Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-7 downregulates the oncogene VDAC1 to influence hepatocellular carcinoma proliferation and metastasis

  • Original Article
  • Published:
Tumor Biology

Abstract

Recent studies have been shown that voltage-dependent anion channel 1 (VDAC1) plays an important role in carcinogenesis. However, its molecular biological function in hepatocellular carcinoma (HCC) has not been entirely clarified. This study investigated the expression of VDAC1 in HCC and its prognostic value for HCC patients. Furthermore, we also identify the relevant VDAC1 direct target. Western blot, real-time quantitative PCR (qRT-PCR), and immunohistochemical (IHC) staining were performed to detect the expression of VDAC1 in HCC. Furthermore, the relationship between the VDAC1 level and clinicopathological features and prognostic values was explored. The effects of VDAC1 on HCC cell proliferation, migration, and invasion were also investigated in vitro. Predicted target gene of VDAC1 was determined by dual-luciferase reporter assay, qRT-PCR, and Western blot analyses. Our results revealed elevated VDAC1 messenger RNA (mRNA) (P = 0.0020) and protein (P = 0.0035) expression in tumor tissue samples compared with paired adjacent non-tumorous tissue samples. High VDAC1 expression was correlated with distant metastasis (P = 0.025), differentiation (P = 0.002), and advanced tumor stage (P = 0.004) in HCC patients. Kaplan-Meier survival analysis demonstrated that high expression of VDAC1 was significantly correlated with a poor prognosis for HCC patients (P < 0.001). The multivariate analysis revealed that VDAC1 expression was an independent prognostic factor of the overall survival rate of HCC patients. Furthermore, knockdown of VDAC1 inhibits HCC cell proliferation, migration, and invasion in vitro. Moreover, further study revealed that miR-7 was a putative target of VDAC1. Our study suggested that miR-7 suppressed the expression of VDAC1. VDAC1 plays an important role in tumor progression and may be used as a potential role in the prognosis of HCC patients.

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

Similar content being viewed by others

References

  1. Roberts LR. Sorafenib in liver cancer—just the beginning. N Engl J Med. 2008;359:420–2.

    Article  CAS  PubMed  Google Scholar 

  2. Olsen SK, Brown RS, Siegel AB. Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies. Therap Adv Gastroenterol. 2010;3:55–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.

    Article  CAS  PubMed  Google Scholar 

  4. Benz R. Permeation of hydrophilic solutes through mitochondrial outer membranes: review on mitochondrial porins. Biochim Biophys Acta Rev Biomembr. 1994;1197:167–96.

    Article  CAS  Google Scholar 

  5. Hiller S, Abramson J, Mannella C, Wagner G, Zeth K. The 3D structures of VDAC represent a native conformation. Trends Biochem Sci. 2010;35:514–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fiek C, Benz R, Roos N, Brdiczka D. Evidence for identity between the hexokinase-binding protein and the mitochondrial porin in the outer membrane of rat liver mitochondria. Biochimica Et Biophysica Acta. 1982;688:429–40.

    Article  CAS  PubMed  Google Scholar 

  7. Shimizu S, Narita M, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 1999;399:483–7.

    Article  CAS  PubMed  Google Scholar 

  8. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med. 2010;31:227–85.

    Article  CAS  PubMed  Google Scholar 

  9. Shoshan-Barmatz V, Ben-Hail D. VDAC, a multi-functional mitochondrial protein as a pharmacological target. Mitochondrion. 2012;12:24–34.

    Article  CAS  PubMed  Google Scholar 

  10. Koren I, Raviv ZBV. Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo. Cancer Biol Ther. 2010;9:1046–52.

    Article  CAS  PubMed  Google Scholar 

  11. Eriko S, Kei-Ichi H, Hiroki S, Junko K, Yukie N, Shigeomi S. Furanonaphthoquinones cause apoptosis of cancer cells by inducing the production of reactive oxygen species by the mitochondrial voltage-dependent anion channel. Cancer Biol Ther. 2006;5:1523–9.

    Article  Google Scholar 

  12. Claire G, Jithesh PV, Jaine B, Shu-Dong Z, Fennell DA. Gene expression meta-analysis identifies VDAC1 as a predictor of poor outcome in early stage non-small cell lung cancer. PLoS One. 2011;6:79–89.

    Google Scholar 

  13. Nan J, Kham SKY, Koh GS, Lim JYS, Ariffin H, Chew FT, et al. Identification of prognostic protein biomarkers in childhood acute lymphoblastic leukemia (ALL). J Proteome. 2011;74:843–57.

    Article  Google Scholar 

  14. Li M, Xiao ZQ, Chen ZC, Li JL, Li C, Zhang PF, et al. Proteomic analysis of the aging-related proteins in human normal colon epithelial tissue. J Biochem Mol Biol. 2007;40:72–81.

    CAS  PubMed  Google Scholar 

  15. Animals, humans, neoplasms, oncogenes: oncogenes meet metabolism. From deregulated genes to a broader understanding of tumour physiology. Preface. Ernst Schering Found Symp Proc 2007.

  16. Blachly-Dyson E, Forte M. VDAC channels. IUBMB Life. 2001;52:113–8.

    Article  CAS  PubMed  Google Scholar 

  17. Fulda S. Tumor resistance to apoptosis. Int J Cancer. 2009;124:511–5.

    Article  CAS  PubMed  Google Scholar 

  18. Brahimi-Horn MC, Mazure NM. Hypoxic VDAC1: a potential mitochondrial marker for cancer therapy. Adv Exp Med Biol. 2014;772:101–10.

    Article  CAS  PubMed  Google Scholar 

  19. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891–9.

