MiR‑196a‑5p Modulates Gastric Cancer Stem Cell Characteristics by Targeting Smad4

Overview

Journal Int J Oncol

Specialty Oncology

Date 2017 Apr 26

PMID 28440445

Citations 29

Authors

Yunzhi Pan

Xiong Shu

Lichao Sun

Long Yu

Lixin Sun

Zhihua Yang

Yuliang Ran

Affiliations

Soon will be listed here.

Abstract

Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self-renewal, and a multilineage differentiation potential. Clinical evidence suggests that CSCs in a tumor mass are the cellular determinants to promote cancer invasion and metastasis. MicroRNAs (miRNAs) have emerged as important modulators of cancer stem cell characteristics. Unveiling the candidate miRNAs that regulate CSCs may provide novel therapeutic targets against cancer. We analyzed the miRNA expression profiles regulating the cancer stem-like cell characteristics in gastric cancer. Gastric cancer stem cells (GCSCs) were sorted using the stem cell marker CD44 by fluorescence-activated cell sorting. Functional studies revealed that CD44(+) cells formed more sphere colonies and showed higher invasiveness than CD44(-) cells. miRNA microarray analysis revealed that miR‑196a‑5p was significantly upregulated in CD44(+) cells than CD44(-) cells. Suppression of miR‑196a‑5p led to decreased colony formation and invasion of GCSCs. miR‑196a‑5p decreased the expression of Smad4 by targeting 3'-UTR of the mRNA. The expression of Smad4 in gastric cancer tissues was correlated with differentiation state of tumors, TNM stage and depth of invasion. The stimulation of epithelial-mesenchymal transition (EMT) by miR‑196a‑5p in cancer stem-like cells was abolished by overexpression of Smad4. Collectively, these data demonstrate that miR‑196a‑5p has a key role in EMT and invasion by targeting Smad4 in GCSCs. miR‑196a‑5p may serve as a potential target for gastric cancer therapy.

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References

Li L, Wang D, Wu Y, Nian W, Wu Z, Li Y . Gastric tumor-initiating CD44 cells and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. Oncol Lett. 2016; 10(5):3293-3299. PMC: 4665879. DOI: 10.3892/ol.2015.3727. View

Sakakini N, Turchi L, Bergon A, Holota H, Rekima S, Lopez F . A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells. J Biol Chem. 2016; 291(20):10684-99. PMC: 4865916. DOI: 10.1074/jbc.M116.720698. View

Kim T, Shivdasani R . Stomach development, stem cells and disease. Development. 2016; 143(4):554-65. PMC: 4760317. DOI: 10.1242/dev.124891. View

Leon G, MacDonagh L, Finn S, Cuffe S, Barr M . Cancer stem cells in drug resistant lung cancer: Targeting cell surface markers and signaling pathways. Pharmacol Ther. 2015; 158:71-90. DOI: 10.1016/j.pharmthera.2015.12.001. View

Nishikawa S, Konno M, Hamabe A, Hasegawa S, Kano Y, Fukusumi T . Surgically resected human tumors reveal the biological significance of the gastric cancer stem cell markers CD44 and CD26. Oncol Lett. 2015; 9(5):2361-2367. PMC: 4467359. DOI: 10.3892/ol.2015.3063. View

Takebe N, Harris P, Warren R, Ivy S . Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 2010; 8(2):97-106. DOI: 10.1038/nrclinonc.2010.196. View

Hoshino Y, Nishida J, Katsuno Y, Koinuma D, Aoki T, Kokudo N . Smad4 Decreases the Population of Pancreatic Cancer-Initiating Cells through Transcriptional Repression of ALDH1A1. Am J Pathol. 2015; 185(5):1457-70. DOI: 10.1016/j.ajpath.2015.01.011. View

Liu T, Sun B, Zhao X, Zhao X, Sun T, Gu Q . CD133+ cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene. 2012; 32(5):544-53. DOI: 10.1038/onc.2012.85. View

Li Y, Zhang T, Korkaya H, Liu S, Lee H, Newman B . Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010; 16(9):2580-90. PMC: 2862133. DOI: 10.1158/1078-0432.CCR-09-2937. View

10.

Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L . Report of incidence and mortality in China cancer registries, 2009. Chin J Cancer Res. 2013; 25(1):10-21. PMC: 3555299. DOI: 10.3978/j.issn.1000-9604.2012.12.04. View

11.

Zhao S, Ammanamanchi S, Brattain M, Cao L, Thangasamy A, Wang J . Smad4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells. J Biol Chem. 2008; 283(17):11293-301. PMC: 2431051. DOI: 10.1074/jbc.M800154200. View

12.

Wu Q, Yang Z, Wang F, Hu S, Yang L, Shi Y . MiR-19b/20a/92a regulates the self-renewal and proliferation of gastric cancer stem cells. J Cell Sci. 2013; 126(Pt 18):4220-9. DOI: 10.1242/jcs.127944. View

13.

Sounni N, Noel A . Targeting the tumor microenvironment for cancer therapy. Clin Chem. 2012; 59(1):85-93. DOI: 10.1373/clinchem.2012.185363. View

14.

Takaishi S, Okumura T, Tu S, Wang S, Shibata W, Vigneshwaran R . Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009; 27(5):1006-20. PMC: 2746367. DOI: 10.1002/stem.30. View

15.

Alison M, Lin W, Lim S, Nicholson L . Cancer stem cells: in the line of fire. Cancer Treat Rev. 2012; 38(6):589-98. DOI: 10.1016/j.ctrv.2012.03.003. View

16.

Zhang W, Li Y . miR-148a downregulates the expression of transforming growth factor-β2 and SMAD2 in gastric cancer. Int J Oncol. 2016; 48(5):1877-85. PMC: 4809655. DOI: 10.3892/ijo.2016.3437. View

17.

Mansour S, Atwa M . Clinicopathological Significance of CD133 and ALDH1 Cancer Stem Cell Marker Expression in Invasive Ductal Breast Carcinoma. Asian Pac J Cancer Prev. 2015; 16(17):7491-6. DOI: 10.7314/apjcp.2015.16.17.7491. View

18.

Nataraj S, Prema C, Vimalambike M, Shivalingaiah S, Sundaram S, Kumar A . Major Protein of Carcinoembryonic Antigen Gene Family - CD66c, A Novel Marker in Colon Carcinoma. J Clin Diagn Res. 2016; 10(2):XC01-XC04. PMC: 4800633. DOI: 10.7860/JCDR/2016/17180.7286. View

19.

Lau W, Teng E, Chong H, Lopez K, Tay A, Salto-Tellez M . CD44v8-10 is a cancer-specific marker for gastric cancer stem cells. Cancer Res. 2014; 74(9):2630-41. DOI: 10.1158/0008-5472.CAN-13-2309. View

20.

Torre L, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. DOI: 10.3322/caac.21262. View