Top

Published in:

Open Access 01-12-2019 | Colorectal Cancer | Primary research

Cell migration and proliferation are regulated by miR-26a in colorectal cancer via the PTEN–AKT axis

Authors: Jossimar Coronel-Hernández, Eduardo López-Urrutia, Carlos Contreras-Romero, Izamary Delgado-Waldo, Gabriela Figueroa-González, Alma D. Campos-Parra, Rebeca Salgado-García, Antonio Martínez-Gutierrez, Miguel Rodríguez-Morales, Nadia Jacobo-Herrera, Luis Ignacio Terrazas, Abraham Silva-Carmona, César López-Camarillo, Carlos Pérez-Plasencia

Published in: Cancer Cell International | Issue 1/2019

Abstract

Background

Invasion and metastasis are determinant events in the prognosis of Colorectal cancer (CRC), a common neoplasm worldwide. An important factor for metastasis is the acquired capacity of the cell to proliferate and invade adjacent tissues. In this paper, we explored the role of micro-RNA-26a in the regulation of proliferation and migration in CRC-derived cells through the negative regulation of PTEN, a key negative regulator of the AKT pathway.

Methods

Expression levels of PTEN and mir-26a were surveyed in normal and CRC-derived cell lines; paraffin embedded human tissues, TCGA CRC expression data and a Balb/c mice orthotopic induced CRC model. CRC was induced by an initial intraperitoneal dose of the colonic carcinogen Azoxymethane followed by inflammatory promoter Dextran Sulfate Sodium Salt. Luciferase assays provide information about miR-26a–PTEN 3′UTR interaction. Proliferation and migration by real time cell analysis and wound-healing functional analyses were performed to assess the participation of mir-26a on important hallmarks of CRC and its regulation on the PTEN gene.

Results

We observed a negative correlation between PTEN and mir-26a expression in cell lines, human tissues, TCGA data, and tissues derived from the CRC mouse model. Moreover, we showed that negative regulation of PTEN exerted by miR-26a affected AKT phosphorylation levels directly. Functional assays showed that mir-26a directly down-regulates PTEN, and that mir-26a over-expressing cells had higher proliferation and migration rates.

Conclusions

All this data proposes an important role of mir-26a as an oncomir in the progression and invasion of CRC. Our data suggested that mir-26a could be used as a biomarker of tumor development in CRC patients, however more studies must be conducted to establish its clinical role.

Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene. 2008;27(41):5477–85. http://www.nature.com/articles/onc2008248.

Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64(214):3014–21.CrossRefPubMed

Molinari F, Frattini M. Functions and regulation of the PTEN gene in colorectal cancer. Front Oncol. 2013;3(January):326. https://doi.org/10.3389/fonc.2013.00326/abstract.CrossRefPubMed

Bartel DP, Lee R, Feinbaum R. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMed

Hayes J, Peruzzi PP, Lawler S. MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med. 2014;20(8):460–9. https://doi.org/10.1016/j.molmed.2014.06.005.CrossRefPubMed

Liu J, Zheng M, Tang Y, Liang X, Yang Q. microRNAs, an active and versatile group in cancers. Int J Oral Sci. 2011;3(4):165–75. http://www.nature.com/ijos/journal/v3/n4/abs/ijos201123a.html.

Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, et al. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009;23(11):1327–37.CrossRefPubMedPubMedCentral

Zhang J, Han C, Wu T. MicroRNA-26a promotes cholangiocarcinoma growth by activating?—catenin. Gastroenterology. 2012;143(1):1–19.CrossRef

Shen W, Song M, Liu J, Qiu G, Li T, Hu Y, et al. MiR-26a promotes ovarian cancer proliferation and tumorigenesis. PLoS ONE. 2014;9(1):e86871.CrossRefPubMedPubMedCentral

10.

Batchu RB, Gruzdyn OV, Qazi AM, Kaur J, Mahmud EM, Weaver DW, et al. Enhanced phosphorylation of p53 by microRNA-26a leading to growth inhibition of pancreatic cancer. Surgery. 2015;158(4):981–7. https://doi.org/10.1016/j.surg.2015.05.019.CrossRefPubMed

11.

Chai ZT, Kong J, Zhu XD, Zhang YY, Lu L, Zhou JM, et al. MicroRNA-26a inhibits angiogenesis by down-regulating VEGFA through the PIK3C2α/Akt/HIF-1α pathway in hepatocellular carcinoma. PLoS ONE. 2013;8(10):1–12.CrossRef

12.

Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q, et al. MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res. 2011;71(1):225–33.CrossRefPubMed

13.

Yang L, Belaguli N, Berger DH. MicroRNA and colorectal cancer. World J Surg. 2009;33(4):638–46. https://doi.org/10.1007/s00268-008-9865-5.CrossRefPubMed

14.

López-Urrutia E, Coronel-Hernández J, García-Castillo V, Contreras-Romero C, Martínez-Gutierrez A, Estrada-Galicia D, et al. MiR-26a downregulates retinoblastoma in colorectal cancer. Tumor Biol. 2017;39(4):101042831769594. https://doi.org/10.1177/1010428317695945.CrossRef

15.

Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Vlassov A, et al. MicroRNA-182-5p targets a network of genes involved in DNA repair. RNA. 2013;19:230–42.CrossRefPubMedPubMedCentral

16.

Sachdeva M, Mito JK, Lee CL, Zhang M, Li Z, Dodd RD, et al. MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest. 2014;124(10):4305–19.CrossRefPubMedPubMedCentral

17.

Chen J, Yan D, Wu W, Zhu J, Ye W, Shu Q. MicroRNA-130a promotes the metastasis and epithelial-mesenchymal transition of osteosarcoma by targeting PTEN. Oncol Rep. 2016;35(6):3285–92. https://doi.org/10.3892/or.2016.4719.CrossRefPubMed

18.

Tian K, Di R, Wang L. MicroRNA-23a enhances migration and invasion through PTEN in osteosarcoma. Cancer Gene Ther. 2015;22(7):351–9. https://doi.org/10.1038/cgt.2015.27.CrossRefPubMed

19.

Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419.CrossRefPubMed

20.

Figueroa-gonzález G, García-castillo V, Coronel-hernández J, León-cabrera S, Arias-romero LE, Terrazas LI, et al. Anti-inflammatory and antitumor activity of a triple therapy for a colitis-related colorectal cancer. J cancer. 2016;7:1632.CrossRefPubMedPubMedCentral

21.

Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2007;36(Database):D149–53. https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkm995.

22.

Lee Y-R, Ming C. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Science. 2017;355(6320):64–7. https://doi.org/10.1038/s41580-018-0015-0.CrossRef

23.

Sawai H, Yasuda A, Ochi N, Ma J, Matsuo Y, Wakasugi T, et al. Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival. BMC Gastroenterol. 2008;8:56. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2611992&tool=pmcentrez&rendertype=abstract.

24.

Carracedo A, Pandolfi PP. The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27(41):5527–41. http://www.nature.com/articles/onc2008247.

25.

Parsons R. Human cancer, PTEN and the PI-3 kinase pathway. Semin Cell Dev Biol. 2004;15(2):171–6.CrossRefPubMed

26.

Lin P-C, Lin J-K, Lin H-H, Lan Y-T, Lin C-C, Yang S-H, et al. A comprehensive analysis of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in colorectal cancer. World J Surg Oncol. 2015;13:186.CrossRefPubMedPubMedCentral

27.

Nip H, Dar AA, Saini S, Colden M, Varahram S, Chowdhary H, et al. Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer. Oncotarget. 2016; 7(42):68371–84. http://www.oncotarget.com/fulltext/12031.

28.

Shen H, Li L, Yang S, Wang D, Zhong S, Zhao J, et al. MicroRNA-29a contributes to drug-resistance of breast cancer cells to adriamycin through PTEN/AKT/GSK3β signaling pathway. Gene. 2016;593(1):84–90.CrossRefPubMed

29.

Liu B, Wu X, Liu B, Wang C, Liu Y, Zhou Q, et al. MiR-26a enhances metastasis potential of lung cancer cells via AKT pathway by targeting PTEN. Biochim Biophys Acta Mol Basis Dis. 2012;1822(11):1692–704.CrossRef

30.

Zhang J, Wang J, Zhao F, Liu Q, Jiang K, Yang G. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010;411(11–12):846–52.CrossRefPubMed

31.

Bai J, Zhu X, Ma J, Wang W. miR-205 regulates A549 cells proliferation by targeting PTEN. Int J Clin Exp Pathol. 2015;8(2):1175–83.PubMedPubMedCentral

32.

Ren P, Gong F, Zhang Y, Jiang J, Zhang H. MicroRNA-92a promotes growth, metastasis, and chemoresistance in non-small cell lung cancer cells by targeting PTEN. Tumor Biol. 2016;37(3):3215–25. https://doi.org/10.1007/s13277-015-4150-3.CrossRef

33.

