Surgery, Changshu Second People's Hospital, No. 18 Taishan Road, Changshu 215500, Jiangsu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0304-4920.359795

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  Abstract 


Hepatocellular carcinoma is a common malignant tumor with high recurrence rate. Long non-coding RNA (lncRNA) ZNF561 antisense RNA 1 (ZNF561-AS1) functions as an oncogenic lncRNA to promote the tumorigenesis of colorectal cancer. The role of ZNF561-AS1 in hepatocellular carcinoma remains unknown. ZNF561-AS1 was elevated in hepatocellular carcinoma tissues and cells. Silence of ZNF561-AS1 reduced cell viability and inhibited the proliferation of hepatocellular carcinoma. The angiogenesis of hepatocellular carcinoma was also suppressed by loss of ZNF561-AS1 with a decrease of angiopoietin 2, fibroblast growth factor 1, and vascular endothelial growth factor. ZNF561-AS1 bind to miR-302a-3p, and decreased expression of miR-302a-3p in hepatocellular carcinoma. Moreover, miR-302a-3p reduced platelet-derived growth factor-D (PDGFD) in hepatocellular carcinoma, and inhibition of miR-302a-3p attenuated ZNF561-AS1 silence-induced decrease of PDGFD. In conclusion, silence of ZNF561-AS1 might inhibit cell proliferation and angiogenesis of hepatocellular carcinoma through downregulation of miR-302a-3p-mediated PDGFD.

Keywords: Angiogenesis, hepatocellular carcinoma, miR-302a-3p, platelet-derived growth factor-D, proliferation, ZNF561 antisense RNA 1


How to cite this article:
Zheng J, Guo Z, Wen Z, Chen H. ZNF561 antisense RNA 1 contributes to angiogenesis in hepatocellular carcinoma through upregulation of platelet-derived growth Factor-D. Chin J Physiol 2022;65:258-65

How to cite this URL:
Zheng J, Guo Z, Wen Z, Chen H. ZNF561 antisense RNA 1 contributes to angiogenesis in hepatocellular carcinoma through upregulation of platelet-derived growth Factor-D. Chin J Physiol [serial online] 2022 [cited 2022 Nov 26];65:258-65. Available from: https://www.cjphysiology.org/text.asp?2022/65/5/258/359795




  Introduction Top


Hepatocellular carcinoma is one of the most common malignant tumors in the world, and accounts for 70%–85% of all primary liver cancers.[1] The high recurrence rate and heterogeneity of hepatocellular carcinoma contribute to cancer-related death.[2] Hepatocellular carcinoma is regarded as a vascular tumor. Angiogenesis, remodeling and expansion of vascular network are the critical regulator of tumor invasion and metastasis.[3] Abnormal angiogenesis is also associated with occurrence and poor prognosis of hepatocellular carcinoma.[3] Antiangiogenic therapy is currently recommended for the treatment of hepatocellular carcinoma with advanced stage.[4]

Long non-coding RNAs (lncRNAs) have been shown to be a molecular scaffolding to guide proteins to chromosomal targets, or host genes for microRNAs (miRNAs) to prevent the interaction with target genes, thus participating in the tumorigenesis of hepatocellular carcinoma.[5] LncRNAs were also regarded as potential targets for angiogenesis.[6] In hepatocellular carcinoma, lncRNA OR3A4 promoted angiogenesis and tumor metastasis.[7] ZNF561 antisense RNA 1 (ZNF561-AS1) was identified to be dysregulated in laryngeal squamous cell carcinoma, and downregulation of ZNF561-AS1 promoted the tumor migration and invasion through regulation of miR-217-WNT5A axis.[8] However, ZNF561-AS1 also functioned as an oncogenic lncRNA to enhance the proliferation and survival of colorectal cancer through modulation of miR-26a-3p/miR-128-5p-SRSF6 axis.[9] However, the role of ZNF561-AS1 in hepatocellular carcinoma remains unclear.

microRNAs were also implicated in the pathogenesis and angiogenesis of hepatocellular carcinoma.[10] miR-302 cluster has been shown to target vascular endothelial growth factor-A (VEGF-A) and inhibit the angiogenesis of leukemia cells.[11] miR-302a directly targeted VEGF-A to suppress cell proliferation and metastasis of hepatocellular carcinoma,[12] miR-302a-3p also functioned as a tumor suppressor and was involved in lncRNA SNHG16-mediated hepatocellular carcinoma.[13] miR-302a-3p was predicted as a potential target of ZNF561-AS1. Therefore, the role of ZNF561-AS1/miR-302a-3p axis in hepatocellular carcinoma was then investigated. Effects of ZNF561-AS1 on cell proliferation and angiogenesis of hepatocellular carcinoma were investigated, and the underlying mechanism involved in ZNF561-AS1/miR-302a-3p-mediated hepatocellular carcinoma was also evaluated.


