Top

Clinical and Translational Oncology

Published in:

01-09-2019 | Metastasis | Research Article

Hypoxia-induced LncRNA PCGEM1 promotes invasion and metastasis of gastric cancer through regulating SNAI1

Authors: J. Zhang, H. Y. Jin, Y. Wu, Z. C. Zheng, S. Guo, Y. Wang, D. Yang, X. Y. Meng, X. Xu, Y. Zhao

Published in: Clinical and Translational Oncology | Issue 9/2019

Abstract

Purpose

Hypoxia is an indispensable factor in the progression of metastasis. Hypoxia inducible factor-1α (HIF-1α), the core element in generating the hypoxia response, induces invasion and metastasis by promoting epithelial–mesenchymal transition (EMT). This study explored the underlying mechanism of hypoxia associated with the invasion and metastasis of gastric cancer (GC).

Methods

Six methods were employed to assess the function of the long noncoding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) including gene silencing, RT-PCR, the separation of nuclear and cytoplasmic fractions, scrape motility assay, transwell migration assay, and Western-blot.

Results

LncRNA PCGEM1 was overexpressed in GC cells and tissues, and was induced by hypoxia in GC cells. Additional experiments confirmed that the knockdown of PCGEM1 significantly repressed the invasion and metastasis of GC cells. SNAI1, a key transcription factor of EMT, was regulated by PCGEM1. Overexpression of SNAI1 rescued the inhibition of PCGEM1-knockdown during the invasion and metastasis of GC cells. In addition, PCGEM1 and SNAI1 jointly affected the biomarkers of EMT.

Conclusion

Our findings indicated that PCGEM1 is a hypoxia-responsive lncRNA, and contributes to the invasion and metastasis of GC. The potential mechanism is attributed to the regulation of EMT by PCGEM1 and its influence on the expression of SNAI1.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. A Cancer J Clin. 2017;7(1):7–30. https://doi.org/10.3322/caac.21387.CrossRef

Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410. https://doi.org/10.1038/nrc3064.CrossRefPubMed

Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H. Regulatory mechanisms of hypoxia-inducible factor 1 activity: two decades of knowledge. Cancer Sci. 2018;109(3):560–71. https://doi.org/10.1111/cas.13483.CrossRefPubMedPubMedCentral

Tsai YP, Chen HF, Chen SY, Cheng WC, Wang HW, Shen ZJ, et al. TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator. Genome Biol. 2014;15(12):513. https://doi.org/10.1186/s13059-014-0513-0.CrossRefPubMedPubMedCentral

Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science (New York, NY). 2016;352(6282):175–80. https://doi.org/10.1126/science.aaf4405.CrossRef

Zhang J, Wu Y, Lin YH, Guo S, Ning PF, Zheng ZC, et al. Prognostic value of hypoxia-inducible factor-1 alpha and prolyl 4-hydroxylase beta polypeptide overexpression in gastric cancer. World J Gastroenterol. 2018;24(22):2381–91. https://doi.org/10.3748/wjg.v24.i22.2381.CrossRefPubMedPubMedCentral

Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489(7414):101–8. https://doi.org/10.1038/nature11233.CrossRefPubMedPubMedCentral

Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29(4):452–63. https://doi.org/10.1016/j.ccell.2016.03.010.CrossRefPubMedPubMedCentral

Lau E. Non-coding RNA: zooming in on lncRNA functions. Nat Rev Genet. 2014;15(9):574–5. https://doi.org/10.1038/nrg3795.CrossRefPubMed

10.

Brady LK, Wang H, Radens CM, Bi Y, Radovich M, Maity A, et al. Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation. PLoS Biol. 2017;15(9):e2002623. https://doi.org/10.1371/journal.pbio.2002623.CrossRefPubMedPubMedCentral

11.

Wu X, Tudoran OM, Calin GA, Ivan M. The many faces of long noncoding RNAs in cancer. Antioxid Redox Signal. 2018;29(9):922–35. https://doi.org/10.1089/ars.2017.7293.CrossRefPubMedPubMedCentral

12.

Liu L, Zhao X, Zou H, Bai R, Yang K, Tian Z. Hypoxia promotes gastric cancer malignancy partly through the HIF-1alpha dependent transcriptional activation of the long non-coding RNA GAPLINC. Front Physiol. 2016;7:420. https://doi.org/10.3389/fphys.2016.00420.CrossRefPubMedPubMedCentral

13.

Chen WM, Huang MD, Kong R, Xu TP, Zhang EB, Xia R, et al. Antisense long noncoding RNA HIF1A-AS2 Is upregulated in gastric cancer and associated with poor prognosis. Dig Dis Sci. 2015;60(6):1655–62. https://doi.org/10.1007/s10620-015-3524-0.CrossRefPubMed

14.

Liu X, Wang Y, Sun L, Min J, Liu J, Chen D, et al. Long noncoding RNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia. Cancer Sci. 2018;109(4):988–1000. https://doi.org/10.1111/cas.13519.CrossRefPubMedPubMedCentral

15.

