Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-125b promotes invasion and metastasis of gastric cancer by targeting STARD13 and NEU1

  • Original Article
  • Published:
Tumor Biology

Abstract

MicroRNAs have been documented playing key roles in cancer development and progression. Here, we investigate the role of miR-125b in gastric cancer metastasis. We found that the expression of miR-125b was up-regulated in gastric cancer tissue specimens compared with their corresponding nontumorous tissues, and the up-regulated miR-125b level was significantly associated with TNM stage and lymph node-metastasis. Overexpression of miR-125b promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo. STARD13 and NEU1 were identified as direct target genes of miR-125b by luciferase assays, and they were involved in the cell migration and invasion regulated by miR-125b in gastric cancer. Taken together, miR-125b functions as an oncogene in gastric cancer and represents a new potential therapeutic target for gastric 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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jemal A, Forman D, Bray F, Center MM, Ferlay J, Ward E. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Coburn NG. Lymph nodes and gastric cancer. J Surg Oncol. 2009;99(4):199–206.

    Article  PubMed  Google Scholar 

  3. Shi Y, Zhou Y. The role of surgery in the treatment of gastric cancer. J Surg Oncol. 2010;101(8):687–92.

    Article  PubMed  Google Scholar 

  4. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.

    Article  CAS  PubMed  Google Scholar 

  5. Karnoub AE, Dash AB, Vo AP, Andrew S, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449(7162):557–63.

    Article  CAS  PubMed  Google Scholar 

  6. Hanyu A, Kojima KK. Functional in vivo optical imaging of tumor angiogenesis, growth, and metastasis prevented by administration of anti-human vegf antibody in xenograft model of human fibrosarcoma Ht1080 cells. Cancer Sci. 2009;100(11):2085–92.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang Z, Liu X, Feng B, Liu N, Wu Q, Han Y, et al. STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer. Oncogene. 2015;34:4808–20.

    Article  CAS  PubMed  Google Scholar 

  8. Xing F, Sharma S, Liu Y, Mo Y-Y, Wu K, Zhang Y-Y, et al. miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-|[alpha]. Oncogene. 2015;4:4890–900.

    Article  Google Scholar 

  9. Zhang S, Zhang C, Liu W, Zheng W, Zhang Y, Wang S, et al. MicroRNA-24 upregulation inhibits proliferation, metastasis and induces apoptosis in bladder cancer cells by targeting CARMA3. Int J Oncol. 2015;47:1351–60.

    PubMed  Google Scholar 

  10. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    Article  CAS  PubMed  Google Scholar 

  11. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–8. doi:10.1038/nature03702.

    Article  CAS  PubMed  Google Scholar 

  12. Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(29):4677–84. doi:10.1200/jco.2005.05.5194.

    Article  CAS  Google Scholar 

  13. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New Engl J Med. 2005;353(17):1793–801. doi:10.1056/NEJMoa050995.

    Article  CAS  PubMed  Google Scholar 

  14. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9(3):189–98. doi:10.1016/j.ccr.2006.01.025.

    Article  CAS  PubMed  Google Scholar 

  15. Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. J Am Med Assoc. 2007;297(17):1901–8. doi:10.1001/jama.297.17.1901.

    Article  CAS  Google Scholar 

  16. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. J Am Med Assoc. 2008;299(4):425–36. doi:10.1001/jama.299.4.425.

    Article  CAS  Google Scholar 

  17. Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood. 2008;111(6):3183–9. doi:10.1182/blood-2007-07-098749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.

    Article  CAS  PubMed  Google Scholar 

  19. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69. doi:10.1038/nrc1840.

    Article  CAS  PubMed  Google Scholar 

  20. Van SE, Wildiers H, Vergote I, Vermeulen PB, Dirix LY, Van Laere SJ. Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management. Breast Cancer Res. 2015;17(1):1–15.

    Article  Google Scholar 

  21. Krishnan P, Ghosh S, Wang B, Li D, Narasimhan A, Berendt R, et al. Next generation sequencing profiling identifies miR-574-3p and miR-660-5p as potential novel prognostic markers for breast cancer. BMC Genomics. 2015;16.

  22. Jun-Nian Z, Quan Z, Hai-Yang W, Biao Z, Si-Ting L, Xue N, et al. MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4. Hepatology. 2015;62:801–15.

    Article  Google Scholar 

  23. Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13(3):272–86. doi:10.1016/j.ccr.2008.02.013.

    Article  CAS  PubMed  Google Scholar 

  24. Zheng B, Liang L, Wang C, Huang S, Cao X, Zha R, et al. MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(24):7574–83. doi:10.1158/1078-0432.ccr-11-1714.

    Article  CAS  Google Scholar 

  25. Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11(2):136–46. doi:10.1016/s1470-2045(09)70343-2.

