Skip to main content

Advertisement

SpringerLink
Log in

Comprehensive gene and microRNA expression profiling reveals a role for miRNAs in the oncogenic roles of SphK1 in papillary thyroid cancer

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The oncogenic roles of sphingosine kinase 1 (SphK1) in various cancers, including thyroid cancer, have been well demonstrated. However, the microRNAs (miRNAs) associated with the oncogenic roles of SphK1 remain largely unknown.

Methods

Global gene and miRNA expression in TPC1-Vector and TPC1-SphK1 cells was analyzed using digital gene expression (DGE) analysis and small RNA-seq, respectively. miRNA–mRNA interactions were explored by microT-CDS, and the predicted networks were visualized using CytoScape®. Cell invasion and migration were assessed by performing Transwell invasion and wound-healing assays. Luciferase reporter and immunoblot assays were used to evaluate the targeting of fibronectin 1 (FN1) by miR-144-3p.

Results

In this study, we found that overexpression of SphK1 differentially regulates the expression of 46 miRNAs and 506 mRNAs in papillary thyroid cancer (PTC) TPC1 cells. Combining bioinformatics predictions of mRNA targets with DGE data on mRNA expression allowed us to identify the mRNA targets of deregulated miRNAs. The direct interaction between miR-144-3p and FN1, which mediates the pro-invasive role of SphK1 in PTC cells, was experimentally validated.

Conclusions

Our results demonstrated that SphK1 overexpression drives a regulatory network governing miRNA and mRNA expression in PTC cells. We also demonstrated the roles played by miR-144-3p and FN1 in mediating the oncogenic function of SphK1, which enhanced the understanding of the etiology of PTC.

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

Similar content being viewed by others

References

  • Akao Y, Banno Y, Nakagawa Y, Hasegawa N, Kim TJ, Murate T, Igarashi Y, Nozawa Y (2006) High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun 342:1284–1290

    Article  CAS  PubMed  Google Scholar 

  • Bao M, Chen Z, Xu Y, Zhao Y, Zha R, Huang S, Liu L, Chen T, Li J, Tu H, He X (2012) Sphingosine kinase 1 promotes tumour cell migration and invasion via the S1P/EDG1 axis in hepatocellular carcinoma. Liver Int 32:331–338

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergelin N, Blom T, Heikkila J, Lof C, Alam C, Balthasar S, Slotte JP, Hinkkanen A, Tornquist K (2009) Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Endocrinology 150:2055–2063

    Article  CAS  PubMed  Google Scholar 

  • Cancer Genome Atlas Research, N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  • Datta A, Loo SY, Huang B, Wong L, Tan SS, Tan TZ, Lee SC, Thiery JP, Lim YC, Yong WP, Lam Y, Kumar AP, Yap CT (2014) SPHK1 regulates proliferation and survival responses in triple-negative breast cancer. Oncotarget 5:5920–5933

    Article  PubMed  PubMed Central  Google Scholar 

  • Guan H, Liu L, Cai J, Liu J, Ye C, Li M, Li Y (2011) Sphingosine kinase 1 is overexpressed and promotes proliferation in human thyroid cancer. Mol Endocrinol 25:1858–1866

    Article  CAS  PubMed  Google Scholar 

  • Guan H, Cai J, Zhang N, Wu J, Yuan J, Li J, Li M (2012) Sp1 is upregulated in human glioma, promotes MMP-2-mediated cell invasion and predicts poor clinical outcome. Int J Cancer 130:593–601

    Article  CAS  PubMed  Google Scholar 

  • Guan H, Wei G, Wu J, Fang D, Liao Z, Xiao H, Li M, Li Y (2013) Down-regulation of miR-218-2 and its host gene SLIT3 cooperate to promote invasion and progression of thyroid cancer. J Clin Endocrinol Metab 98:E1334–E1344

    Article  CAS  PubMed  Google Scholar 

  • Guan H, Liang W, Xie Z, Li H, Liu J, Liu L, Xiu L, Li Y (2015) Down-regulation of miR-144 promotes thyroid cancer cell invasion by targeting ZEB1 and ZEB2. Endocrine 48:566–574