  Materials and Methods Top


Human samples

A total of 20 pairs of hepatocellular carcinoma and paracarcinoma tissues were collected from the patients recruited at Changshu Second People's Hospital. Cirrhotic liver tissues (n = 7) were also isolated from patients through surgery. This study was approved by the Ethics Committee of Changshu Second People's Hospital (Approval No. 2013026) and in accordance with those of the 1964 Helsinki Declaration and its later amendments for ethical research involving human subjects. Informed consent was obtained from all the participants.

Cell culture and transfection

Liver sinusoidal endothelial cells (LSECs), human umbilical vein endothelial cells (HUVECs), and human hepatocellular carcinoma cells (Hep3B, SNU-387, Huh7, and MHCC97L) were purchased from ScienCell (Carlsbad, CA, USA). Cells were cultured in Dulbecco's Modified Eagle's Medium containing 10% fetal bovine serum (Gibco, Gaithersburg, MD, USA) at 37°C. Hep3B and SNU-387 were transfected with miR-302a-3p inhibitor or NC inhibitor (RiboBio, Guangzhou, China) using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA). miR-302a-3p inhibitor and shZNF561-AS1-2# (RiboBio) were co-transfected into Hep3B and SNU-387.

Cell proliferation assays

Hep3B and SNU-387 were seeded in 96-well plates, and cultured in the medium for 24, 48, or 72 h. Cells were then treated with CCK8 solution (Beyotime, Beijing, China), and the absorbance at 450 nm was examined through Microplate Autoreader (Thermo Fisher, Waltham, MA, USA). To detect proliferation, Hep3B and SNU-387 were seeded in 6-well plates and then cultured in the medium for another 10 days. Cell colonies were photographed under a light microscope (Olympus, Tokyo, Japan).

Tube formation assay

Hep3B and SNU-387 were seeded and then cultured in a 5-mL serum-free medium for another 24 h. HUVECs were suspended in the cultured medium, and then seeded into 96-well culture plates that are precoated with extracellular matrix gel (Cell Biolabs, San Diego, CA, USA). After 24 h of incubation, capillary-like structures were photographed under the microscope (Olympus). A number of branching points were calculated using LAS V3.7 software (LEICA, Solms, Germany).

Dual-Luciferase Reporter Assay

Sequences of wild-type or mutant 3'-UTR of ZNF561-AS1 or platelet-derived growth factor-D (PDGFD) were constructed into pmirGLO luciferase reporter vector (Promega, Madison, WI, USA), and named as ZNF561-AS1/PDGFD-WT or ZNF561-AS1/PDGFD-MUT. Hep3B and SNU-387 were co-transfected with ZNF561-AS1/PDGFD-WT or ZNF561-AS1/PDGFD-MUT with miR-302a-3p mimic or NC mimic (RiboBio) for 48 h. Luciferase activities were determined by Dual-Luciferase® Reporter Assay System (Promega).

Quantitative reverse transcription–polymerase chain reaction RNA

RNAs or miRNAs were isolated from cells and tissues using Trizol (Invitrogen) or miRcute miRNA Isolation Kit (Tiangen, Beijing, China), respectively. RNAs were reverse transcribed into cDNAs, and then subjected to quantitative reverse transcription–polymerase chain reaction analysis of ZNF561-AS1, miR-302a-3p, and PDGFD with SYBR Green Master (Roche, Mannheim, Germany). GAPDH or U6 served as endogenous controls. The fold changes were determined by 2−ΔΔCT method with primers in [Table 1].
Table 1: Primers

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Western blot

Proteins were extracted from cells using RIPA buffer (KeyGen Biotech, Jiangsu, China), and separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Proteins were electrotransferred onto polyvinylidene difluoride membrane, and the membrane was blocked with 5% skim milk. Primary antibodies: anti-angiopoietin 2 (ANGPT2) and anti-fibroblast growth factor 1 (FGF-1) (1:2000), anti-VEGF and anti-β-actin (1:2500), anti-PDGFD (1:3000), and anti-p-FAK and anti-FAK (1:3500) were used to probe the membranes overnight. Following incubation with HRP-labeled secondary antibody (1:4000), the immunoreactivities were detected by enhanced chemiluminescence (KeyGen Biotech). All the proteins were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

Statistical analysis

All the data were expressed as mean ± standard error of the mean, and analyzed through Student's t-test or one-way analysis of variance in GraphPad Prism 7.0 (GraphPad Software, San Diego, CA, USA). Survival curves plotted through Kaplan–Meier method and log-rank test were used to analyze. P < 0.05 was considered statistically significant.