    Article  CAS  PubMed  Google Scholar 

  20. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  21. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37.

    Article  CAS  PubMed  Google Scholar 

  22. Shoshan-Barmatz V, Golan M. Mitochondrial VDAC1: function in cell life and death and a target for cancer therapy. Curr Med Chem. 2012;19:714–35.

    Article  CAS  PubMed  Google Scholar 

  23. Ko JH, Gu W, Lim I, Zhou T, Bang H. Expression profiling of mitochondrial voltage-dependent anion channel-1 associated genes predicts recurrence-free survival in human carcinomas. PLoS One. 2014;9:e110094.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Campbell AM, Chan SH. Mitochondrial membrane cholesterol, the voltage dependent anion channel (VDAC), and the Warburg effect. J Bioenerg Biomembr. 2008;40:193–7.

    Article  CAS  PubMed  Google Scholar 

  25. Arif T, Vasilkovsky L, Refaely Y, Konson A, Shoshan-Barmatz V. Silencing VDAC1 expression by siRNA inhibits cancer cell proliferation and tumor growth in vivo. Mol Ther Nucleic Acids. 2014;3:e159.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Abu-Hamad S, Sivan S, Shoshan-Barmatz V. The expression level of the voltage-dependent anion channel controls life and death of the cell. Proc Natl Acad Sci U S A. 2006;103:5787–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shoshan-Barmatz V, Mizrachi D. VDAC1: from structure to cancer therapy. Front Oncol. 2012;2:164.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Skalsky RL, Br. C: Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. Plos One 2011;6:46–46.

  29. Foekens JA, Sieuwerts AM, Marcel S, Look MP, Vanja DW, Boersma AWM, et al. Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer. Proc Natl Acad Sci U S A. 2008;105:13021–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Veerla S, Lindgren DA, Frigyesi A, Staaf J, Persson H, Liedberg F, et al. MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31. Int J Cancer. 2009;124:2236–42.

    Article  CAS  PubMed  Google Scholar 

  31. Kong D, Piao YS, Yamashita S, Oshima H, Oguma K, Fushida S, et al. Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells. Oncogene. 2012;31:3949–60.

    Article  CAS  PubMed  Google Scholar 

  32. Ikeda Y, Tanji E, Makino N, Kawata S, Furukawa T. MicroRNAs associated with mitogen-activated protein kinase in human pancreatic cancer. Mol Cancer Res. 2012;10:259–69.

    Article  CAS  PubMed  Google Scholar 

  33. Cheng AM, Byrom MW, Jeffrey S, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33:1290–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM. Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci U S A. 2009;106:13052–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MTS, et al. MicroRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene. 2012;32:5078–88.

    Article  PubMed  Google Scholar 

  36. Ma C, Qi Y, Shao L, Liu M, Li X, Tang H. Downregulation of miR-7 upregulates Cullin 5 (CUL5) to facilitate G1/S transition in human hepatocellular carcinoma cells. IUBMB Life. 2013;65:1026–34.

    Article  CAS  PubMed  Google Scholar 

  37. Yu-Ting C, Hua-Heng L, Yung-Chang L, Yuan-Hung W, Chun-Fu H, Yu-Rung K, et al. EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer Res. 2010;70:8822–31.

    Article  Google Scholar 

  38. Yu Z, Ni L, Chen D, Zhang Q, Su Z, Wang Y, et al. Identification of miR-7 as an oncogene in renal cell carcinoma. J Mol Histol. 2013;44:669–77.

    Article  CAS  PubMed  Google Scholar 

  39. Saydam O, Senol O, Wurdinger T, Mizrak A, Ozdener GB, Stemmer-Rachamimov AO, et al. miRNA-7 attenuation in schwannoma tumors stimulates growth by upregulating three oncogenic signaling pathways. Cancer Res. 2011;71:852–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by medical innovation team and talents of Jiangsu province (LJ201134).

Authors’ contribution

Feiran Wang conceived of the study, performed the Western blot, qPCR analysis, and molecular studies, and drafted the manuscript. Yong Qiang participated in the design of the study and carried out the IHC analysis. Yasu Jiang and Yinda Wang collected the clinical data and tissue samples. Xian Shao and Lei Yin performed the statistical analysis. Zhong Chen participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of General Surgery, Affiliated Hospital of Nantong University, Xi Si Road, Nantong, Jiangsu Province, 226001, China

      Feiran Wang, Lirong Zhu, Yasu Jiang, Yinda Wang, Xian Shao, Lei Yin & Zhong Chen

    2. Department of General Surgery, The First People’s Hospital of Jingmen, Dongbao District, Jingmen, Hubei, 448000, China

      Yong Qiang

    3. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

      Jiahui Chen

    4. Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University and Research Institute of Hepatobiliary Surgery of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China

      Zhong Chen

    Authors
    1. Feiran Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yong Qiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lirong Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yasu Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yinda Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xian Shao
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Lei Yin
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jiahui Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Zhong Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jiahui Chen or Zhong Chen.

    Ethics declarations

    Written informed consent was obtained from each patient and was approved by the Institute Research Ethics Committee at the Affiliated Hospital of Nantong University.

    Conflicts of interest

    None

    Additional information

    Feiran Wang, Yong Qiang, and Lirong Zhu contributed equally to this work.

    Jiahui Chen and Zhong Chen are considered as co-corresponding author.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Wang, F., Qiang, Y., Zhu, L. et al. MicroRNA-7 downregulates the oncogene VDAC1 to influence hepatocellular carcinoma proliferation and metastasis. Tumor Biol. 37, 10235–10246 (2016). https://doi.org/10.1007/s13277-016-4836-1

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-016-4836-1

    Keywords

    Search

    Navigation