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Ying L, Tian Y, Yang P, Zhu Y, Wang Z, Qiu F, Lin J (2013) miR-144 downregulation increases bladder cancer cell proliferation by targeting EZH2 and regulating Wnt signaling. FEBS J 280:4531–4538

    Article  CAS  PubMed  Google Scholar 

  • Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, Tian W, Zhang Q, Wang C, Zhang Q, Zhuang SM, Zheng L, Liang A, Tao W, Cao X (2011) Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 19:232–243

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Prasad M, Lemon WJ, Hampel H, Wright FA, Kornacker K, LiVolsi V, Frankel W, Kloos RT, Eng C, Pellegata NS, de la Chapelle A (2001) Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci USA 98:15044–15049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Jeon M, Lee J, Nam SJ, Shin I, Lee JE, Kim S (2015) Induction of fibronectin by HER2 overexpression triggers adhesion and invasion of breast cancer cells. Exp Cell Res 333:116–126

    Article  CAS  PubMed  Google Scholar 

  • Li J, Song Z, Wang Y, Yin Y, Liu Y, Yuan R, Nan X (2016a) Overexpression of SphK1 enhances cell proliferation and invasion in triple-negative breast cancer via the PI3K/AKT signaling pathway. Tumour Biol 37:10587–10593

    Article  CAS  PubMed  Google Scholar 

  • Li R, Liu J, Li Q, Chen G, Yu X (2016b) miR-29a suppresses growth and metastasis in papillary thyroid carcinoma by targeting AKT3. Tumour Biol 37:3987–3996

    Article  CAS  PubMed  Google Scholar 

  • Lou X, Han X, Jin C, Tian W, Yu W, Ding D, Cheng L, Huang B, Jiang H, Lin B (2013) SOX2 targets fibronectin 1 to promote cell migration and invasion in ovarian cancer: new molecular leads for therapeutic intervention. OMICS 17:510–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luu C, Heinrich EL, Duldulao M, Arrington AK, Fakih M, Garcia-Aguilar J, Kim J (2013) TP53 and let-7a micro-RNA regulate K-Ras activity in HCT116 colorectal cancer cells. PLoS ONE 8:e70604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv N, Shan Z, Gao Y, Guan H, Fan C, Wang H, Teng W (2016) Twist1 regulates the epithelial-mesenchymal transition via the NF-kappaB pathway in papillary thyroid carcinoma. Endocrine 51:469–477

    Article  CAS  PubMed  Google Scholar 

  • Ma Y, Qin H, Cui Y (2013) MiR-34a targets GAS1 to promote cell proliferation and inhibit apoptosis in papillary thyroid carcinoma via PI3 K/Akt/Bad pathway. Biochem Biophys Res Commun 441:958–963

    Article  CAS  PubMed  Google Scholar 

  • Pan J, Tao YF, Zhou Z, Cao BR, Wu SY, Zhang YL, Hu SY, Zhao WL, Wang J, Lou GL, Li Z, Feng X, Ni J (2011) An novel role of sphingosine kinase-1 (SPHK1) in the invasion and metastasis of esophageal carcinoma. J Transl Med 9:157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qi Z, Yang DY, Cao J (2014) Increased micro-RNA 17, 21, and 192 gene expressions improve early diagnosis in non-small cell lung cancer. Med Oncol 31:195

    Article  PubMed  Google Scholar 

  • Qin MB, Huang JA, Liu SQ, Tang GD, Jiang HX (2011) Inhibition of SPHK1 suppresses phorbol 12-myristate 13-acetate-induced metastatic phenotype in colorectal cancer HT-29 cells. Oncol Res 19:573–582

    Article  PubMed  Google Scholar 

  • Shao Y, Li P, Zhu ST, Yue JP, Ji XJ, Ma D, Wang L, Wang YJ, Zong Y, Wu YD, Zhang ST (2016) MiR-26a and miR-144 inhibit proliferation and metastasis of esophageal squamous cell cancer by inhibiting cyclooxygenase-2. Oncotarget 7:15173–15186

    PubMed  PubMed Central  Google Scholar 

  • Shida D, Inoue S, Yoshida Y, Kodaka A, Tsuji T, Tsuiji M (2016) Sphingosine kinase 1 is upregulated with lysophosphatidic acid receptor 2 in human colorectal cancer. World J Gastroenterol 22:2503–2511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29

