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:

The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3

Oncogene volume 38, pages 3134–3150 (2019)Cite this article

Subjects

Abstract

Gastric cancer (GC) is the second leading cause of death among patients with cancer in China. The primary reason of GC treatment failure is metastasis. Therefore, identifying metastatic biomarkers and clarifying the regulatory mechanisms involved in the GC metastatic process are important. Here, we found that KIAA1199, a cell migration-inducing protein, was significantly overexpressed in GC and correlated with lymph node metastasis and poorer patient survival. Additionally, the introduction of KIAA1199 dramatically promoted GC cell proliferation and migration in vitro and in vivo, and the inhibition of KIAA1199 suppressed GC cell growth and migration and induced GC cell apoptosis. Cell migration is a functional consequence of the epithelial-mesenchymal transition (EMT). In this study, we found that KIAA1199 inhibition or overexpression regulated the expression of E-cadherin and N-cadherin through KIAA1199 binding to WW domain binding protein 11 (WBP11) and protein tyrosine phosphatase type IVA, member 3 (PTP4A3) and through the subsequent activation of the FGFR4/Wnt/β-catenin and EGFR signaling pathways. More importantly, ectopic expression of WBP11 or PTP4A3 blocked the stimulatory effects of KIAA1199 on GC cell proliferation and migration. Meanwhile, we illustrated that KIAA1199 was a target gene of miR-29c-3p and that miR-29c-3p overexpression led to decreased migration of GC cells in vitro and in vivo by suppressing the expression of KIAA1199 and several key proteins in the Wnt/β-catenin and EGFR signaling pathways (e.g., WBP11, FGFR4, and PTP4A3). Taken together, these data demonstrate that KIAA1199 promotes GC metastasis by activating EMT-related signaling pathways and that miR-29c-3p regulates GC cell migration in vitro and in vivo by regulating KIAA1199 expression and activating the FGFR4/Wnt/β-catenin and EGFR signaling pathways. These findings provide a new understanding of GC development and progression and may provide novel therapeutic strategies for GC.

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. 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 

  2. Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385:977–1010.

    Article  Google Scholar 

  3. Thrumurthy SG, Chaudry MA, Chau I, Allum W. Does surgery have a role in managing incurable gastric cancer?. Nat Rev Clin Oncol. 2015;12:676–82.

    Article  Google Scholar 

  4. Abe S, Usami S, Nakamura Y. Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters’ cells and the fibrocytes, as the cause of nonsyndromic hearing loss. J Hum Genet. 2003;48:564–70.

    Article  CAS  Google Scholar 

  5. Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999;6:337–45.

    Article  CAS  Google Scholar 

  6. Li L, Yan LH, Manoj S, Li Y, Lu L. Central role of CEMIP in tumorigenesis and its potential as therapeutic target. J Cancer. 2017;8:2238–46.

    Article  Google Scholar 

  7. Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A, Kadam P, et al. Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst. 2013;105:1402–16.

    Article  CAS  Google Scholar 

  8. Michishita E, Garces G, Barrett JC, Horikawa I. Upregulation of the KIAA1199 gene is associated with cellular mortality. Cancer Lett. 2006;239:71–7.

    Article  CAS  Google Scholar 

  9. Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M, Kawabata K, Sayo T, et al. KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc Natl Acad Sci USA. 2013;110:5612–7.

    Article  CAS  Google Scholar 

  10. Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M. Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann Surg Oncol. 2009;16:2042–51.

    Article  Google Scholar 

  11. Jia S, Qu T, Wang X, Feng M, Yang Y, Feng X, et al. KIAA1199 promotes migration and invasion by Wnt/beta-catenin pathway and MMPs mediated EMT progression and serves as a poor prognosis marker in gastric cancer. PLoS ONE. 2017;12:e0175058.

    Article  Google Scholar 

  12. Diepenbruck M, Tiede S, Saxena M, Ivanek R, Kalathur RKR, Luond F, et al. miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis. Nat Commun. 2017;8:1168.

    Article  Google Scholar 

  13. Ju J, Chen A, Deng Y, Liu M, Wang Y, Wang Y, et al. NatD promotes lung cancer progression by preventing histone H4 serine phosphorylation to activate Slug expression. Nat Commun. 2017;8:928.

    Article  Google Scholar 

  14. Mitra R, Chen X, Greenawalt EJ, Maulik U, Jiang W, Zhao Z, et al. Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. Nat Commun. 2017;8:1604.