Yang Y, Yang JJ, Tao H, Jin W. MicroRNA-21 controls hTERT via PTEN in human colorectal cancer cell proliferation. J Physiol Biochem. 2015;71(1):59–68.CrossRefPubMed

34.

Ke T-W, Wei P-L, Yeh K-T, Chen WT-L, Cheng Y-W. MiR-a promotes cell metastasis of colorectal cancer through PTEN-mediated PI3K/AKT pathway. Ann Surg Oncol. 2015;22(8):2649–55.CrossRefPubMed

35.

Zheng L, Zhang Y, Liu Y, Zhou M, Lu Y, Yuan L, et al. MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. J Transl Med. 2015;13(1):252.CrossRefPubMedPubMedCentral

36.

Wu W, Yang J, Feng X, Wang H, Ye S, Yang P, et al. MicroRNA-32 (miR-32) regulates phosphataseand tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells. Mol Cancer. 2013;32:1–11.

37.

Tsunoda T, Takashima Y, Yoshida Y, Doi K, Tanaka Y, Fujimoto T, et al. Oncogenic KRAS regulates miR-200c and miR-221/222 in a 3D-specific manner in colorectal cancer cells. Anticancer Res. 2011;31(7):2453–9.PubMed

38.

Ahmed D, Eide PW, Eilertsen IA, Danielsen SA, Eknæs M, Hektoen M, et al. Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis. 2013;2:0424.CrossRef

39.

Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010;138(6):2101–14.CrossRefPubMed

40.

Balzola F, Bernstein C, Ho GT, Lees C. Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease: commentary. Inflamm Bowel Dis Monit. 2011;11(3):126–7.

41.

Chen J, Zhang K, Xu Y, Gao Y, Li C, Wang R, et al. The role of microRNA-26a in human cancer progression and clinical application. Tumor Biol. 2016;1:1–14. https://doi.org/10.1007/s13277-016-5017-y.CrossRef

42.

Chen B, Liu Y, Jin X, Lu W, Liu J, Xia Z, et al. MicroRNA-26a regulates glucose metabolism by direct targeting PDHX in colorectal cancer cells. BMC Cancer. 2014;14(1):443.CrossRefPubMedPubMedCentral

43.

Kariagina A, Aupperlee MD, Haslam SZ. PTEN loss induces epithelial–mesenchymal transition in human colon cancer cells. 2010;18(1):11–33.

44.

Wang F, Xu J, Liu H, Liu Z, Xia F. Metformin induces apoptosis by microRNA-26a-mediated downregulation of myeloid cell leukaemia-1 in human oral cancer cells. Mol Med Rep. 2016;13(6):4671–6.CrossRefPubMed

45.

Han W, Fu X, Xie J, Meng Z, Gu Y, Wang X, et al. miR-26a enhances autophagy to protect against ethanol-induced acute liver injury. J Mol Med. 2015;93(9):1045–55.CrossRefPubMed

46.

Jin F, Wang Y, Li M, Zhu Y, Liang H, Wang C, et al. MiR-26 enhances chemosensitivity and promotes apoptosis of hepatocellular carcinoma cells through inhibiting autophagy. Cell Death Dis. 2017;8(1):e2540. https://doi.org/10.1038/cddis.2016.461.CrossRefPubMedPubMedCentral

Title: Cell migration and proliferation are regulated by miR-26a in colorectal cancer via the PTEN–AKT axis
Authors: Jossimar Coronel-Hernández
Eduardo López-Urrutia
Carlos Contreras-Romero
Izamary Delgado-Waldo
Gabriela Figueroa-González
Alma D. Campos-Parra
Rebeca Salgado-García
Antonio Martínez-Gutierrez
Miguel Rodríguez-Morales
Nadia Jacobo-Herrera
Luis Ignacio Terrazas
Abraham Silva-Carmona
César López-Camarillo
Carlos Pérez-Plasencia
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-019-0802-5

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Multilevel regulation of RUVBL2 expression predicts poor prognosis in hepatocellular carcinoma

LINC00309 is associated with short disease-free survival in breast cancer

Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A

Role of microRNA-92a in metastasis of osteosarcoma cells in vivo and in vitro by inhibiting expression of TCF21 with the transmission of bone marrow derived mesenchymal stem cells

Expression signatures and roles of microRNAs in inflammatory breast cancer

Expression of the Wnt ligands gene family and its relationship to prognosis in hepatocellular carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer