Skip to main content

Advertisement

SpringerLink
Log in

A Novel lncRNA lncRNA-4045 Promotes the Progression of Hepatocellular Carcinoma by Affecting the Expression of AKR1B10

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Long noncoding RNAs (lncRNAs) have been shown to be related to the occurrence and development of a variety of cancers including hepatocellular carcinoma (HCC). However, a large number of potential HCC-related lncRNAs remain undiscovered and are yet to be fully understood.

Methods

Differentially expressed lncRNAs were first obtained from the tumor tissues and adjacent normal tissues of five HCC patients using high-throughput microarray chips. Then the expression levels of 10 differentially expressed lncRNAs were verified in 50 pairs of tissue samples from patients with HCC by quantitative real-time PCR (qRT-PCR). The oncogenic effects of lncRNA-4045 (ENST00000524045.6) in HCC cell lines were verified through a series of in vitro experiments including CCK-8 assay, plate clone formation assay, transwell assay, scratch assay, and flow cytometry. Subsequently, the potential target genes of lncRNA-4045 were predicted by bioinformatics analysis, fluorescence in situ hybridization assay, and RNA sequencing. The mechanism of lncRNA-4045 in HCC was explored by WB assay as well as rescue and enhancement experiments.

Results

The results from microarray chips showed 1,708 lncRNAs to have been significantly upregulated and 2725 lncRNAs to have been significantly downregulated in HCC tissues. Via validation in 50 HCC patients, a novel lncRNA lncRNA-4045 was found significantly upregulated in HCC tissues. Additionally, a series of in vitro experiments showed that lncRNA-4045 promoted the proliferation, invasion, and migration of HCC cell lines, and inhibited the apoptosis of HCC cell lines. The results of qRT-PCR in HCC tissues showed that the expression levels of AKR1B10 were significantly positively correlated with lncRNA-4045. LncRNA-4045 knockdown significantly down-regulated AKR1B10 protein expression, and overexpression of lncRNA-4045 led to significant up-regulation of AKR1B10 protein in HCC cell lines. Lastly, down-regulation of AKR1B10 could partially eliminate the enhancement of cell proliferation induced by lncRNA-4045 overexpression, while up-regulation of AKR1B10 was shown to enhance those effects.

Conclusion

LncRNA-4045 may promote HCC via enhancement of the expression of AKR1B10 protein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16

Similar content being viewed by others

References

  1. Sung H, Ferlay J, Siegel RLet al. . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA: a cancer journal for clinicians. 2021;71:209–249.

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022 CA: a cancer journal for clinicians. 2022;72:7–33.

  3. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma Lancet (London, England). 2022;400:1345–1362.

    Article  CAS  PubMed  Google Scholar 

  4. Toh MR, Wong EYT, Wong SH et al. Global Epidemiology and Genetics of Hepatocellular Carcinoma Gastroenterology. 2023;164:766–782.

    PubMed  Google Scholar 

  5. Zeng H, Chen W, Zheng R et al. Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries The Lancet. Global health. 2018;6:e555–e567.

    PubMed  Google Scholar 

  6. Herman AB, Tsitsipatis D, Gorospe M. Integrated lncRNA function upon genomic and epigenomic regulation Molecular cell. 2022;82:2252–2266.

    CAS  PubMed  Google Scholar 

  7. Bhan A, Soleimani M, Mandal SS. Long Noncoding RNA and Cancer: A New Paradigm Cancer research. 2017;77:3965–3981.

    CAS  Google Scholar 

  8. Entezari M, Taheriazam A, Orouei Set al. . LncRNA-miRNA axis in tumor progression and therapy response: An emphasis on molecular interactions and therapeutic interventions Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;154:113609.

  9. Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function Nature reviews. Genetics. 2016;17:47–62.

    CAS  PubMed  Google Scholar 

  10. Cao C, Sun J, Zhang Det al. . The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of β-catenin in HCC cells Gastroenterology. 2015;148:415–426.e418.

  11. Yuan JH, Liu XN, Wang TTet al. . The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1 Nature cell biology. 2017;19:820–832.

  12. Wang Y, Yang L, Chen Tet al. . A novel lncRNA MCM3AP-AS1 promotes the growth of hepatocellular carcinoma by targeting miR-194–5p/FOXA1 axis Molecular cancer. 2019;18:28.

  13. Pan W, Li W, Zhao Jet al. . lncRNA-PDPK2P promotes hepatocellular carcinoma progression through the PDK1/AKT/Caspase 3 pathway Molecular oncology. 2019;13:2246–2258.

  14. Finn RS, Qin S, Ikeda M et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma The New England journal of medicine. 2020;382:1894–1905.