Wang Y, Liu X, Zhang H, Sun L, Zhou Y, Jin H, et al. Hypoxia-inducible lncRNA-AK058003 promotes gastric cancer metastasis by targeting gamma-synuclein. Neoplasia (New York, NY). 2014;16(12):1094–106. https://doi.org/10.1016/j.neo.2014.10.008.CrossRef

16.

Yang Z, Wang R, Zhang T, Dong X. Hypoxia/lncRNA-AK123072/EGFR pathway induced metastasis and invasion in gastric cancer. Int J Clin Exp Med. 2015;8(11):19954–68.PubMedPubMedCentral

17.

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96. https://doi.org/10.1038/nrm3758.CrossRefPubMedPubMedCentral

18.

Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, et al. PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci USA. 2000;97(22):12216–21. https://doi.org/10.1073/pnas.97.22.12216.CrossRefPubMedPubMedCentral

19.

Luo D, Wang J, Li J, Post M. Mouse snail is a target gene for HIF. Mol Cancer Res. 2011;9(2):234–45. https://doi.org/10.1158/1541-7786.mcr-10-0214.CrossRefPubMed

20.

Deng SJ, Chen HY, Ye Z, Deng SC, Zhu S, Zeng Z. Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription. Oncogene. 2018. https://doi.org/10.1038/s41388-018-0382-1.CrossRefPubMedPubMedCentral

21.

Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, et al. The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007;2(9):e845. https://doi.org/10.1371/journal.pone.0000845.CrossRefPubMedPubMedCentral

22.

Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E, et al. Oncofetal H19 RNA promotes tumor metastasis. Biochem Biophys Acta. 2014;1843(7):1414–26. https://doi.org/10.1016/j.bbamcr.2014.03.023.CrossRefPubMed

23.

Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, et al. Hypoxia stimulates the cytoplasmic localization of oncogenic long noncoding RNA LINC00152 in colorectal cancer. Int J Oncol. 2018;52(2):453–60. https://doi.org/10.3892/ijo.2017.4218.CrossRefPubMed

24.

Zhang A, Zhang J, Kaipainen A, Lucas JM, Yang H. Long non-coding RNA: a newly deciphered “code” in prostate cancer. Cancer Lett. 2016;375(2):323–30. https://doi.org/10.1016/j.canlet.2016.03.003.CrossRefPubMed

25.

Zhang S, Li Z, Zhang L, Xu Z. MEF2 activated long noncoding RNA PCGEM1 promotes cell proliferation in hormone refractory prostate cancer through downregulation of miR148a. Mol Med Rep. 2018;18(1):202–8. https://doi.org/10.3892/mmr.2018.8977.CrossRefPubMedPubMedCentral

26.

Ho TT, Huang J, Zhou N, Zhang Z, Koirala P, Zhou X, et al. Regulation of PCGEM1 by p54/nrb in prostate cancer. Sci Rep. 2016;6:34529. https://doi.org/10.1038/srep34529.CrossRefPubMedPubMedCentral

27.

Chen S, Wang LL, Sun KX, Liu Y, Guan X, Zong ZH, et al. LncRNA PCGEM1 induces ovarian carcinoma tumorigenesis and progression through RhoA pathway. Cell Physiol Biochem. 2018;47(4):1578–88. https://doi.org/10.1159/000490931.CrossRefPubMed

28.

Li Q, Shen F, Zhao L. The relationship between lncRNA PCGEM1 and STAT3 during the occurrence and development of endometrial carcinoma. Biomed Pharmacother Biomed Pharmacother. 2018;107:918–28. https://doi.org/10.1016/j.biopha.2018.08.091.CrossRefPubMed

29.

Park JY, Lee JE, Park JB, Yoo H, Lee SH, Kim JH. Roles of long non-coding RNAs on tumorigenesis and glioma development. Brain Tumor Res Treat. 2014;2(1):1–6. https://doi.org/10.14791/btrt.2014.2.1.1.CrossRefPubMedPubMedCentral

Title: Hypoxia-induced LncRNA PCGEM1 promotes invasion and metastasis of gastric cancer through regulating SNAI1
Authors: J. Zhang
H. Y. Jin
Y. Wu
Z. C. Zheng
S. Guo
Y. Wang
D. Yang
X. Y. Meng
X. Xu
Y. Zhao
Publication date: 01-09-2019
Publisher: Springer International Publishing
Keywords: Metastasis
Gastric Cancer
Gastric Cancer
Published in: Clinical and Translational Oncology / Issue 9/2019
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-019-02035-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 9/2019

Nodal FDG-PET/CT uptake influences outcome and relapse location among esophageal cancer patients submitted to chemotherapy or radiochemotherapy

Differential expression of S1P receptor subtypes in human bladder transitional cell carcinoma

The incidence proportion of erectile dysfunction in patients treated with cryotherapy for prostate cancer: a meta-analysis

Distinct prognostic values of Annexin family members expression in acute myeloid leukemia

Quality of life in elderly breast cancer patients with localized disease receiving endocrine treatment: a prospective study

A candidate for lung cancer treatment: arsenic trioxide

Keynote webinar | Spotlight on antibody–drug conjugates in cancer