  Results Top


ZNF561 antisense RNA 1 was elevated in hepatocellular carcinoma

The expression of ZNF561-AS1 in hepatocellular carcinoma was predicted in GEPIA (http://gepia.cancer-pku.cn/). Result showed the significantly elevation of ZNF561-AS1 in the tumor tissues (n = 369) compared to normal tissues (n = 160) [Figure 1]a. ZNF561-AS1 was also upregulated in hepatocellular carcinoma tissues compared to paracarcinoma tissues [Figure 1]b. Moreover, hepatocellular carcinoma cells (Hep3B, SNU-387, Huh7, and MHCC97L) also expressed higher ZNF561-AS1 than LSECs [Figure 1]c. Hep3B and SNU-387 showed the highest expression of ZNF561-AS1 among hepatocellular carcinoma cells that were subjected to the functional assays.
Figure 1: ZNF561-AS1 was elevated in hepatocellular carcinoma. (a) Expression of ZNF561-AS1 was elevated in hepatocellular carcinoma tissues based on GEPIA (http://gepia.cancer-pku.cn/). (b) ZNF561-AS1 was upregulated in hepatocellular carcinoma tissues compared to paracarcinoma tissues. (c) ZNF561-AS1 was up-regulated in hepatocellular carcinoma cells (Hep3B, SNU-387, Huh7, and MHCC97 L) compared to LSECs. *P < 0.05, **P < 0.01 and ***P < 0.001 versus normal tissues or LSECs. ZNF561-AS1: ZNF561 antisense RNA 1, LSECs: Liver sinusoidal endothelial cells.

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ZNF561 antisense RNA 1 contributed to cell proliferation of hepatocellular carcinoma

Hep3B and SNU-387 were transfected with shZNF561-AS1-1# and shZNF561-AS1-2# to decrease ZNF561-AS1 expression [Figure 2]a. shZNF561-AS1-2# showed lower expression than shZNF561-AS1-1# [Figure 2]a. Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# decreased the cell number of Hep3B and SNU-387 [Figure 2]b, and reduced the number of colonies [Figure 2]c, suggesting an antiproliferative effect of ZNF561-AS1 silence on hepatocellular carcinoma.
Figure 2: ZNF561-AS1 contributed to cell proliferation of hepatocellular carcinoma. (a) Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# decreased ZNF561-AS1 expression in Hep3B and SNU-387. (b) Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# decreased the cell number of Hep3B and SNU-387. (c) Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# reduced the number of colonies in Hep3B and SNU-387. *P < 0.05, **P < 0.01, and ***P < 0.001 versus shNC. ZNF561-AS1: ZNF561 antisense RNA 1.

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ZNF561 antisense RNA 1 contributed to angiogenesis of hepatocellular carcinoma

Angiogenetic capability of Hep3B and SNU-387 was suppressed by knockdown of ZNF561-AS1 [Figure 3]a. Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# downregulated protein expression of ANGPT2, FGF-1, and VEGF in Hep3B and SNU-387 [Figure 3]b to exert an antiangiogenetic effect on hepatocellular carcinoma.
Figure 3: ZNF561-AS1 contributed to the angiogenesis of hepatocellular carcinoma. (a) Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# suppressed the angiogenetic capability of Hep3B and SNU-387. (b) Transfection with shZNF561-AS1-1# and shZNF561-AS1-2# downregulated protein expression of ANGPT2, FGF-1, and VEGF in Hep3B and SNU-387.**P < 0.01 and ***P < 0.001 versus shNC. ZNF561-AS1: ZNF561 antisense RNA 1, VEGF: Vascular endothelial growth factor.

