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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 65  |  Issue : 6  |  Page : 311-318

LncRNA colorectal neoplasia differentially expressed promotes glycolysis of liver cancer cells by regulating hypoxia-inducible factor 1α


1 Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
2 Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China

Date of Submission15-Jun-2022
Date of Decision06-Sep-2022
Date of Acceptance19-Sep-2022
Date of Web Publication26-Dec-2022

Correspondence Address:
Dr. Lijin Zhao
Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Huichuan District, Zunyi, Guizhou Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0304-4920.365458

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  Abstract 


LncRNAs are associated with tumorigenesis of liver cancer. LncRNA Colorectal Neoplasia Differentially Expressed (CRNDE) was identified as an oncogenic lncRNA and involved in tumor growth and metastasis. The role of CRNDE in liver cancer was investigated. CRNDE was elevated in liver cancer cells. Knockdown of CRNDE decreased cell viability and inhibited proliferation of liver cancer. Moreover, knockdown of CRNDE reduced levels of extracellular acidification rate, glucose consumption, and lactate production to repress glycolysis of liver cancer. Silence of CRNDE enhanced the expression of miR-142 and reduced enhancer of zeste homolog 2 (EZH2) and hypoxia-inducible factor 1α (HIF-1α). Over-expression of HIF-1α attenuated CRNDE silence-induced decrease of glucose consumption and lactate production. Injection with sh-CRNDE virus reduced in vivo tumor growth of liver cancer through up-regulation of miR-142 and down-regulation of EZH2 and HIF-1α. In conclusion, knockdown of CRNDE suppressed cell proliferation, glycolysis, and tumor growth of liver cancer through EZH2/miR-142/HIF-1α.

Keywords: Colorectal neoplasia differentially expressed, enhancer of zeste homolog 2, glycolysis, hypoxia-inducible factor 1α, liver cancer, miR-142, proliferation


How to cite this article:
Tang D, Zhao L, Mu R, Ao Y, Zhang X, Li X. LncRNA colorectal neoplasia differentially expressed promotes glycolysis of liver cancer cells by regulating hypoxia-inducible factor 1α. Chin J Physiol 2022;65:311-8

How to cite this URL:
Tang D, Zhao L, Mu R, Ao Y, Zhang X, Li X. LncRNA colorectal neoplasia differentially expressed promotes glycolysis of liver cancer cells by regulating hypoxia-inducible factor 1α. Chin J Physiol [serial online] 2022 [cited 2023 Jan 28];65:311-8. Available from: https://www.cjphysiology.org/text.asp?2022/65/6/311/365458




  Introduction Top


Liver cancer is a common primary cancer and leading cause of cancer-related death worldwide.[1] Diabetes, heavy alcohol drinking, cirrhosis, hepatitis C virus infections, and hepatitis B virus are regarded as the risk factors of liver cancer.[2] Clinical approaches, such as targeted chemotherapy, transarterial chemoembolization, radiation therapy, liver transplantation, and surgical resection, make great improvement in the management of liver cancer.[3] However, the therapeutic benefits of these strategies are limited due to heterogeneous, complicated mechanisms, drug resistance, and metastasis of liver cancer.[4] Therefore, novel targets might be useful for the clinical effectiveness of liver cancer.

LncRNA, with the ability to regulate downstream target genes,[5],[6] have been found to be involved in proliferation, metastasis, and drug resistance of liver cancer.[7] LncRNA Colorectal Neoplasia Differentially Expressed (CRNDE) was identified to be an oncogenic lncRNA in numerous cancers.[8],[9],[10] Over-expression of CRNDE promoted cell proliferation and reduced tumor survival of mice with acute promyelocytic leukemia.[11] However, the deletion of the CRNDE diminished proliferative responses in multiple myeloma cells.[12] In liver cancer, CRNDE bind to histone modification enzyme, enhancer of zeste homolog 2 (EZH2) to inhibit expression of tumor-suppressor genes, thus promoting proliferation, migration, and chemoresistance of liver cancer.[13] In liver cancer, tumor cells tend to convert glucose into lactic acid, which is known as aerobic glycolysis or the Warburg effect.[14] Aerobic glycolysis is characterized by increased glucose uptake and lactic acid production, contributes to the proliferation, growth, and invasion of liver cancer.[14] The role of CRNDE in aerobic glycolysis of liver cancer cells remains unknown.