    Article  Google Scholar 

  15. Natsuizaka M, Whelan KA, Kagawa S, Tanaka K, Giroux V, Chandramouleeswaran PM, et al. Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun. 2017;8:1758.

    Article  Google Scholar 

  16. Llorian M, Beullens M, Andres I, Ortiz JM, Bollen M. SIPP1, a novel pre-mRNA splicing factor and interactor of protein phosphatase-1. Biochem J. 2004;378:229–38.

    Article  CAS  Google Scholar 

  17. Iwasaki Y, Thomsen GH. The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling. Development. 2014;141:3740–51.

    Article  CAS  Google Scholar 

  18. He X. Antagonizing Wnt and FGF receptors: an enemy from within (the ER). Cell. 2005;120:156–8.

    CAS  PubMed  Google Scholar 

  19. Kato H, Semba S, Miskad UA, Seo Y, Kasuga M, Yokozaki H. High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clin Cancer Res. 2004;10:7318–28.

    Article  CAS  Google Scholar 

  20. Bessette DC, Qiu D, Pallen CJ. PRL PTPs: mediators and markers of cancer progression. Cancer Metastas- Rev. 2008;27:231–52.

    Article  CAS  Google Scholar 

  21. Guo K, Li J, Tang JP, Koh V, Gan BQ, Zeng Q. Catalytic domain of PRL-3 plays an essential role in tumor metastasis: formation of PRL-3 tumors inside the blood vessels. Cancer Biol Ther. 2004;3:945–51.

    Article  CAS  Google Scholar 

  22. Xiong J, Li Z, Zhang Y, Li D, Zhang G, Luo X, et al. PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN. Oncol Rep. 2016;36:1819–28.

    Article  CAS  Google Scholar 

  23. Al-Aidaroos AQ, Yuen HF, Guo K, Zhang SD, Chung TH, Chng WJ, et al. Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. J Clin Invest. 2013;123:3459–71.

    Article  CAS  Google Scholar 

  24. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  CAS  Google Scholar 

  25. Zaravinos A. The regulatory role of microRNAs in EMT and cancer. J Oncol. 2015;2015:865816.

    Article  Google Scholar 

  26. Pencheva N, Tavazoie SF. Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol. 2013;15:546–54.

    Article  CAS  Google Scholar 

  27. Han TS, Hur K, Xu G, Choi B, Okugawa Y, Toiyama Y, et al. MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1. Gut. 2015;64:203–14.

    Article  CAS  Google Scholar 

  28. Yu B, Chen X, Li J, Gu Q, Zhu Z, Li C, et al. microRNA-29c inhibits cell proliferation by targeting NASP in human gastric cancer. BMC Cancer. 2017;17:109.

    Article  Google Scholar 

  29. Wang Y, Liu C, Luo M, Zhang Z, Gong J, Li J, et al. Chemotherapy-induced miRNA-29c/catenin-delta signaling suppresses metastasis in gastric cancer. Cancer Res. 2015;75:1332–44.

    Article  CAS  Google Scholar 

  30. Wrighton KH. Cell migration: EMT promotes contact inhibition of locomotion. Nat Rev Mol Cell Biol. 2015;16:518.

    Article  CAS  Google Scholar 

  31. Tiwari A, Schneider M, Fiorino A, Haider R, Okoniewski MJ, Roschitzki B, et al. Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS ONE. 2013;8:e69473.

    Article  CAS  Google Scholar 

  32. Zhang Y, Jia S, Jiang WG. KIAA1199 and its biological role in human cancer and cancer cells (review). Oncol Rep. 2014;31:1503–8.

    Article  CAS  Google Scholar 

  33. Shostak K, Zhang X, Hubert P, Goktuna SI, Jiang Z, Klevernic I, et al. NF-kappaB-induced KIAA1199 promotes survival through EGFR signalling. Nat Commun. 2014;5:5232.

    Article  CAS  Google Scholar 

  34. Cheng XB, Kohi S, Koga A, Hirata K, Sato N. Hyaluronan stimulates pancreatic cancer cell motility. Oncotarget. 2016;7:4829–40.

    PubMed  Google Scholar 

  35. Ye GD, Sun GB, Jiao P, Chen C, Liu QF, Huang XL, et al. OVOL2, an inhibitor of WNT signaling, reduces invasive activities of human and mouse cancer cells and is down-regulated in human colorectal tumors. Gastroenterology. 2016;150:659–71 e16.