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ZNF561 antisense RNA 1 binding to miR-302a-3p

ZNF561-AS1 was predicted to bind to miR-302a-3p using Carolina database [Figure 4]a. Luciferase activity of ZNF561-AS1-WT was reduced by transfection with miR-302a-3p mimic [Figure 4]b. Transfection with shZNF561-AS1-2# upregulated the expression of miR-302a-3p in Hep3B and SNU-387 [Figure 4]c. miR-302a-3p was reduced in hepatocellular carcinoma tissues [Figure 4]d, and negatively associated with ZNF561-AS1 [Figure 4]e, demonstrating the binding ability between miR-302a-3p and ZNF561-AS1.
Figure 4: ZNF561-AS1 binding to miR-302a-3p. (a) Potential binding site between ZNF561-AS1 and miR-302a-3p. (b) Transfection with miR-302a-3p mimics reduced luciferase activity of ZNF561-AS1-WT in Hep3B and SNU-387. (c) Transfection with shZNF561-AS1-2# upregulated expression of miR-302a-3p in Hep3B and SNU-387. (d) miR-302a-3p was reduced in hepatocellular carcinoma tissues compared to paracarcinoma tissues. (e) Expression of miR-302a-3p was negatively associated with ZNF561-AS1 in hepatocellular carcinoma tissues. *P < 0.05 and ***P < 0.001 versus normal tissues, shNC or NC mimic. ZNF561-AS1: ZNF561 antisense RNA 1.

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miR-302a-3p binding to 3'UTR of platelet-derived growth factor-D

PDGFD was predicted as a target gene of miR-302a-3p using Starbase [Figure 5]a. Luciferase activity of PDGFD-WT was also reduced by transfection with miR-302a-3p mimic [Figure 5]b. Transfection with miR-302a-3p inhibitor downregulated the expression of miR-302a-3p and upregulated PDGFD in Hep3B and SNU-387 [Figure 5]c. Protein expression of PDGFD was enhanced by inhibition of miR-302a-3p [Figure 5]d. Moreover, p-FAK expression was also enhanced by inhibition of miR-302a-3p in Hep3B and SNU-387 [Figure 5]d. Transfection with shZNF561-AS1-2# upregulated miR-302a-3p while downregulated PDGFD expression in Hep3B and SNU-387 [Figure 5]e and [Figure 5]f. Inhibition of miR-302a-3p attenuated ZNF561-AS1 silence-induced increase of miR-302a-3p and decrease of PDGFD [Figure 5]e and [Figure 5]f. Inhibition of miR-302a-3p also attenuated ZNF561-AS1 silence-induced downregulation of p-FAK [Figure 5]f. PDGFD was enhanced in hepatocellular carcinoma tissues [Figure 5]g, and positively associated with ZNF561-AS1 [Figure 5]h, indicating that ZNF561-AS1 bind to miR-302a-3p and regulate PDGFD.
Figure 5: miR-302a-3p binding to 3'UTR of PDGFD. (a) Potential binding site between PDGFD and miR-302a-3p. (b) Transfection with miR-302a-3p mimics reduced luciferase activity of PDGFD-WT in Hep3B and SNU-387. (c) Transfection with miR-302a-3p inhibitor downregulated expression of miR-302a-3p and upregulated PDGFD in Hep3B and SNU-387. (d) Transfection with miR-302a-3p inhibitor upregulated protein expression of PDGFD and p-FAK in Hep3B and SNU-387. (e) Transfection with miR-302a-3p inhibitor attenuated ZNF561-AS1 silence-induced increase of miR-302a-3p and decrease of PDGFD in Hep3B and SNU-387. (f) Inhibition of miR-302a-3p attenuated ZNF561-AS1 silence-induced down-regulation of PDGFD and p-FAK in Hep3B and SNU-387. (g) PDGFD was enhanced in hepatocellular carcinoma tissues compared to paracarcinoma tissues. (h) Expression of PDGFD was positively associated with ZNF561-AS1 in hepatocellular carcinoma tissues. *P < 0.05, **P < 0.01, ***P < 0.001 versus normal tissues, shNC, NC mimic or NC inhibitor. #P < 0.05, ##P < 0.01, ###P < 0.001 versus shZNF561-AS1-2#. PDGFD: Platelet-derived growth factor-D, ZNF561-AS1: ZNF561 antisense RNA 1.

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  Discussion Top


ZNF561-AS1 functioned as a competing endogenous RNA to bind to miR-217, and participated in the tumorigenesis of laryngeal cancer.[8] Moreover, ZNF561-AS1 targeted miR-26a-3p and miR-128-5p to promote the proliferation and metastasis of colorectal cancer.[9] This study identified that ZNF561-AS1 was an oncogenic lncRNA in hepatocellular carcinoma through the promotion of cell proliferation and angiogenesis.