LncRNAs bind to miRNAs to induce competing endogenous RNAs network, and regulate expression of genes involved in progression and growth of liver cancer.[15] CRNDE interacted with miR-217 and triggered MAPK1 to stimulate proliferation and metastasis of hepatocellular carcinoma.[16] MiR-142 was involved in proliferation and invasion of liver cancer,[17] and over-expression of miR-142 reduced proliferation and aerobic glycolysis in hepatocellular carcinoma.[18] Therefore, CRNDE might regulate aerobic glycolysis of liver cancer through interaction with miR-142.

EZH2 promoted H3K27me3 of deleted in liver cancer 1 to stimulate growth and glycolysis of esophageal cancer cells.[19] Highly expression of EZH2 was positively correlated to glycolysis signaling pathways in liver cancer.[20] Hypoxia-inducible factor 1α (HIF-1α) functions as a transcriptional factor to regulate genes involved in metabolism and survival.[21] HIF-1α enhanced proliferation and glycolysis of liver cancer cells.[22] EZH2 bind to H3K27me3 of promoter in HIF-1α to regulate apoptosis of cancer cells in response to hypoxic stress.[23] However, the role of CRNDE/EZH2/HIF-1α in aerobic glycolysis of liver cancer cells has not been reported yet.

In this study, effects of CRNDE/EZH2/HIF-1α on cell prolifeartion and glycolysis of liver cancer cells were investigated.


  Materials and Methods Top


Bioinformatic analysis

UALCAN (http://ualcan.path.uab.edu/) was used to detect the expression of CRNDE in liver cancer tissues and normal tissues.

Cell culture and transfection

Liver cancer cells (Huh7, MHCC97-H, BEL-7405) and liver sinusoidal endothelial cells (LSECs) were acquired from Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China) and cultured in RPMI 1640 medium containing 10% fetal bovine serum (Thermo Fisher, Waltham, MA, USA). Huh7 and MHCC97-H were transfected with si-NC, si-EZH2, si-CRNDE#1, or si-CRNDE#2 (GenePharma, Suzhou, China) via Lipofectamine 2000 (Thermo Fisher). Cells were also transfected with miR-142 mimic or NC mimic, and cotransfected with si-CRNDE#1 and pcDNA-HIF-1α (OE-HIF-1α).

Cell viability and proliferation assays

Huh7 and MHCC97-H were seeded in 96-well plates and subjected to different transfections for 24 h. Cells were then incubated for another 24, 48, or 72 h. Cells were treated with CCK8 solution (Beyotime, Beijing, China) for 2 h. Absorbance at 450 nm was measured using Microplate Autoreader (Thermo Fisher). To detect cell proliferation, cells were inoculated into 6-well plates and subjected to different transfections for 24 h. Cells were treated with EdU reaction mix from Cell-Light EdU DNA Cell Proliferation kit (Guangzhou Ribobio Co., Ltd., Guangzhou, China) and observed under fluorescence microscope (Olympus, Tokyo, Japan) followed by DAPI staining.

Detection of extracellular acidification rate, glucose consumption, and lactate production

Huh7 and MHCC97-H with indicated transfections were seeded into Seahorse plates (Seahorse Bioscience, Billerica, MA, USA), and incubated with Seahorse buffer with 2-deoxyglucose, glucose, and oligomycin. Level of extracellular acidification rate (ECAR) was analyzed by Seahorse XFe96 Extracellular Flux Analyzer with XF-96 wave software (Seahorse Bioscience). To detect glucose consumption, Huh7 and MHCC97-H in glucose-free medium were treated with 100 μM 2-NBDG (Sigma-Aldrich, St. Louis, MO, USA). Fluorescent intensity was calculated using the microplate reader. To detect lactate production, supernatants of cultured medium were harvested and subjected to Lactate Assay Kit (Sigma-Aldrich).

