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Tumor Biology

, Volume 37, Issue 8, pp 10075–10084 | Cite as

miR-152 functions as a tumor suppressor in colorectal cancer by targeting PIK3R3

  • Bo Li
  • Zhongshi Xie
  • Bai Li
Original Article

Abstract

Accumulating evidence showed that microRNA-152 (miR-152) was frequently downregulated, and functioned as tumor suppressor in many cancers, but little is known about its biological role and intrinsic regulatory mechanisms in colorectal cancer (CRC). Here, we explored the potential role of miR-152 in CRC and the possible molecular mechanisms. Our results proved that miR-152 expression was downregulated in CRC cell lines and tissue samples, and its expression was inversely correlated with advanced tumor-node-metastasis (TNM) stage (P < 0.01) and lymph node metastasis (P < 0.01). Function assays demonstrated that restoring the expression of miR-152 in CRC cells dramatically reduced the cell proliferation and cell migration and invasion and promoted apoptosis and caspase-3 activity in vitro, as well as suppressed tumor growth in vivo. Mechanistic investigations defined phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) as a direct and functional downstream target of miR-152. In addition, we also found that PIK3R3 expression was upregulated and was inversely correlated with miR-152 expression in clinical CRC tissues. Downregulation of PIK3R3 mimicked the tumor-suppressive effects of miR-152 overexpression in CRC cells. Taken together, these results elucidated the function of miR-152 in CRC progression and suggested that miR-152 might function as tumor suppressor in CRC by targeting PIK3R3.

Keyword

Colorectal cancer MicroRNAs miR-152 PIK3R3 Tumor suppressor 

Notes

Compliance with ethical standards

Conflicts of interest

None

Ethical approval

The study protocol was approved by the Ethics Committee of Jilin University (Changchun, China).

Informed consent

Prior informed consent was obtained from all patients.

References

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22:191–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol. 2011;3:83–92.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  6. 6.
    Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell. 2012;149:515–24.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Shenouda SK, Alahari SK. MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev. 2009;28:369–78.CrossRefPubMedGoogle Scholar
  8. 8.
    Amirkhah R, Schmitz U, Linnebacher M, Wolkenhauer O, Farazmand A. MicroRNA-mRNA interactions in colorectal cancer and their role in tumor progression. Genes Chromosomes Cancer. 2015;54:129–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Tokarz P, Blasiak J. The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment. Acta Biochim Pol. 2012;59:467–74.PubMedGoogle Scholar
  10. 10.
    Wu Y, Huang A, Li T, Su X, Ding H, Li H, et al. Mir-152 reduces human umbilical vein endothelial cell proliferation and migration by targeting adam17. FEBS Lett. 2014;588:2063–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Chen Y, Song Y, Wang Z, Yue Z, Xu H, Xing C, et al. Altered expression of mir-148a and mir-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg. 2010;14:1170–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou X, Zhao F, Wang ZN, Song YX, Chang H, Chiang Y, et al. Altered expression of mir-152 and mir-148a in ovarian cancer is related to cell proliferation. Oncol Rep. 2012;27:447–54.PubMedGoogle Scholar
  13. 13.
    Tang XL, Lin L, Song LN, Tang XH. Hypoxia-inducible mir-152 suppresses the expression of wnt1 and erbb3, and inhibits the proliferation of cervical cancer cells. Exp Biol Med. 2015.Google Scholar
  14. 14.
    Huang H, Hu M, Li P, Lu C, Li M. Mir-152 inhibits cell proliferation and colony formation of cd133(+) liver cancer stem cells by targeting kit. Tumour Biol. 2015;36:921–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Cheng Z, Ma R, Tan W, Zhang L. Mir-152 suppresses the proliferation and invasion of nsclc cells by inhibiting fgf2. Exp Mol Med. 2014;46:e112.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhai R, Kan X, Wang B, Du H, Long Y, Wu H, et al. Mir-152 suppresses gastric cancer cell proliferation and motility by targeting cd151. Tumour Biol. 2014;35:11367–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu K, Li X, Cao Y, Ge Y, Wang J, Shi B. Mir-132 inhibits cell proliferation, invasion and migration of hepatocellular carcinoma by targeting pik3r3. Int J Oncol. 2015;47:1585–93.PubMedGoogle Scholar
  18. 18.
    Wu L, Shi B, Huang K, Fan G. Microrna-128 suppresses cell growth and metastasis in colorectal carcinoma by targeting irs1. Oncol Rep. 2015;34:2797–805.PubMedGoogle Scholar
  19. 19.
    Sheng L, He P, Yang X, Zhou M, Feng Q. Mir-612 negatively regulates colorectal cancer growth and metastasis by targeting akt2. Cell Death Dis. 2015;6:e1808.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Guo ST, Jiang CC, Wang GP, Li YP, Wang CY, Guo XY, et al. Microrna-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer. Oncogene. 2013;32:1910–20.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang H, Cao F, Li X, Miao H, E J, Xing J, Fu CG. Mir-320b suppresses cell proliferation by targeting c-myc in human colorectal cancer cells. BMC Cancer. 2015;15:748.Google Scholar
  22. 22.
    Chen Z, Liu S, Tian L, Wu M, Ai F, Tang W, et al. Mir-124 and mir-506 inhibit colorectal cancer progression by targeting dnmt3b and dnmt1. Oncotarget. 2015;6:38139–50.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu DZ, Ander BP, Tian Y, Stamova B, Jickling GC, Davis RR, et al. Integrated analysis of mRNA and microRNA expression in mature neurons, neural progenitor cells and neuroblastoma cells. Gene. 2012;495:120–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Xia X, Cheng A, Akinmade D, Hamburger AW. The n-terminal 24 amino acids of the p55 gamma regulatory subunit of phosphoinositide 3-kinase binds Rb and induces cell cycle arrest. Mol Cell Biol. 2003;23:1717–25.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Klahan S, Wu MS, Hsi E, Huang CC, Hou MF, Chang WC. Computational analysis of mRNA expression profiles identifies the itg family and pik3r3 as crucial genes for regulating triple negative breast cancer cell migration. BioMed Res Int. 2014;2014:536591.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Soroceanu L, Kharbanda S, Chen R, Soriano RH, Aldape K, Misra A, et al. Identification of igf2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma. Proc Natl Acad Sci U S A. 2007;104:3466–71.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang L, Huang J, Yang N, Greshock J, Liang S, Hasegawa K, et al. Integrative genomic analysis of phosphatidylinositol 3′-kinase family identifies pik3r3 as a potential therapeutic target in epithelial ovarian cancer. Clin Cancer Res. 2007;13:5314–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Xu L, Wen Z, Zhou Y, Liu Z, Li Q, Fei G, et al. Microrna-7-regulated tlr9 signaling-enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/akt pathway. Mol Biol Cell. 2013;24:42–55.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wang G, Yang X, Li C, Cao X, Luo X, Hu J. Pik3r3 induces epithelial-to-mesenchymal transition and promotes metastasis in colorectal cancer. Mol Cancer Ther. 2014;13:1837–47.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Gastrointestinal Colorectal and Anal SurgeryChina-Japan Union Hospital of Jilin UniversityChangchunChina
  2. 2.Department of Colorectal and Anal Surgerythe First Hospital of Jilin UniversityChangchunChina

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