Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2

Cancer Gene Therapy volume 26, pages 103–113 (2019)Cite this article

Subjects

Abstract

To explore the mechanisms of GINS2 on cell proliferation and apoptosis in thyroid cancer (TC) cells. Expressions of GINS2 were inhibited in K1 and SW579 cells using gene interference technology. The abilities of proliferation and apoptosis, and cell cycle were determined by MTT assay and flow cytometric assay. The downstream molecules of GINS2 were searched by microarray and bioinformatics and validated by qRT-PCR and western blotting. In the in vivo study, the tumor growth was compared and the whole-body fluorescent imaging was analyzed. After GINS2 was interfered, cell proliferation was significantly inhibited (P < 0.01) and apoptosis rate increased (P < 0.01) in both K1 and SW579 cells. Cell cycle changed significantly in K1 cells, but not in SW579 cells. With bioinformatics upstream analysis, TGF-β1 was found as the most significantly upstream regulator. Expressions of TGF-β1 and its downstream target molecules CITED2 and LOXL2 were validated and found downregulated significantly in mRNA and protein levels (P < 0.05). The results of the nude mouse xenograft assay suggested that the volume and weight of tumor in ones infected with shGINS2 were statistically smaller than controls (P < 0.05). GINS2 plays an important role in cell proliferation and apoptosis of thyroid cancer by regulating the expressions of CITED2 and LOXL2, which may be a potential biomarker for diagnosis or prognosis and a drug target for therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. McGuire S. World Cancer report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press. Adv Nutr. 2016;7:418–9.

    Article  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.

    Article  Google Scholar 

  3. Tuttle RM, Ball DW, Byrd D, Dilawari RA, Doherty GM, Duh QY, et al. Thyroid carcinoma. J Natl Compr Canc Netw. 2010;8:1228–74.

    Article  Google Scholar 

  4. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.

    Article  CAS  Google Scholar 

  5. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–214.

    Article  Google Scholar 

  6. Haugen BR. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: what is new and what has changed? Cancer. 2017;123:372–81.

    Article  Google Scholar 

  7. Marinsek N, Barry ER, Makarova KS, Dionne I, Koonin EV, Bell SD. GINS, a central nexus in the archaeal DNA replication fork. EMBO Rep. 2006;7:539–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Carroni M, De March M, Medagli B, Krastanova I, Taylor IA, Amenitsch H, et al. New insights into the GINS complex explain the controversy between existing structural models. Sci Rep. 2017;7:40188.

    Article  CAS  Google Scholar 

  9. Kubota Y, Takase Y, Komori Y, Hashimoto Y, Arata T, Kamimura Y, et al. A novel ring-like complex of Xenopus proteins essential for the initiation of DNA replication. Genes Dev. 2003;17:1141–52.

    Article  CAS  Google Scholar 

  10. Takayama Y, Kamimura Y, Okawa M, Muramatsu S, Sugino A, Araki H. GINS, a novel multiprotein complex required for chromosomal DNA replication in budding yeast. Genes Dev. 2003;17:1153–65.

    Article  CAS  Google Scholar 

  11. Labib K, Gambus A. A key role for the GINS complex at DNA replication forks. Trends Cell Biol. 2007;17:271–8.

    Article  CAS  Google Scholar 

  12. MacNeill SA. Structure and function of the GINS complex, a key component of the eukaryotic replisome. Biochem J. 2010;425:489–500.

    Article  CAS  Google Scholar 

  13. Ouyang F, Liu J, Xia M, Lin C, Wu X, Ye L, et al. GINS2 is a novel prognostic biomarker and promotes tumor progression in early-stage cervical cancer. Oncol Rep. 2017;37:2652–62.

    Article  CAS  Google Scholar 

  14. Zheng M, Zhou Y, Yang X, Tang J, Wei D, Zhang Y, et al. High GINS2 transcript level predicts poor prognosis and correlates with high histological grade and endocrine therapy resistance through mammary cancer stem cells in breast cancer patients. Breast Cancer Res Treat. 2014;148:423–36.