Quantitative real-time polymerase chain reaction

Cells and tumor tissues were lysed in Trizol (Sigma-Aldrich) or miRcute miRNA isolation kit (Tiangen, Beijing, China). The RNAs were then reverse-transcribed into cDNAs, and the cDNAs were subjected to quantitative real-time polymerase chain reaction (qRT-PCR) analysis with SYBR Green Master (Roche, Mannheim, Germany). U6 (Forward: 5'-CTCGCTTCGGCAGCACA-3' and Reverse: 5'-AACGCTTCACGAATTTGCGT-3') and GAPDH (Forward: 5'-GGATTTGGTCGTATTGGG-3' and Reverse: 5'-GGAAGATGGTGATGGGATT-3') were used as endogenous controls. Expression of CRNDE (Forward: 5'-AAATTCATCCCAAGGCTGGT-3' and Reverse: 5'-AAACCACTCGAGCACTTTGA-3') and miR-142 (Forward: 5'-CCGGAATTCGGGGTTC ACAGAACTGAAGG-3' and Reverse: 5'-TATCATATGGCT GCATCAGGGT-3') were determined by 2-ΔΔCT method.

Western blot

Cells and tumor tissues were lysed in RIPA buffer (Beyotime), and protein samples were segregated using SDS-PAGE. The samples were transferred onto nitrocellulose membranes, and the membranes were blocked in 5% dry milk. Membranes were incubated with primary antibodies: anti-PLOD1, anti-GLUT1 and anti-LDHA (1:2000), anti-EZH2 and anti-HIF-1α (1:3000), anti-β-ACTIN (1:4000). The membranes were then incubated with secondary antibodies (1:4500), and subjected to chemiluminescence reagent kit (Beyotime). All the proteins were purchased from Abcam (Cambridge, MA, USA).

Mouse xenograft assay

Four to 6 weeks old female BALB/c nude mice (n = 6; 18-22 g) were divided into two groups: sh-NC (n = 3) and sh-CRNDE#1 (n = 3). The study was approved by the Animal Experiments Ethics Committee of Zunyi Medical University (Approval No. 2020025) and in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines. To produce viral vectors, sh-NC and sh-CRNDE#1 (Invitrogen, Carlsbad, CA, USA) were subcloned into pAAV-U6-GFP vector (Cell Biolabs, San Diego, CA, USA). HEK-293 cells were transfected with pAAV-U6-GFP-shRNA, pAAV-DJ Rep-Cap and pHelper for 3 days. The shRNA virus was collected using AAV purification kits (Takara Bio, Tokyo, Japan), and infected Huh7 to generate cells with stably knockdown of CRNDE. Huh7 cells were then subcutaneously injected into nude mice, and the tumor volume was calculated every week. The tumors were isolated and weighted 6 weeks after v injection.

Immunohistochemistry

This study was approved by the Medical Ethics Committee of Zunyi Medical University (Approval No. 2020025), and all the selected subjects gave informed consent to participate. Tumor tissues were fixed with 10% formalin and embedded in paraffin. The tissues were sliced into 4 μm thick sections and dewaxed and rehydrated sections were treated with 5% H2O2. Sections were immersed in Tris-EDTA buffer containing 0.05% Tween 20 and blocked in 5% dry milk. Sections were then incubated overnight with anti-Ki-67 (1:80) and then treated with horseradish peroxidase-conjugated secondary antibody. Slides were examined under the microscope (Olympus).