    Article  CAS  PubMed  Google Scholar 

  26. Guan Y, Yao H, Zheng Z, Qiu G, Sun K. MiR-125b targets BCL3 and suppresses ovarian cancer proliferation. Int J Cancer. 2011;128(10):2274–83. doi:10.1002/ijc.25575.

    Article  CAS  PubMed  Google Scholar 

  27. Huang L, Luo J, Cai Q, Pan Q, Zeng H, Guo Z, et al. MicroRNA-125b suppresses the development of bladder cancer by targeting E2F3. Int J Cancer. 2011;128(8):1758–69. doi:10.1002/ijc.25509.

    Article  CAS  PubMed  Google Scholar 

  28. Liang L, Wong CM, Ying Q, Fan DN, Huang S, Ding J, et al. MicroRNA-125b suppressed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. Hepatology. 2010;52(5):1731–40. doi:10.1002/hep.23904.

    Article  CAS  PubMed  Google Scholar 

  29. Kappelmann M, Kuphal S, Meister G, Vardimon L, Bosserhoff AK. MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression. Oncogene. 2013;32(24):2984–91. doi:10.1038/onc.2012.307.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang Y, Yan LX, Wu QN, Du ZM, Chen J, Liao DZ, et al. miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res. 2011;71(10):3552–62. doi:10.1158/0008-5472.can-10-2435.

    Article  CAS  PubMed  Google Scholar 

  31. Shi XB, Xue L, Yang J, Ma AH, Zhao J, Xu M, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci U S A. 2007;104(50):19983–8. doi:10.1073/pnas.0706641104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shi XB, Xue L, Ma AH, Tepper CG, Kung HJ, White RW. miR-125b promotes growth of prostate cancer xenograft tumor through targeting pro-apoptotic genes. Prostate. 2011;71(5):538–49. doi:10.1002/pros.21270.

    Article  CAS  PubMed  Google Scholar 

  33. Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449(7163):682–8. doi:10.1038/nature06174.

    Article  CAS  PubMed  Google Scholar 

  34. Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol. 2010;12(3):247–56. doi:10.1038/ncb2024.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP. TGF-beta upregulates miR-181a expression to promote breast cancer metastasis. J Clin Inves. 2013;123(1):150–63. doi:10.1172/jci64946.

    Article  CAS  Google Scholar 

  36. Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, et al. MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 2010;6(3):e1000879. doi:10.1371/journal.pgen.1000879.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yamada A, Horimatsu T, Okugawa Y, Nishida N, Honjo H, Ida H, et al. Serum miR-21, miR-29a and miR-125b are promising biomarkers for the early detection of colorectal neoplasia. Clin Cancer Res. 2015;21:4234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li J, You T, Jing J. MiR-125b inhibits cell biological progression of Ewing's sarcoma by suppressing the PI3K/Akt signalling pathway. Cell Prolif. 2014;47(2):152–60.

    Article  CAS  PubMed  Google Scholar 

  39. Mark B, Frankel WL, Fabio P, Stefano V, Hansjuerg A, Hagan JP, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA J Am Med Assoc. 2007;297(17):1901–8.

    Article  Google Scholar 

  40. Nelson PT, Baldwin DA, Kloosterman WS, Plasterk RH, Mourelatos Z. RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain. Rna Publ Rna Soc. 2006;12(2):187–91.

    Article  CAS  Google Scholar 

  41. Song F, Yang D, Liu B, Guo Y, Zheng H, Li L, et al. Integrated microRNA network analyses identify a poor-prognosis subtype of gastric cancer characterized by the miR-200 family. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(4):878–89. doi:10.1158/1078-0432.ccr-13-1844.

    Article  CAS  Google Scholar 

  42. Wu JG, Wang JJ, Jiang X, Lan JP, He XJ, Wang HJ, et al. MiR-125b promotes cell migration and invasion by targeting PPP1CA-Rb signal pathways in gastric cancer, resulting in a poor prognosis. Gastric Cancer Offi J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2015;18(4):729–39. doi:10.1007/s10120-014-0421-8.

    CAS  Google Scholar 

  43. Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, et al. miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res MCR. 2011;9(7):824–33. doi:10.1158/1541-7786.mcr-10-0529.

    Article  CAS  PubMed  Google Scholar 

  44. Nadine R, Hellmuth-Alexander M, Monika J, Hans-Joachim M, Ina W, Kurt M, et al. Reference miRNAs for miRNAome analysis of urothelial carcinomas. PLoS One. 2012;7(6):e39309.

    Article  Google Scholar 

  45. Rittinger K, Walker PA, Eccleston JF, Nurmahomed K, Owen D, Laue E, et al. Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP. Nature. 1997;388(6643):693–7. doi:10.1038/41805.

