Skip to main content

Advertisement

SpringerLink
Log in

Oncogenic miR-23a in Pancreatic Ductal Adenocarcinogenesis Via Inhibiting APAF1

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

Abstract

Background

miR-23a, which participates in invasion of pancreatic ductal adenocarcinoma cells into the mesothelial barrier, is a critical regulator in many cancers. It, however, is still unknown whether miR-23a regulates pancreatic cell proliferation and apoptosis or not.

Aims

We sought to investigate the role of miR-23a in regulation of pancreatic cell proliferation and apoptosis.

Methods

miRNA, mRNA, and protein expressions were determined by qRT-PCR and Western blot, respectively. Dual-luciferase reporter assay was used in detection for binding ability of miR-23a to APAF1. Ectopic miR-23a and APAF 1 were introduced to pancreatic cells, and their roles in proliferation and apoptosis were detected by MTT, colony formation, and apoptosis assays, respectively.

Results

Up-regulation of miR-23a and down-regulation of APAF 1 were found in pancreatic ductal cancer, respectively. miR-23a significantly inhibited the luciferase activity by targeting APAF 1 3′UTR. Ectopic miR-23a significantly suppressed the APAF 1 gene expression in pancreatic cancer cells. Similar to siAPAF1, miR-23a significantly promoted pancreatic cancer cell proliferation and repressed apoptosis. Furthermore, miR-23a inhibitor and exogenous APAF 1 could recover the effects.

Conclusions

It is suggested that miR-23a, acting as an oncogenic regulator by directly targeting APAF 1 in pancreatic cancer, is a useful potential biomarker in diagnosis and treatment of pancreatic cancer.

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

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Zhang S, et al. Report of incidence and mortality in China cancer registries, 2009. Chin J Cancer Res. 2013;1:10–21.

    Google Scholar 

  3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  4. Kumar-Sinha C, Wei I, Simeone DM. Emerging frontiers in pancreatic cancer research: elaboration of key genes, cells and the extracellular milieu. Curr Opin Gastroenterol. 2012;8:516–522.

    Article  Google Scholar 

  5. Hamacher R, Schmid RM, Saur D, Schneider G. Apoptotic pathways in pancreatic ductal adenocarcinoma. Mol Cancer. 2008;7:64.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Pass HI, Beer DG, Joseph S, Massion P. Biomarkers and molecular testing for early detection, diagnosis, and therapeutic prediction of lung cancer. Thorac Surg Clin. 2013;23:211–224.

    Article  PubMed  Google Scholar 

  7. Yong FL, Wang CW, Roslani AC, Law CW. The involvement of miR-23a/APAF1 regulation axis in colorectal cancer. Int J Mol Sci. 2014;15:11713–11729.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Wang N, Zhu M, Tsao SW, Man K, Zhang Z, Feng Y. MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma. Mol Cancer. 2013;12:119.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Piepoli A, Tavano F, Copetti M, et al. Mirna expression profiles identify drivers in colorectal and pancreatic cancers. PLoS One. 2012;7:e33663.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Listing H, Mardin WA, Wohlfromm S, Mees ST, Haier J. MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer. Br J Cancer. 2014;. doi:10.1038/bjc.2014.587.

    PubMed  Google Scholar 

  11. Wu CC, Bratton SB. Regulation of the intrinsic apoptosis pathway by reactive oxygen species. Antioxid Redox Signal. 2013;19:546–558.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Umetani N, Hoon DS. Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. Brain Pathol. 2003;13:431–439.

    Google Scholar 

  13. Fu WN, Bertoni F, Kelsey SM, et al. Role of DNA methylation in the suppression of Apaf-1 protein in human leukaemia. Oncogene. 2003;22:451–455.

    Article  CAS  PubMed  Google Scholar 

  14. Chen Q, Xu J, Li L, et al. MicroRNA-23a/b and microRNA-27a/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis. Cell Death Dis. 2014;5:e1132.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Lian S, Shi R, Bai T, et al. Anti-miRNA-23a oligonucleotide suppresses glioma cells growth by targeting apoptotic protease activating factor-1. Curr Pharm Des. 2013;19:6382–6389.

    Article  CAS  PubMed  Google Scholar 

  16. Li B, Sun M, Gao F, et al. Up-regulated expression of miR-23a/b targeted the pro-apoptotic Fas in radiation-induced thymic lymphoma. Cell Physiol Biochem. 2013;32:1729–1740.

    Article  CAS  PubMed  Google Scholar 

  17. Mi S, Lu J, Sun M, et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci USA. 2007;104:19971–19976.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol. 2007;25:387–392.

    Article  CAS  PubMed  Google Scholar 

  19. Saumet A, Vetter G, Bouttier M, et al. Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. Blood. 2009;113:412–421.

    Article  CAS  PubMed  Google Scholar 

  20. Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 2008;68:2094–2105.

    Article  CAS  PubMed  Google Scholar 

  21. Corvaro M, Fuoco C, Wagner M, Cecconi F. Analysis of apoptosome dysregulation in pancreatic cancer and of its role in chemoresistance. Cancer Biol Ther. 2007;6:209–217.

    Article  CAS  PubMed  Google Scholar 

  22. Hoskins JW, Jia J, Flandez M, et al. Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. Carcinogenesis. 2014;25:2670–2678.

    Article  Google Scholar 

  23. Chhabra R, Dubey R, Saini N. Cooperative and individualistic functions of the microRNAs in the miR-23a ~27a ~24-2 cluster and its implication in human diseases. Mol Cancer.. 2010;9:232.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Liu X, Ru J, Zhang J, et al. miR-23a targets interferon regulatory factor 1 and modulates cellular proliferation and paclitaxel-induced apoptosis in gastric adenocarcinoma cells. PLoS One. 2013;8:e64707.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Li X, Liu X, Xu W, et al. c-MYC-regulated miR-23a/24-2/27a cluster promotes mammary carcinoma cell invasion and hepatic metastasis by targeting Sprouty2. J Biol Chem. 2013;288:18121–18133.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Permuth-Wey J, Chen YA, Fisher K, et al. A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas. PLoS One. 2015;10:e0116869.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundations of China (81172577, 81372876 and 81301767).

Conflict of interest

Fu WN is currently receiving two Grants from National Natural Science Foundations of China (81172577 and 81372876). Liu N is currently getting a Grant from National Natural Science Foundations of China (81301767). For the remaining authors, none declared the conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110013, People’s Republic of China

    Ning Liu, Yuan-Yuan Sun, Xiao-Wen Zhang, Sheng Chen, Ye Wang, Zhao-Xiong Zhang & Wei-Neng Fu

  2. Department of Pancreatic Surgery, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Heping District, Shenyang, Liaoning Province, 110001, People’s Republic of China

    Ning Liu & Shao-Wei Song

  3. Department of Laboratory Medicine, No. 202 Hospital of PLA, No. 5, Guangrong Street, Heping District, Shenyang, Liaoning Province, 110001, People’s Republic of China

    Guang-Bin Qiu

Authors
  1. Ning Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan-Yuan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Wen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ye Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhao-Xiong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shao-Wei Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guang-Bin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei-Neng Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shao-Wei Song, Guang-Bin Qiu or Wei-Neng Fu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, N., Sun, YY., Zhang, XW. et al. Oncogenic miR-23a in Pancreatic Ductal Adenocarcinogenesis Via Inhibiting APAF1 . Dig Dis Sci 60, 2000–2008 (2015). https://doi.org/10.1007/s10620-015-3588-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-015-3588-x

Keywords

Search

Navigation