Statistical analysis

All the data with at least triplicates were expressed as mean ± standard error of the mean and analyzed by Student's t-test or one-way analysis of variance. P < 0.05 was considered statistically significant.


  Results Top


Colorectal neoplasia differentially expressed was up-regulated in liver cancer

To investigate the role of CRNDE in liver cancer, bioinformatic analysis was firstly used to determine the expression of CRNDE in liver cancer tissues. Data based on TCGA showed the up-regulation of CRNDE in liver cancer tissues (n = 371) compared to normal tissues (n = 50) (P < 0.001) [Figure 1]a. Similarly, liver cancer cells (Huh7, MHCC97-H, BEL-7405) also showed higher CRNDE expression than LSECs [Figure 1]b, suggesting potential regulatory role of CRNDE in liver cancer.
Figure 1: CRNDE was up-regulated in liver cancer. (a) CRNDE was up-regulated in liver cancer tissues (n = 371) compared to normal tissues (n = 50). (b) CRNDE was up-regulated in liver cancer cells (Huh7, MHCC97-H, BEL-7405) compared to LSECs detected by qRT-PCR. **, *** versus normal or LSECs, P < 0.01, P < 0.001. CRNDE: Colorectal neoplasia differentially expressed, LSECs: Liver sinusoidal endothelial cells, qRT-PCR: Quantitative real-time polymerase chain reaction.

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Colorectal neoplasia differentially expressed promoted cell proliferation of liver cancer

As shown in [Figure 1]b, Huh7 and MHCC97-H showed higher expression of CRNDE than BEL-7405. Therefore, Huh7 and MHCC97-H were then subjected to loss-of functional assays. Transfection with si-CRNDE#1 or si-CRNDE#2 reduced expressions of CRNDE in Huh7 and MHCC97-H compared to control or transfection with siNC (P < 0.001) [Figure 2]a. Knockdown of CRNDE reduced cell viability (P < 0.01) [Figure 2]b of Huh7 and MHCC97-H. Moreover, silence of CRNDE suppressed cell proliferation of Huh7 and MHCC97-H [Figure 2]c through down-regulation of number of EdU positive cells [Figure 2]d, revealing anti-proliferative effect of CRNDE deficiency on liver cancer.
Figure 2: CRNDE promoted cell proliferation of liver cancer. (a) Transfection with si-CRNDE#1 or si-CRNDE#2 reduced expression of CRNDE in Huh7 and MHCC97-H detected by qRT-PCR. (b) Knockdown of CRNDE reduced cell viability of Huh7 and MHCC97-H detected by CCK8. (c) Knockdown of CRNDE suppressed cell proliferation of Huh7 and MHCC97-H detected by EdU staining. (d) Knockdown of CRNDE reduced number of EdU positive cells in Huh7 and MHCC97-H. *, **, *** versus si-NC, P < 0.05, P < 0.01, P < 0.001. EZH2: Enhancer of zeste homolog 2, CRNDE: Colorectal neoplasia differentially expressed.

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Colorectal neoplasia differentially expressed promoted glycolysis of liver cancer

The role of CRNDE in glycolysis of liver cancer was then assessed. Silence of CRNDE decreased level of ECAR in Huh7 and MHCC97-H (P < 0.001) [Figure 3]a. Glucose consumption [Figure 3]b and lactate production [Figure 3]c were also inhibited by loss of CRNDE. Knockdown of CRNDE down-regulated protein expression of GLUT1 and LDHA in Huh7 and MHCC97-H (P < 0.05) [Figure 3]d, indicating that loss of CRNDE reduced glycolysis of liver cancer.
Figure 3: CRNDE promoted glycolysis of liver cancer. (a) Silence of CRNDE decreased level of ECAR in Huh7 and MHCC97-H detected by Seahorse XFe96 Extracellular Flux Analyzer. (b) Silence of CRNDE decreased glucose consumption in Huh7 and MHCC97-H detected by fluorescent intensity of 2-NBDG. (c) Silence of CRNDE decreased lactate production in Huh7 and MHCC97-H detected by Lactate Assay Kit. (d) Knockdown of CRNDE down-regulated protein expression of GLUT1 and LDHA in Huh7 and MHCC97-H detected by western blot. *, **, *** versus si-NC, P < 0.05, P < 0.01, P < 0.001. EZH2: Enhancer of zeste homolog 2, CRNDE: Colorectal neoplasia differentially expressed.

