Skip to main content
SpringerLink
Log in

Long Noncoding RNA GAPLINC Promotes Cells Migration and Invasion in Colorectal Cancer Cell by Regulating miR-34a/c-MET Signal Pathway

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

Abstract

Background

Gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC) has been detected in colorectal cancer (CRC) cells and reportedly performs many functions related to tumor proliferation and metastasis. Aim The present study aimed to comprehensively explore the biological functions of GAPLINC and their underlying mechanism in CRC cell.

Methods

The human cancer LncRNA PCR array was used to detect the differentially expressed long noncoding RNAs in human CRC samples. Real-time PCR, dual-luciferase assay, RNA pull-down assay, Transwell assay, and western blot analysis were performed to explore the molecular mechanism underlying GAPLINC functions related to migration and invasion of a human CRC cell line (HCT116).

Results

Compared to the non-cancerous tissues, GAPLINC expression was obviously increased in CRC tissues. In HCT116, silencing of GAPLINC weakened cell migration and invasion, while overexpression of GAPLINC significantly promoted cell migration and invasion. Through dual-luciferase, RNA pull-down, and Transwell assays, we verified that miR-34a was the downstream molecule of GAPLINC and that miR-34a negatively regulated the migration and invasion of HCT116 cell. Furthermore, we found that GAPLINC positively regulated the miR-34a target gene c-MET in CRC tissues.

Conclusions

Our findings revealed that GAPLINC was up-regulated in CRC tissues and was involved in the migration and invasion of CRC cells by regulating miR-34a/c-MET signaling pathway.

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. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767.

    Article  CAS  PubMed  Google Scholar 

  2. Vinson KE, George DC, Fender AW, et al. The Notch pathway in colorectal cancer. Int J Cancer. 2016;138:1835–1842.

    Article  CAS  PubMed  Google Scholar 

  3. Yashiro M. Molecular alterations of colorectal cancer with inflammatory bowel disease. Dig Dis Sci. 2015;60:2251–2263.

    Article  CAS  PubMed  Google Scholar 

  4. Karsa LV, Lignini TA, Patnick J, et al. The dimensions of the CRC problem. Best Pract Res Clin Gastroenterol. 2010;24:381–396.

    Article  CAS  PubMed  Google Scholar 

  5. Djebali CA, Davis A, Merkel A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cullen BR. MicroRNAs as mediators of viral evasion of the immune system. Nat Immunol. 2013;14:205–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629–641.

    Article  CAS  PubMed  Google Scholar 

  8. Schmitt AM, Chang HY. Gene regulation: long RNAs wire up cancer growth. Nature. 2013;500:536–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Huang T, Alvarez A, Hu B, et al. Noncoding RNAs in cancer and cancer stem cells. Chin J Cancer. 2013;32:582–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Zhang L, Zheng X, et al. Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR-645-IFIT2 axis. Cancer Lett. 2016;382:137–146.

    Article  CAS  PubMed  Google Scholar 

  11. Wei X, Wang C, Ma C, et al. Long noncoding RNA ANRIL is activated by hypoxia-inducible factor-1alpha and promotes osteosarcoma cell invasion and suppresses cell apoptosis upon hypoxia. Cancer Cell Int. 2016;16:73.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Xie CH, Cao YM, Huang Y, et al. Long non-coding RNA TUG1 contributes to tumorigenesis of humanosteosarcoma by sponging miR-9-5p and regulating POU2F1 expression. Bio Med Res Int. 2016;37:15031–15041.

    CAS  Google Scholar 

  13. Zheng H, Min J. Role of long noncoding RNA HOTAIR in the growth and apoptosis of osteosarcoma cell MG-63. Bio Med Res Int. 2016;2016:5757641.

    Google Scholar 

  14. Liu H, Wang G, Yang L, et al. Knockdown of long non-coding RNA UCA1 increases the tamoxifen sensitivity of breast cancer cells through inhibition of Wnt/beta-catenin pathway. PLoS One. 2016;11:e0168406.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ouimet M, Drouin S, Lajoie M, et al. A childhood acute lymphoblastic leukemia- specific lncRNA implicated in prednisolone resistance, cell proliferation, and migration. Oncotarget. 2017;8:7477–7488.

    Article  PubMed  Google Scholar 

  16. Ren K, Li Z, Li Y, et al. Long non-coding RNA taurine up regulated gene 1 promotes cell proliferation and invasion in gastric cancervia negatively modulating miRNA-145-5p. Oncol Res. 2017;25:789–798.

    Article  PubMed  Google Scholar 

  17. Yang ZY, Yang F, Zhang YL, et al. LncRNA-ANCR down-regulation suppresses invasion and migration of colorectal cancer cells by regulating EZH2 expression. Cancer Biomark. 2017;18:95–104.

    Article  CAS  PubMed  Google Scholar 

  18. Hu Y, Wang J, Qian J, et al. Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res. 2014;74:6890–6902.

    Article  CAS  PubMed  Google Scholar 

  19. Liu L, Zhao X, Zou H, et al. Hypoxia promotes gastric cancer malignancy partly through the HIF-1α dependent transcriptional activation of the long non-coding RNA GAPLINC. Front Physiol. 2016;7:420.

    PubMed  PubMed Central  Google Scholar 

  20. Yang P, Chen T, Xu Z, et al. Long noncoding RNA GAPLINC promotes invasion in colorectal cancer by targeting SNAI2 through binding with PSF and NONO. Oncotarget. 2016;7:42183–42194.

    PubMed  PubMed Central  Google Scholar 

  21. Wu XL, He XX, Li S, et al. Long non-coding RNA ucoo2kmd.1 regulates CD44- dependent cell growth by competing for miR-211-3p in colorectal cancer. PLoS One. 2016;11:e0151287.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fang XY, Pan HF, Leng RX, et al. Long noncoding RNAs: novel insights into gastric cancer. Cancer Lett. 2015;356:357–366.

    Article  CAS  PubMed  Google Scholar 

  23. Schweiger T, Starkl V, Glueck O, et al. Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases. Eur J Cardiothorac Surg. 2016;49:1103–1111.

    Article  PubMed  Google Scholar 

  24. Al-Maghrabi J, Emam E, Gomaa W, et al. c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence. BMC Cancer. 2015;15:676.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shoji H, Yamada Y, Taniguchi H, et al. Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection. Cancer Sci. 2014;105:1002–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang G, Zhu H, Shi Y, et al. cir-ITCH plays an inhibitory role in colorectal cancer by regulating the Wnt/beta-catenin pathway. PloS One. 2015;10:e0131225.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhao JW, Cheng LM. Long non-coding RNA CCAT1/miR-148a axis promotes osteosarcoma proliferation and migration through regulating PIK3IP1. Acta Biochim Biophys Sin. 2017;25:1–10.

    Article  Google Scholar 

  28. Lehmann U, Kreipe H. Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies. Methods. 2001;25:409–418.

    Article  CAS  PubMed  Google Scholar 

  29. He ZZ, Wang YJ, Huang GF, et al. The lncRNA UCA1 interacts with miR-182 to modulate glioma proliferation and migration by targeting Iaspp. Arch Biochem Biophys. 2017;623–624:1–8.

    Article  PubMed  Google Scholar 

  30. Li N, Zhou P, Zheng J, et al. A polymorphism in the lincRNAENST00000515084 exon was found to modulate breast cancer risk via GWAS-based association analyses. PLoS One. 2014;9:e98251.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhang M, Liu Y, Yu B, et al. Over-expression of long non-coding RNA GAPLINC promotes colorectal cancer cell metastasis and poor prognosis. Int J Clin Exp Med. 2016;9:3203–3208.

    Google Scholar 

  32. Yu F, Zheng J, Mao Y, et al. Long non-coding RNA growth arrest-specific transcript5 (GAS5) inhibits liver fibrogenesis through a mechanism of competing endogenous RNA. J Biol Chem. 2015;290:28286–28298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang F, Huo XS, Yuan SX, et al. Repression of the long noncoding RNALET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 2013;49:1083–1096.

    Article  CAS  PubMed  Google Scholar 

  34. Orom UA, Derrien T, Beringer M, et al. Long noncoding RNAs with enhancer-like function in human cells. Cell.. 2010;143:46–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Geisler S, Lojek L, Khalil AM, et al. Decapping of long noncoding RNAs regulates inducible genes. Mol Cell. 2012;45:279–291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ma MZ, Li CX, Zhang Y, et al. Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol Cancer. 2014;13:156.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Steele G Jr, Busse P, Huberman MS, et al. A pilot study of sphincter-sparing management of adenocarcinoma of the rectum. Arch Surg. 1991;126:696–701.