    Article  CAS  Google Scholar 

  15. Liang P, Song Z, Chen D, Linghu R, Wang Y, Zhang X, et al. GINS2 regulates matrix metallopeptidase 9 expression and cancer stem cell property in human triple negative Breast cancer. Biomed Pharmacother. 2016;84:1568–74.

    Article  CAS  Google Scholar 

  16. Zhang X, Zhong L, Liu BZ, Gao YJ, Gao YM, Hu XX. Effect of GINS2 on proliferation and apoptosis in leukemic cell line. Int J Med Sci. 2013;10:1795–804.

    Article  CAS  Google Scholar 

  17. Dewar JM, Walter JC. Mechanisms of DNA replication termination. Nat Rev Mol Cell Biol. 2017;18:507–16.

    Article  CAS  Google Scholar 

  18. Boyer AS, Walter D, Sorensen CS. DNA replication and cancer: From dysfunctional replication origin activities to therapeutic opportunities. Semin Cancer Biol. 2016;37-38:16–25.

    Article  CAS  Google Scholar 

  19. Bleichert F, Botchan MR, Berger JM. Mechanisms for initiating cellular DNA replication. Science 2017;355:eaah6317.

  20. Costa A, Hood IV, Berger JM. Mechanisms for initiating cellular DNA replication. Annu Rev Biochem. 2013;82:25–54.

    Article  CAS  Google Scholar 

  21. Nagahama Y, Ueno M, Miyamoto S, Morii E, Minami T, Mochizuki N, et al. PSF1, a DNA replication factor expressed widely in stem and progenitor cells, drives tumorigenic and metastatic properties. Cancer Res. 2010;70:1215–24.

    Article  CAS  Google Scholar 

  22. Hokka D, Maniwa Y, Tane S, Nishio W, Yoshimura M, Okita Y, et al. Psf3 is a prognostic biomarker in lung adenocarcinoma. Lung Cancer. 2013;79:77–82.

    Article  Google Scholar 

  23. Tauchi S, Sakai Y, Fujimoto S, Ogawa H, Tane S, Hokka D, et al. Psf3 is a prognostic biomarker in lung adenocarcinoma: a larger trial using tissue microarrays of 864 consecutive resections. Eur J Cardiothorac Surg. 2016;50:758–64.

    Article  Google Scholar 

  24. Yamane K, Naito H, Wakabayashi T, Yoshida H, Muramatsu F, Iba T, et al. Regulation of SLD5 gene expression by miR-370 during acute growth of cancer cells. Sci Rep. 2016;6:30941.

    Article  CAS  Google Scholar 

  25. Kang YH, Galal WC, Farina A, Tappin I, Hurwitz J. Properties of the human Cdc45/Mcm2-7/GINS helicase complex and its action with DNA polymerase epsilon in rolling circle DNA synthesis. Proc Natl Acad Sci USA. 2012;109:6042–7.

    Article  CAS  Google Scholar 

  26. Barkley LR, Song IY, Zou Y, Vaziri C. Reduced expression of GINS complex members induces hallmarks of pre-malignancy in primary untransformed human cells. Cell Cycle. 2009;8:1577–88.

    Article  CAS  Google Scholar 

  27. Huang HK, Bailis JM, Leverson JD, Gomez EB, Forsburg SL, Hunter T. Suppressors of Bir1p (Survivin) identify roles for the chromosomal passenger protein Pic1p (INCENP) and the replication initiation factor Psf2p in chromosome segregation. Mol Cell Biol. 2005;25:9000–15.

    Article  CAS  Google Scholar 

  28. Lau E, Tsuji T, Guo L, Lu SH, Jiang W. The role of pre-replicative complex (pre-RC) components in oncogenesis. FASEB J. 2007;21:3786–94.

    Article  CAS  Google Scholar 

  29. Zimmerman KM, Jones RM, Petermann E, Jeggo PA. Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress. Mol Cancer Res. 2013;11:370–80.