    Article  PubMed  Google Scholar 

  • Sponziello M, Rosignolo F, Celano M, Maggisano V, Pecce V, De Rose RF, Lombardo GE, Durante C, Filetti S, Damante G, Russo D, Bulotta S (2016) Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells. Mol Cell Endocrinol 431:123–132

    Article  CAS  PubMed  Google Scholar 

  • Steffens S, Schrader AJ, Vetter G, Eggers H, Blasig H, Becker J, Kuczyk MA, Serth J (2012) Fibronectin 1 protein expression in clear cell renal cell carcinoma. Oncol Lett 3:787–790

    CAS  PubMed  PubMed Central  Google Scholar 

  • Strub GM, Maceyka M, Hait NC, Milstien S, Spiegel S (2010) Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 688:141–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swierniak M, Wojcicka A, Czetwertynska M, Stachlewska E, Maciag M, Wiechno W, Gornicka B, Bogdanska M, Koperski L, de la Chapelle A, Jazdzewski K (2013) In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma. J Clin Endocrinol Metab 98:E1401–E1409

    Article  CAS  PubMed  Google Scholar 

  • Wang F, Song G, Liu M, Li X, Tang H (2011) miRNA-1 targets fibronectin1 and suppresses the migration and invasion of the HEp2 laryngeal squamous carcinoma cell line. FEBS Lett 585:3263–3269

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Zhu CF, Ma MZ, Chen G, Song M, Zeng ZL, Lu WH, Yang J, Wen S, Chiao PJ, Hu Y, Huang P (2015) Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer. Oncotarget 6:21148–21158

    Article  PubMed  PubMed Central  Google Scholar 

  • Xiong H, Wang J, Guan H, Wu J, Xu R, Wang M, Rong X, Huang K, Huang J, Liao Q, Fu Y, Yuan J (2014) SphK1 confers resistance to apoptosis in gastric cancer cells by downregulating Bim via stimulating Akt/FoxO3a signaling. Oncol Rep 32:1369–1373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang YL, Ji C, Cheng L, He L, Lu CC, Wang R, Bi ZG (2012) Sphingosine kinase-1 inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells. Cancer Sci 103:1538–1545

    Article  CAS  PubMed  Google Scholar 

  • Zhang LY, Ho-Fun Lee V, Wong AM, Kwong DL, Zhu YH, Dong SS, Kong KL, Chen J, Tsao SW, Guan XY, Fu L (2013) MicroRNA-144 promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma through repression of PTEN. Carcinogenesis 34:454–463

    Article  PubMed  Google Scholar 

  • Zhang Z, Yan Z, Yuan Z, Sun Y, He H, Mai C (2015) SPHK1 inhibitor suppresses cell proliferation and invasion associated with the inhibition of NF-kappaB pathway in hepatocellular carcinoma. Tumour Biol 36:1503–1509

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, He W, Li J, Huang S, Wan X, Luo H, Wu D (2015) MiRNA-125b inhibits proliferation and migration by targeting SphK1 in bladder cancer. Am J Transl Res 7:2346–2354

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by Grants from the National Natural Science Foundation of China (No. 81370076, 81272417) and the Natural Science Foundation of Guangdong Province (No. 2016A030310169).

Author information

Authors and Affiliations

  1. Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, China

    Weiwei Liang, Weiling Cui, Yan Guo, Lijuan Xu & Hongyu Guan

  2. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Zhiwei Xie

  3. Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, 74 Zhongshan Road II, Guangzhou, 510080, Guangdong, China

    Jueheng Wu

Authors
  1. Weiwei Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiwei Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weiling Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lijuan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jueheng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongyu Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jueheng Wu or Hongyu Guan.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals that were performed by any of the authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 12 kb)

Supplementary material 2 (XLSX 56 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, W., Xie, Z., Cui, W. et al. Comprehensive gene and microRNA expression profiling reveals a role for miRNAs in the oncogenic roles of SphK1 in papillary thyroid cancer. J Cancer Res Clin Oncol 143, 601–611 (2017). https://doi.org/10.1007/s00432-016-2315-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-016-2315-0

Keywords

Search

Navigation