    Article  PubMed  Google Scholar 

  38. Li W, Zheng J, Deng J, et al. Increased levels of the long intergenic non-protein coding RNA POU3F3 promote DNA methylation in esophageal squamous cell carcinoma cells. Gastroenterology. 2014;146:1714–1726.

    Article  CAS  PubMed  Google Scholar 

  39. Ma Y, Yang Y, Wang F, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/beta-catenin signalling pathway via suppression of activator protein 2alpha. Gut. 2015;0:1–12.

    Google Scholar 

  40. Wang Q, Yang L, Hu X, et al. Up regulated NNT-AS1, a long noncoding RNA, contributes to proliferation and migration of colorectal cancer cells in vitro and in vivo. Oncotarget. 2016;8:3441–3453.

    PubMed Central  Google Scholar 

  41. Nissan A, Stojadinovic A, Mitrani-Rosenbaum S, et al. Colon cancer associated transcript-1: a novel RNA expressed in malignant and pre-malignant human tissues. Int J Cancer. 2012;130:1598–1606.

    Article  CAS  PubMed  Google Scholar 

  42. Chen J, Zhang K, Song H, et al. Long noncoding RNA CCAT1 acts as an oncogene and promotes chemoresistance in docetaxel-resistant lung adenocarcinoma cells. Oncotarget. 2016;7:62474–62489.

    PubMed  PubMed Central  Google Scholar 

  43. Guo X, Hua Y. CCAT1: an oncogenic long noncoding RNA in human cancers. J Cancer Res Clin Oncol. 2017;143:555–562.

    Article  CAS  PubMed  Google Scholar 

  44. Wang ZH, Guo XQ, Zhang QS, et al. Long non-coding RNA CCAT1 promotes glioma cell proliferation via inhibiting microRNA-410. Biochem Biophys Res Commun. 2016;480:715–720.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang E, Han L, Yin D, et al. H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. Nucleic Acids Res. 2016;45:3086–3101.

    Article  PubMed Central  Google Scholar 

  46. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395–419.

    Article  CAS  PubMed  Google Scholar 

  47. De Luca T, Pelosi A, Trisciuoglio D, et al. MiR-211 and MITF modulation by Bcl-2 protein in melanoma cells. Mol Carcinog. 2016;55:2304–2312.

    Article  PubMed  Google Scholar 

  48. Kim UJ, Lee MN, Kim EJ, et al. MicroRNA miR-199a regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2). J Biol Chem. 2008;283:18158–18166.

    Article  CAS  PubMed  Google Scholar 

  49. He L, He X, Lim LP, et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li N, Fu H, Tie Y, et al. MiR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 2009;275:44–53.

    Article  CAS  PubMed  Google Scholar 

  51. Dang Y, Luo D, Rong M, et al. Underexpression of miR-34a in Hepatocellular Carcinoma and its contribution towards enhancement of proliferating inhibitory effects of agents targeting c-MET. PLoS One. 2013;8:e61054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was sponsored by the grant from the Guangzhou Medical and Health Technology Project (No. 20171A011245) and Guangzhou Integrated TCM&WM Technology Project (No. 20172A011001).

Author information

Authors and Affiliations

  1. Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Yuqi Luo, Jun Ouyang & Shizhen Zhong

  2. Department of General Surgery, Nansha Hospital of Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, 511457, China

    Yuqi Luo, Minjie Wen, Wentao Ou & Haitao Yu

  3. Ningbo international Travel Healthcare Center, Ningbo, 315000, China

    Donggen Zhou

  4. Department of Gastroenterology, Nansha Hospital of Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, 511457, China

    Lin Jia & Yaoxin Huang

Authors
  1. Yuqi Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donggen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shizhen Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Minjie Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wentao Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haitao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lin Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yaoxin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JOY and YQL conceived and designed the experiments; YQL, SZZ, and QGZ performed the experiments; MJW, WTO, HTY, and YXH analyzed the data; JOY and YQL wrote the paper; JOY, YQL, and QGZ revised the paper.

Corresponding author

Correspondence to Jun Ouyang.

Ethics declarations

Conflicts of interest

The authors declare no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, Y., Ouyang, J., Zhou, D. et al. Long Noncoding RNA GAPLINC Promotes Cells Migration and Invasion in Colorectal Cancer Cell by Regulating miR-34a/c-MET Signal Pathway. Dig Dis Sci 63, 890–899 (2018). https://doi.org/10.1007/s10620-018-4915-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-018-4915-9

Keywords

Search

Navigation