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Colorectal neoplasia differentially expressed promoted glycolysis of liver cancer through regulation of hypoxia-inducible factor 1α

Downstream target of CRNDE involved in liver cancer was evaluated. Protein expression of EZH2 and HIF-1α were reduced by the knockdown of CRNDE in Huh7 and MHCC97-H [Figure 4]a. Silence of CRNDE increased the expression of miR-142 (P < 0.001) [Figure 4]b. Over-expression of HIF-1α attenuated CRNDE loss-induced decrease of glucose consumption [Figure 4]c, lactate production [Figure 4]d, and GLUT1 and LDHA expression [Figure 4]e. Moreover, knockdown of EZH2 increased expression of miR-142 in Huh7 and MHCC97-H [Supplemental Figure S1]a and over-expression of miR-142 decreased HIF-1α [Supplemental Figure S1]b. Therefore, silence of CRNDE reduced glycolysis of liver cancer through down-regulation of EZH2 and resulted in increase in miR-142 to reduce HIF-1α.
Figure 4: CRNDE promoted glycolysis of liver cancer through regulation of HIF-1α. (a) Silence of CRNDE decreased Protein expression of EZH2 and HIF-1α in Huh7 and MHCC97-H detected by western blot. (b) Silence of CRNDE increased expression of miR-142 in Huh7 and MHCC97-H detected by qRT-PCR. (c) Over-expression of HIF-1α attenuated CRNDE loss-induced decrease of glucose consumption in Huh7 and MHCC97-H detected by fluorescent intensity of 2-NBDG. (d) Over-expression of HIF-1α attenuated CRNDE loss-induced decrease of lactate production in Huh7 and MHCC97-H detected by Lactate Assay Kit. (e) Over-expression of HIF-1α attenuated CRNDE loss-induced decrease of GLUT1 and LDHA expression in Huh7 and MHCC97-H detected by western blot. *, **, *** versus si-NC, P < 0.05, P < 0.01, P < 0.001. ##, ### versus si-CRNDE#1, P < 0.01, P < 0.001. EZH2: Enhancer of zeste homolog 2, CRNDE: Colorectal neoplasia differentially expressed, HIF-1α: Hypoxia-inducible factor 1α, qRT-PCR: Quantitative real-time polymerase chain reaction.

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Colorectal neoplasia differentially expressed promoted tumor growth of liver cancer

Mice were injected with Huh7 cell with sh-CRNDE virus to investigate role of CRNDE on tumor growth of liver cancer. sh-CRNDE virus injection reduced tumor volume and weight (P < 0.01) [Figure 5]a. Knockdown of CRNDE down-regulated expression of CRNDE and up-regulated miR-142 in tumor tissues (P < 0.001) [Figure 5]b. Moreover, protein expression of EZH2 and HIF-1α was also suppressed by silence of CRNDE [Figure 5]c. Immunohistochemistry showed that loss of CRNDE reduced expression of ki-67 to inhibit tumor growth [Figure 5]d.
Figure 5: CRNDE promoted tumor growth of liver cancer. (a) sh-CRNDE virus injection reduced tumor volume and weight of liver cancer in mouse xenograft assay. (b) Knockdown of CRNDE down-regulated expression of CRNDE and up-regulated miR-142 in tumor tissues detected by qRT-PCR. (c) Knockdown of CRNDE down-regulated protein expression of EZH2 and HIF-1α in tumor tissues detected by western blot. (d) Immunohistochemistry showed that loss of CRNDE reduced expression of ki-67 in tumor tissues. **, *** versus sh-NC, P < 0.01, P < 0.001. EZH2: Enhancer of zeste homolog 2, CRNDE: Colorectal neoplasia differentially expressed, HIF-1α: Hypoxia-inducible factor 1α, qRT-PCR: Quantitative real-time polymerase chain reaction.