    Article  CAS  Google Scholar 

  30. Jayaraman S, Doucet M, Kominsky SL. Down-regulation of CITED2 attenuates breast tumor growth, vessel formation and TGF-beta-induced expression of VEGFA. Oncotarget. 2017;8:6169–78.

    Article  Google Scholar 

  31. Chou YT, Yang YC. Post-transcriptional control of Cited2 by transforming growth factor beta. Regulation via Smads and Cited2 coding region. J Biol Chem. 2006;281:18451–62.

    Article  CAS  Google Scholar 

  32. Su D, Song JX, Gao Q, Guan L, Li Q, Shi C, et al. Cited2 participates in cardiomyocyte apoptosis and maternal diabetes-induced congenital heart abnormality. Biochem Biophys Res Commun. 2016;479:887–92.

    Article  CAS  Google Scholar 

  33. Minemura H, Takagi K, Sato A, Takahashi H, Miki Y, Shibahara Y, et al. CITED2 in breast carcinoma as a potent prognostic predictor associated with proliferation, migration and chemoresistance. Cancer Sci. 2016;107:1898–908.

    Article  CAS  Google Scholar 

  34. Wu ZZ, Sun NK, Chao CC. Knockdown of CITED2 using short-hairpin RNA sensitizes cancer cells to cisplatin through stabilization of p53 and enhancement of p53-dependent apoptosis. J Cell Physiol. 2011;226:2415–28.

    Article  CAS  Google Scholar 

  35. Chou YT, Hsieh CH, Chiou SH, Hsu CF, Kao YR, Lee CC, et al. CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence. Cell Death Differ. 2012;19:2015–28.

    Article  CAS  Google Scholar 

  36. Iturbide A, Garcia de Herreros A, Peiro S. A new role for LOX and LOXL2 proteins in transcription regulation. FEBS J. 2015;282:1768–73.

    Article  CAS  Google Scholar 

  37. Williamson PR, Kagan HM. Reaction pathway of bovine aortic lysyl oxidase. J Biol Chem. 1986;261:9477–82.

    CAS  PubMed  Google Scholar 

  38. Kim BR, Dong SM, Seo SH, Lee JH, Lee JM, Lee SH, et al. Lysyl oxidase-like 2 (LOXL2) controls tumor-associated cell proliferation through the interaction with MARCKSL1. Cell Signal. 2014;26:1765–73.

    Article  CAS  Google Scholar 

  39. Salvador F, Martin A, Lopez-Menendez C, Moreno-Bueno G, Santos V, Vazquez-Naharro A, et al. Lysyl oxidase-like protein LOXL2 promotes lung metastasis of breast cancer. Cancer Res. 2017;77:5846–59.

  40. Yang J, Savvatis K, Kang JS, Fan P, Zhong H, Schwartz K, et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat Commun. 2016;7:13710.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was supported by grants from National Natural Science Foundation of China (No. 81571718 and No. 81703791), Shanghai Municipal Commission of Health and Family Planning (No. 201740084), Key Specialty Construction Project of Pudong Health and Family Planning Commission of Shanghai (No. PWZzk2017-21), Science and Technology Development Fund (No. 14DZ1940605), Science and Technology Development Fund of Shanghai Pudong New Area (No. PKJ2017-Y13) and Talents Training Program of Seventh People’s Hospital of Shanghai University of TCM (No. XX2017-04).

Author information

Author notes

  1. These authors contributed equally: Ying Ye, Ya-Nan Song

Authors and Affiliations

  1. Department of Nuclear Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Ying Ye, Ya-Nan Song, Sai-Fei He, Ju-Hua Zhuang, Guo-Yu Wang & Wei Xia

Authors
  1. Ying Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ya-Nan Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sai-Fei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ju-Hua Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guo-Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Xia.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ye, Y., Song, YN., He, SF. et al. GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2. Cancer Gene Ther 26, 103–113 (2019). https://doi.org/10.1038/s41417-018-0045-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-018-0045-y

This article is cited by

Search

Advanced search

Quick links