ZNF561-AS1 was elevated in hepatocellular carcinoma tissues and cells. Loss of ZNF561-AS1 reduced cell proliferation of hepatocellular carcinoma. However, the effects of ZNF561-AS1 on cell apoptosis, invasion, and migration of hepatocellular carcinoma remain unclear. Angiogenesis of hepatocellular carcinoma was suppressed by knockdown of ZNF561-AS1. ANGPT2 is a member of ANGPTs, and interferes with ANGPT-1-induced phosphorylation of Tie2 to promote the angiogenesis of hepatocellular carcinoma.[14] FGF-1 and VEGF are involved in the formation of new blood vessels, and participate in the angiogenesis of hepatocellular carcinoma.[4] Inhibitors of FGFs and VEGF were used as antiangiogenic therapies in the treatment of hepatocellular carcinoma.[4] Knockdown of ZNF561-AS1 reduced protein expression of ANGPT2, FGF-1, and VEGF to inhibit the angiogenesis of hepatocellular carcinoma, suggesting that ZNF561-AS1 might also be regarded as an angiogenic target in hepatocellular carcinoma.

Luciferase activity assay confirmed that miR-302a-3p was target of ZNF561-AS1. miR-302a-3p was known as a tumor suppressor and predicted poor prognosis in hepatocellular carcinoma.[15] Silence of ZNF561-AS1 increased the expression of miR-302a-3p in hepatocellular carcinoma, thus inhibiting the tumorigenesis of hepatocellular carcinoma. PDGFD was identified as a target gene of miR-302a-3p in hepatocellular carcinoma. PDGFD belongs to a member of PDGFs, and functions as a growth factor in the angiogenesis of hepatocellular carcinoma.[4] PDGFD contributed to the angiogenesis and aggressiveness of colorectal cancer,[16] and promoted epithelial–mesenchymal transition of hepatocellular carcinoma.[17] Inhibition of PDGF was considered to be antiangiogenic therapy in hepatocellular carcinoma.[18] This study showed that inhibition of miR-302a-3p enhanced PDGFD expression, while knockdown of ZNF561-AS1 reduced PDGFD expression in hepatocellular carcinoma. Moreover, inhibition of miR-302a-3p attenuated ZNF561-AS1 silence-induced decrease of PDGFD, indicating that loss of ZNF561-AS1 might suppress cell proliferation and angiogenesis of hepatocellular carcinoma through upregulation of miR-302a-3p and downregulation of PDGFD.

FAK signaling has been shown to be involved in tumor cell proliferation, metastasis, and angiogenesis.[19] Inhibition of FAK signaling blocked tumor growth of hepatocellular carcinoma,[20] and activation of FAK facilitated for angiogenesis of hepatocellular carcinoma.[21] PDGFD promoted activation of FAK signaling in melanoma.[22] This study demonstrated that inhibition of miR-302a-3p increased protein expression of p-FAK, and knockdown of ZNF561-AS1 reduced p-FAK expression in hepatocellular carcinoma. Moreover, inhibition of miR-302a-3p attenuated ZNF561-AS1 silence-induced decrease of p-FAK, revealing that loss of ZNF561-AS1 might suppress cell proliferation and angiogenesis of hepatocellular carcinoma through inactivation of FAK signaling.


  Conclusion Top


Collectively, ZNF561-AS1 functioned as an oncogenic lncRNA in hepatocellular carcinoma. Loss of ZNF561-AS1 increased miR-302a-3p to suppress proliferation and angiogenesis of hepatocellular carcinoma through inactivation of PDGFD-mediated FAK signaling. Therefore, ZNF561-AS1/miR-302a-3p/PDGFD/FAK might be a novel target in the treatment of hepatocellular carcinoma. However, the effect of ZNF561-AS1/miR-302a-3p/PDGFD/FAK on in vivo tumor growth of hepatocellular carcinoma should be investigated in further research.

Ethics approval

Ethical approval was obtained from the Ethics Committee of Changshu Second People's Hospital (Approval no. 2013026).

Statement of informed consent

Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

Data availability

The authors declare that all data supporting the findings of this study are available within the article and any raw data can be obtained from the corresponding author upon request.

Financial support and sponsorship

This work was supported by Jiangsu Changshu Planning Project (Grant No. CSWS201305).

Conflicts of interest

There are no conflicts of interest.



 
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