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  Discussion Top


LncRNA CRNDE functioned as an oncogenic lncRNA in hepatocellular carcinoma, knockdown of CRNDE reduced cell proliferation, migration, and chemoresistance of hepatocellular carcinoma.[13] This study found that silence of CRNDE inhibited aerobic glycolysis of liver cancer through EZH2/miR-142/HIF-1α.

In line with previous study,[13] results in this study also found the up-regulation of CRNDE in liver cancer tissues and cells. Knockdown of CRNDE reduced cell proliferation of liver cancer. Moreover, silence of CRNDE also reduced in vivo tumor growth of liver cancer. Emerging evidence has shown that lncRNAs mediated glycolytic transporters, such as GLUT1, GLUT3, and GLUT4, to affect aerobic glycolysis of liver cancer.[24] Moreover, lncRNAs also regulated glycolytic enzymes, hexokinase, phosphofructokinase, or LDHA, to control glucose into lactate to produce ATP.[24] CRNDE was regulated by insulin/IGF signaling and modulated aerobic glycolysis of colorectal cancer cells.[25] This study found that loss of CRNDE reduced levels of ECAR, glucose consumption, lactate production, and protein expression of GLUT1 and LDHA in liver cancer cells, suggesting that loss of CRNDE inhibited aerobic glycolysis of liver cancer through regulation of glycolytic transporters and enzymes. Therefore, insulin/IGF signaling might regulate aerobic glycolysis of liver cancer through CRNDE.

Previous study has shown that CRNDE directly bound to polycomb-repressive complex 2 and recruited EZH2 to promoter regions of p21, thus contributing to radioresistant phenotype of lung adenocarcinoma.[26] CRNDE also recruited EZH2 to tumor-suppressor genes and exerted oncogenic effect on hepatocellular carcinoma.[13] This study showed that silence of CRNDE reduced expression of EZH2 in liver cancer cells. EZH2 has been reported to enhance trimethylation of H3K27 promoter region of miR-142, and epigenetically silenced the expression of miR-142.[27] miR-142 directly bound to 3'-UTR of HIF-1α.[27] In this study, knockdown of CRNDE increased miR-142 expression and decreased HIF-1α in liver cancer cells. Furthermore, silence of CRNDE also enhanced miR-142 expression, reduced EZH2 and HIF-1α in in vivo tumor tissues of liver cancer. miR-142 targeted LDHA to inhibit proliferation and aerobic glycolysis of liver cancer.[18] HIF-1α promoted aerobic glycolysis in liver cancer.[28] This study demonstrated that over-expression of HIF-1α attenuated CRNDE silence-suppressed aerobic glycolysis of liver cancer cells. Therefore, CRNDE might contribute to proliferation and aerobic glycolysis in liver cancer through down-regulation of EZH2 and miR-142-mediated HIF-1α.


  Conclusion Top


In sum, silence of CRNDE exhibited anti-tumor effect in liver cancer through inhibition of cell proliferation and aerobic glycolysis. In addition, loss of CRNDE reduce EZH2 to increase miR-142 and down-regulated HIF-1α in liver cancer. CRNDE/EZH2/miR-142/HIF-1α might be a potential target for liver cancer.

Financial support and sponsorship

This work was supported by Science and Technology Fund project of Guizhou Provincial Health Commission in 2021 (Grant No. gzwkj2021-172) and National Natural Science Foundation of China (Grant No. 81960125).

Conflicts of interest

There are no conflicts of interest.



 
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