    Article  CAS  Google Scholar 

  36. Liu R, Li J, Xie K, Zhang T, Lei Y, Chen Y, et al. FGFR4 promotes stroma-induced epithelial-to-mesenchymal transition in colorectal cancer. Cancer Res. 2013;73:5926–35.

    Article  CAS  Google Scholar 

  37. Ye YW, Zhou Y, Yuan L, Wang CM, Du CY, Zhou XY, et al. Fibroblast growth factor receptor 4 regulates proliferation and antiapoptosis during gastric cancer progression. Cancer. 2011;117:5304–13.

    Article  CAS  Google Scholar 

  38. Yu T, Wang LN, Li W, Zuo QF, Li MM, Zou QM, et al. Downregulation of miR-491-5p promotes gastric cancer metastasis by regulating SNAIL and FGFR4. Cancer Sci. 2018;109:1393–403.

    Article  CAS  Google Scholar 

  39. Yanaka Y, Muramatsu T, Uetake H, Kozaki K, Inazawa J. miR-544a induces epithelial-mesenchymal transition through the activation of WNT signaling pathway in gastric cancer. Carcinogenesis. 2015;36:1363–71.

    Article  CAS  Google Scholar 

  40. Dong Q, Ding X, Chang B, Wang H, Wang A. PRL-3 promotes migration and invasion and is associated with poor prognosis in salivary adenoid cystic carcinoma. J Oral Pathol Med. 2016;45:111–8.

    Article  CAS  Google Scholar 

  41. Dai N, Lu AP, Shou CC, Li JY. Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. World J Gastroenterol. 2009;15:1499–505.

    Article  CAS  Google Scholar 

  42. Rizzolio S, Battistini C, Cagnoni G, Apicella M, Vella V, Giordano S, et al. Downregulating neuropilin-2 triggers a novel mechanism enabling egfr-dependent resistance to oncogene-targeted therapies. Cancer Res. 2018;78:1058–68.

    Article  CAS  Google Scholar 

  43. Evensen NA, Li Y, Kuscu C, Liu J, Cathcart J, Banach A, et al. Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP). Oncotarget. 2015;6:20723–39.

    Article  Google Scholar 

  44. Kohi S, Sato N, Koga A, Matayoshi N, Hirata K. KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer. Oncotarget. 2017;8:17156–63.

    Article  Google Scholar 

  45. Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.

    Article  CAS  Google Scholar 

  46. Mendell JT. MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle. 2005;4:1179–84.

    Article  CAS  Google Scholar 

  47. Zhang D, Zhao L, Shen Q, Lv Q, Jin M, Ma H, et al. Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer. Int J Cancer. 2017;140:2298–309.

    Article  CAS  Google Scholar 

  48. Ruedel A, Dietrich P, Schubert T, Hofmeister S, Hellerbrand C, Bosserhoff AK. Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts. Int J Clin Exp Pathol. 2015;8:4953–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Matsuo M, Nakada C, Tsukamoto Y, Noguchi T, Uchida T, Hijiya N, et al. MiR-29c is downregulated in gastric carcinomas and regulates cell proliferation by targeting RCC2. Mol Cancer. 2013;12:15.

    Article  CAS  Google Scholar 

  50. Li BS, Zuo QF, Zhao YL, Xiao B, Zhuang Y, Mao XH, et al. MicroRNA-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival. Oncogene. 2015;34:2556–65.

    Article  CAS  Google Scholar 

  51. Zuo QF, Zhang R, Li BS, Zhao YL, Zhuang Y, Yu T, et al. MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ. Cell Death Dis. 2015;6:e1623.

    Article  Google Scholar 

  52. Zuo QF, Cao LY, Yu T, Gong L, Wang LN, Zhao YL, et al. MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail. Cell Death Dis. 2015;6:e2000.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Chongqing Youth Science and Technology Talent Training Project (cstc2014kjrc-qnrc10008) and National Science Foundation of China (NSFC) (81872392).

Author information

Authors and Affiliations

  1. National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, 400038, Chongqing, China

    Lina Wang, Ting Yu, Mengmeng Li, Qianfei Zuo, Quanming Zou & Bin Xiao

  2. Department of Pharmacy, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China

    Wei Li

Authors
  1. Lina Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ting Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mengmeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qianfei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Quanming Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bin Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Qianfei Zuo, Quanming Zou or Bin Xiao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Yu, T., Li, W. et al. The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3. Oncogene 38, 3134–3150 (2019). https://doi.org/10.1038/s41388-018-0642-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0642-0

This article is cited by

Search

Advanced search

Quick links