    Article  CAS  PubMed  Google Scholar 

  46. Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, et al. Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem. 2003;278(12):10824–30. doi:10.1074/jbc.M208310200.

    Article  CAS  PubMed  Google Scholar 

  47. Leung TH, Ching YP, Yam JW, Wong CM, Yau TO, Jin DY, et al. Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Proc Natl Acad Sci U S A. 2005;102(42):15207–12. doi:10.1073/pnas.0504501102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kawai K, Seike J, Iino T, Kiyota M, Iwamae Y, Nishitani H, et al. START-GAP2/DLC2 is localized in focal adhesions via its N-terminal region. Biochem Biophys Res Commun. 2009;380(4):736–41. doi:10.1016/j.bbrc.2009.01.095.

    Article  CAS  PubMed  Google Scholar 

  49. Khalil BD, Hanna S, Saykali BA, El-Sitt S, Nasrallah A, Marston D, et al. The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility. Exp Cell Res. 2014;321(2):109–22.

    Article  CAS  PubMed  Google Scholar 

  50. Xiaorong L, Wei W, Liyuan Q, Kaiyan Y. Underexpression of deleted in liver cancer 2 (DLC2) is associated with overexpression of RhoA and poor prognosis in hepatocellular carcinoma. BMC Cancer. 2008;8:205. doi:10.1186/1471-2407-8-205.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ullmannova V, Popescu NC. Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol. 2006;29(5):1127–32.

    CAS  PubMed  Google Scholar 

  52. Miyagi T, Sato K, Hata K, Taniguchi S. Metastatic potential of transformed rat 3Y1 cell lines is inversely correlated with lysosomal-type sialidase activity. FEBS Lett. 1994;349(2):255–9.

    Article  CAS  PubMed  Google Scholar 

  53. Sawada M, Moriya S, Saito S, Shineha R, Satomi S, Yamori T, et al. Reduced sialidase expression in highly metastatic variants of mouse colon adenocarcinoma 26 and retardation of their metastatic ability by sialidase overexpression. Int J Cancer. 2002;97(2):180–5.

    Article  CAS  PubMed  Google Scholar 

  54. Kato T, Wang Y, Yamaguchi K, Milner CM, Shineha R, Satomi S, et al. Overexpression of lysosomal-type sialidase leads to suppression of metastasis associated with reversion of malignant phenotype in murine B16 melanoma cells. Int J Cancer. 2001;92(6):797–804. doi:10.1002/ijc.1268.

    Article  CAS  PubMed  Google Scholar 

  55. Uemura T, Shiozaki K, Yamaguchi K, Miyazaki S, Satomi S, Kato K, et al. Contribution of sialidase NEU1 to suppression of metastasis of human colon cancer cells through desialylation of integrin beta4. Oncogene. 2009;28(9):1218–29. doi:10.1038/onc.2008.471.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (No. 81472245).

Author information

Authors and Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi Province, 710061, China

    Shuai Chang, Shicai He, Guanglin Qiu, Jing Lu, Jin Wang, Junsong Liu, Lin Fan, Wei Zhao & Xiangming Che

Authors
  1. Shuai Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shicai He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guanglin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junsong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiangming Che
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiangming Che.

Ethics declarations

Conflicts of interest

The authors have no conflict of interest.

Ethical approval

The study was approved by the Research Ethics committee of Xi’an Jiaotong University.

Informed consent

Informed consent was obtained from each patient before the surgery.

Electronic supplementary material

Figure S1

The effect of miR-125b on proliferation of gastric cancer cell. A, relative expression of miR-125b in GES-1 and MKN28 cells transfected with miR-125b mimics or mimic control. B, relative expression of miR-125b in MKN45 cells transfected with miR-125b inhibitor or inhibitor control. C, the cell proliferation in MKN28 (transfected with mimics) and MKN45 (transfected with inhibitor) cells was determined by Cell Counting Kit-8. D, relative expression of miR-125b in SGC7901 cells infected with lentivirus. E, the cell proliferation in SGC7901 cells was determined by Cell Counting Kit-8. Three independent experiments were performed. (GIF 101 kb)

High resolution image (TIFF 3.40 mb)

Figure S2

MiR-125b inhibits the expression of STARD13 and NEU1 in vivo. To investigate whether miR-125b regulates STARD13 and NEU1 in vivo, we tested STARD13 and NEU1 expression level in subcutaneously transplanted tumors. The protein levels of STARD13 and NEU1 in LV-miR-125b group are lower than those in LV-control group. (GIF 70 kb)

High resolution image (TIFF 5.21 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, S., He, S., Qiu, G. et al. MicroRNA-125b promotes invasion and metastasis of gastric cancer by targeting STARD13 and NEU1. Tumor Biol. 37, 12141–12151 (2016). https://doi.org/10.1007/s13277-016-5094-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5094-y

Keywords

Search

Navigation