miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

Zhang,Xiangliang; Shi,Huijuan; Tang,Hongsheng; Fang,Zhiyuan; Wang,Jiping; Cui,Shuzhong

doi:10.3892/ijmm.2015.2126

miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

Authors:
- Xiangliang Zhang
- Huijuan Shi
- Hongsheng Tang
- Zhiyuan Fang
- Jiping Wang
- Shuzhong Cui
View Affiliations

Affiliations: Department of Abdominal Surgery (Section 2), The Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China, Department of Pathology, The First Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Surgery, Brigham and Women's Hospital affiliated to Harvard Medical School, Boston, MA 02115, USA
Published online on: March 6, 2015 https://doi.org/10.3892/ijmm.2015.2126
Pages: 1301-1308

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Colon cancer is one of the most common and lethal malignancies worldwide. Despite major advances in the treatment of colon cancer, the prognosis remains very poor. Thus, novel and effective therapies for colon cancer are urgently needed. In the present study, the expression status of miR‑218 and the role of the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway were investigated in colon cancer samples. Firstly, we observed that miR‑218 expression was significantly reduced, while PI3K/Akt/mTOR pathway activity was enhanced. The overexpression of miR‑218 suppressed the proliferation, migration and invasion of LoVo colon cancer cells, whereas the inhibition of miR‑218 promoted these processes. Furthermore, the PI3K/Akt/mTOR signaling pathway was identified as a direct target of miR‑218. The upregulation of miR‑218 inhibited the activation of the PI3K/Akt/mTOR signaling pathway, as well as the expression of matrix metalloproteinase (MMP)9. The downregulation of miR‑218 activated the PI3K/Akt/mTOR signaling pathway and promoted MMP9 expression. Taken together, our results demonstrate that miR‑218 suppresses the proliferation, migration and invasion of LoVo colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway and MMP9. Our data indicate that miR‑218 is a potential target in the treatment of colon cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Haggar FA and Boushey RP: Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 22:191–197. 2009. View Article : Google Scholar :
3	Chen WQ, Zhang SW, Zou XN and Zhao P: Cancer incidence and mortality in China, 2006. Chin J Cancer Res. 23:3–9. 2011. View Article : Google Scholar : PubMed/NCBI
4	Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ and Rees M: Surgical resection of hepatic metastases from colorectal cancer: A systematic review of published studies. Br J Cancer. 94:982–999. 2006. View Article : Google Scholar : PubMed/NCBI
5	Yokota M, Kojima M, Nomura S, Nishizawa Y, Kobayashi A, Ito M, Ochiai A and Saito N: Clinical impact of elastic laminal invasion in colon cancer: Elastic laminal invasion-positive stage II colon cancer is a high-risk equivalent to stage III. Dis Colon Rectum. 57:830–838. 2014. View Article : Google Scholar : PubMed/NCBI
6	Glehen O, Osinsky D, Cotte E, et al: Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: Morbidity and mortality analysis of 216 consecutive procedures. Ann Surg Oncol. 10:863–869. 2003. View Article : Google Scholar : PubMed/NCBI
7	Aghili M, Izadi S, Madani H and Mortazavi H: Clinical and pathological evaluation of patients with early and late recurrence of colorectal cancer. Asia Pac J Clin Oncol. 6:35–41. 2010. View Article : Google Scholar : PubMed/NCBI
8	Medina-Villaamil V, Martínez-Breijo S, Portela-Pereira P, Quindós-Varela M, Santamarina-Caínzos I, Antón-Aparicio LM and Gómez-Veiga F: Circulating MicroRNAs in blood of patients with prostate cancer. Actas Urol Esp. 38:633–639. 2014.In English, Spanish. View Article : Google Scholar : PubMed/NCBI
9	Yang M, Liu R, Sheng J, Liao J, Wang Y, Pan E, Guo W, Pu Y and Yin L: Differential expression profiles of microRNAs as potential biomarkers for the early diagnosis of esophageal squamous cell carcinoma. Oncol Rep. 29:169–176. 2013.
10	Leite KR, Tomiyama A, Reis ST, Sousa-Canavez JM, Sañudo A, Camara-Lopes LH and Srougi M: MicroRNA expression profiles in the progression of prostate cancer – from high-grade prostate intraepithelial neoplasia to metastasis. Urol Oncol. 31:796–801. 2013. View Article : Google Scholar