    CAS  PubMed  Google Scholar 

  15. Shah M, Sarkar D. HCC-Related lncRNAs: Roles and Mechanisms International journal of molecular sciences. 2024;25.

  16. Huang Z, Zhou JK, Peng Y, He W, Huang C. The role of long noncoding RNAs in hepatocellular carcinoma Molecular cancer. 2020;19:77.

    CAS  PubMed  Google Scholar 

  17. Hashemi M, Moosavi MS, Abed HMet al. . Long non-coding RNA (lncRNA) H19 in human cancer: From proliferation and metastasis to therapy Pharmacological research. 2022;184:106418.

  18. Ye M, Zhao L, Zhang Let al. . LncRNA NALT1 promotes colorectal cancer progression via targeting PEG10 by sponging microRNA-574–5p Cell death & disease. 2022;13:960.

  19. Xing C, Sun SG, Yue ZQ, Bai F. Role of lncRNA LUCAT1 in cancer Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;134:111158.

  20. Hu J, Huang H, Xi Zet al. . LncRNA SEMA3B-AS1 inhibits breast cancer progression by targeting miR-3940/KLLN axis Cell death & disease. 2022;13:800.

  21. Fang D, Ou X, Sun Ket al. . m6A modification-mediated lncRNA TP53TG1 inhibits gastric cancer progression by regulating CIP2A stability Cancer science. 2022;113:4135–4150.

  22. Zhao Y, Yuan D, Zhu Det al. . LncRNA-MSC-AS1 inhibits the ovarian cancer progression by targeting miR-425–5p Journal of ovarian research. 2021;14:109.

  23. Tay Y, Rinn J. Pandolfi pp. The multilayered complexity of ceRNA crosstalk and competition Nature. 2014;505:344–352.

    CAS  PubMed  Google Scholar 

  24. Guo K, Qian K, Shi Y, Sun T, Wang Z. LncRNA-MIAT promotes thyroid cancer progression and function as ceRNA to target EZH2 by sponging miR-150–5p Cell death & disease. 2021;12:1097.

  25. Kong X, Duan Y, Sang Yet al. . LncRNA-CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA-215 Journal of cellular physiology. 2019;234:9105–9117.

  26. Yao ZT, Yang YM,Sun MM, et al. New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer Cancer communications (London, England). 2022;42:117–140.

    PubMed  PubMed Central  Google Scholar 

  27. Ren L, Fang X, Shrestha SMet al. . LncRNA SNHG16 promotes development of oesophageal squamous cell carcinoma by interacting with EIF4A3 and modulating RhoU mRNA stability Cellular & molecular biology letters. 2022;27:89.

  28. Kim J, Piao HL, Kim BJet al. . Long noncoding RNA MALAT1 suppresses breast cancer metastasis Nature genetics. 2018;50:1705–1715.

  29. Chen LL. Linking Long Noncoding RNA Localization and Function Trends in biochemical sciences. 2016;41:761–772.

    CAS  PubMed  Google Scholar 

  30. Michlewski G, Cáceres JF. Post-transcriptional control of miRNA biogenesis RNA (New York, N.Y.). 2019;25:1–16.

  31. Zheng YL, Li L, Jia YXet al. . LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway Theranostics. 2019;9:796–810.

  32. Hu YP, Jin YP, Wu XSet al. . LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502–3p/SET/AKT axis Molecular cancer. 2019;18:167.

  33. van Weverwijk A, Koundouros N, Iravani Met al. . Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation Nature communications. 2019;10:2698.

  34. Ahmed SMU, Jiang ZN, Zheng ZH, Li Y, Wang XJ, Tang X. AKR1B10 expression predicts response of gastric cancer to neoadjuvant chemotherapy Oncology letters. 2019;17:773–780.

  35. Liu W, Song J, Du Xet al. . AKR1B10 (Aldo-keto reductase family 1 B10) promotes brain metastasis of lung cancer cells in a multi-organ microfluidic chip model Acta biomaterialia. 2019;91:195–208.

  36. Jung YJ, Lee EH, Lee CGet al. . AKR1B10-inhibitory Selaginella tamariscina extract and amentoflavone decrease the growth of A549 human lung cancer cells in vitro and in vivo Journal of ethnopharmacology. 2017;202:78–84.

  37. Taskoparan B, Seza EG, Demirkol Set al. . Opposing roles of the aldo-keto reductases AKR1B1 and AKR1B10 in colorectal cancer Cellular oncology (Dordrecht). 2017;40:563–578.

  38. Yao Y, Wang X, Zhou Det al. . Loss of AKR1B10 promotes colorectal cancer cells proliferation and migration via regulating FGF1-dependent pathway Aging. 2020;12:13059–13075.

  39. Zhu R, Xiao J, Luo D, Dong M, Sun T, Jin J. Serum AKR1B10 predicts the risk of hepatocellular carcinoma - A retrospective single-center study Gastroenterologia y hepatologia. 2019;42:614–621.

  40. Jin GZ, Yu WL, Dong H et al. SUOX is a promising diagnostic and prognostic biomarker for hepatocellular carcinoma Journal of hepatology. 2013;59:510–517.

    CAS  PubMed  Google Scholar 

  41. Matkowskyj KA, Bai H, Liao Jet al. . Aldoketoreductase family 1B10 (AKR1B10) as a biomarker to distinguish hepatocellular carcinoma from benign liver lesions Human pathology. 2014;45:834–843.

  42. Shi J, Chen L, Chen Y, Lu Y, Chen X, Yang Z. Aldo-Keto Reductase Family 1 Member B10 (AKR1B10) overexpression in tumors predicts worse overall survival in hepatocellular carcinoma Journal of Cancer. 2019;10:4892–4901.

  43. Cheng BY, Lau EY, Leung HWet al. . IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma Cancer research. 2018;78:2332–2342.

  44. Geng N, Jin Y, Li Y, Zhu S, Bai H. AKR1B10 Inhibitor Epalrestat Facilitates Sorafenib-Induced Apoptosis and Autophagy Via Targeting the mTOR Pathway in Hepatocellular Carcinoma International journal of medical sciences. 2020;17:1246–1256.

  45. Jin J, Liao W, Yao W, Zhu R, Li Y, He S. Aldo-keto Reductase Family 1 Member B 10 Mediates Liver Cancer Cell Proliferation through Sphingosine-1-Phosphate Scientific reports. 2016;6:22746.

  46. Zhou Y, Wong CO, Cho KJet al. . SIGNAL TRANSDUCTION. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling Science (New York, N.Y.). 2015;349:873–876.

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China, Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, and Academician Dongxin Lin workstation.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81960613).

Author information

Author notes

  1. Chao Tan and Xi Zeng contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Shuangyong Road, Nanning, 530021, Guangxi, People’s Republic of China

    Meile Mo, Xiaoyun Ma, Bihu Liu, Shun Liu, Dongping Huang & Xiaoqiang Qiu

  2. Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, Zhiyuan Road, Guilin, 541199, Guangxi, People’s Republic of China

    Chao Tan, Xuefeng Guo & Xiaoyun Zeng

  3. Department of Occupational and Environmental Health, School of Public Health, Guilin Medical University, Zhiyuan Road, Guilin, 541199, Guangxi, People’s Republic of China

    Xi Zeng

Authors
  1. Chao Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xi Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuefeng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meile Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoyun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bihu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoyun Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dongping Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoqiang Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chao Tan and Xi Zeng designed the research, performed the experiments, analyzed the data and co-wrote the paper. Meile Mo, Xiaoyun Ma, collected tissue samples and performed the experiments. Bihu Liu collected clinicopathological information and performed bioinformatics analysis. Shun Liu, Xiaoyun Zeng, Dongping Huang, and Xiaoqiang Qiu supervised the research and revised the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Xiaoqiang Qiu.

Ethics declarations

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval and consent to participate

All participants signed informed consent forms before participating in this study. All procedures performed in this study were in accordance with the Declaration of Helsinki. The research was approved by the Academic Ethics Committee of Guangxi Medical University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Additional file 1

: Fig. S1. Hierarchical clustering analysis of differentially expressed lncRNAs and mRNAs in five pairs of HCC and adjacent normal tissues. A: Differentially expressed lncRNAs; B: Differentially expressed mRNAs.

Additional file 2

: Fig. S2 Background expression of lncRNA-4045 in a normal liver cell line and HCC cell lines.

Additional file 3

: Fig. S3 Clustering heat map of differential genes in HCCLM3 with lncRNA-4045 knockdown and negative control.

Additional file 4

: Fig. S4 Comparison of AKR1B10 expression levels in TCGA and GTEx-derived HCC tissues and normal liver tissues. The red box represents HCC tissues, and the gray box represents normal liver tissues. *P < 0.05.

Additional file 5

: Table S1. Clinical information of five HCC patients.

Additional file 6

: Table S2. Top 10 differential genes in HCCLM3 cells with knockdown of lncRNA-4045.

Additional file 7

: Table S3. Top 10 differential genes in data derived from TCGA.

Additional file 8

: WB original image-1

Additional file 9

: WB original image-2

Additional file 10

: WB original image-3

Additional file 11

: WB original image-4

Additional file 12

: WB original image-5

Additional file 13

: WB original image-6

Additional file 14

: WB original image annotation

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tan, C., Zeng, X., Guo, X. et al. A Novel lncRNA lncRNA-4045 Promotes the Progression of Hepatocellular Carcinoma by Affecting the Expression of AKR1B10. Dig Dis Sci (2024). https://doi.org/10.1007/s10620-024-08383-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10620-024-08383-z

Keywords

Search

Navigation