11	He X, Dong Y, Wu CW, Zhao Z, Ng SS, Chan FK, Sung JJ and Yu J: MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene. Mol Med. 18:1491–1498. 2012.PubMed/NCBI
12	Heckmann D, Maier P, Laufs S, et al: The disparate twins: A comparative study of CXCR4 and CXCR7 in SDF-1α-induced gene expression, invasion and chemosensitivity of colon cancer. Clin Cancer Res. 20:604–616. 2014. View Article : Google Scholar
13	Yu H, Gao G, Jiang L, Guo L, Lin M, Jiao X, Jia W and Huang J: Decreased expression of miR-218 is associated with poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol. 6:2904–2911. 2013.PubMed/NCBI
14	Fruman DA and Rommel C: PI3K and cancer: Lessons, challenges and opportunities. Nat Rev Drug Discov. 13:140–156. 2014. View Article : Google Scholar : PubMed/NCBI
15	Liu YZ, Wu K, Huang J, et al: The PTEN/PI3K/Akt and Wnt/β-catenin signaling pathways are involved in the inhibitory effect of resveratrol on human colon cancer cell proliferation. Int J Oncol. 45:104–112. 2014.PubMed/NCBI
16	Jiang QG, Li TY, Liu DN and Zhang HT: PI3K/Akt pathway involving into apoptosis and invasion in human colon cancer cells LoVo. Mol Biol Rep. 41:3359–3367. 2014. View Article : Google Scholar : PubMed/NCBI
17	Xiao ZM, Wang XY and Wang AM: Periostin induces chemo-resistance in colon cancer cells through activation of the PI3K/Akt/survivin pathway. Biotechnol Appl Biochem. Dec 24–2013.Epub ahead of print. View Article : Google Scholar
18	Josse C, Bouznad N, Geurts P, Irrthum A, Huynh-Thu VA, Servais L, Hego A, Delvenne P, Bours V and Oury C: Identification of a microRNA landscape targeting the PI3K/Akt signaling pathway in inflammation-induced colorectal carcinogenesis. Am J Physiol Gastrointest Liver Physiol. 306:G229–G243. 2014. View Article : Google Scholar : PubMed/NCBI
19	Dong M, Yang G, Liu H, Liu X, Lin S, Sun D and Wang Y: Aged black garlic extract inhibits HT29 colon cancer cell growth via the PI3K/Akt signaling pathway. Biomed Rep. 2:250–254. 2014.PubMed/NCBI
20	Li XX, Huang LY, Peng JJ, Liang L, Shi DB, Zheng HT and Cai SJ: Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. Int J Oncol. 45:611–618. 2014.PubMed/NCBI
21	Nuvoli B, Santoro R, Catalani S, Battistelli S, Benedetti S, Canestrari F and Galati R: CELLFOOD™ induces apoptosis in human mesothelioma and colorectal cancer cells by modulating p53, c-myc and pAkt signaling pathways. J Exp Clin Cancer Res. 33:242014. View Article : Google Scholar
22	Enayat S, Ceyhan MS, Başaran AA, Gürsel M and Banerjee S: Anticarcinogenic effects of the ethanolic extract of Salix aegyptiaca in colon cancer cells: Involvement of Akt/PKB and MAPK pathways. Nutr Cancer. 65:1045–1058. 2013. View Article : Google Scholar : PubMed/NCBI
23	Trigka EA, Levidou G, Saetta AA, et al: A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features. Oncol Rep. 30:623–636. 2013.PubMed/NCBI
24	Banerjee N, Kim H, Talcott S and Mertens-Talcott S: Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: Possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR. Carcinogenesis. 34:2814–2822. 2013. View Article : Google Scholar : PubMed/NCBI
25	Pandurangan AK: Potential targets for prevention of colorectal cancer: A focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac J Cancer Prev. 14:2201–2205. 2013. View Article : Google Scholar : PubMed/NCBI
26	Seo BR, Min KJ, Cho IJ, Kim SC and Kwon TK: Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability. PLoS One. 9:e955882014. View Article : Google Scholar : PubMed/NCBI
27	Zang C, Eucker J, Liu H, Müller A, Possinger K and Scholz CW: Concurrent inhibition of PI3-kinase and mTOR induces cell death in diffuse large B cell lymphomas, a mechanism involving down regulation of Mcl-1. Cancer Lett. 339:288–297. 2013. View Article : Google Scholar
28	Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Rasp KH, Illing B, Döhner H, Döhner K and Schittenhelm MM: Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia. Mol Cancer. 12:462013. View Article : Google Scholar : PubMed/NCBI
29	Müller A, Zang C, Chumduri C, Dörken B, Daniel PT and Scholz CW: Concurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma. Int J Cancer. 133:1813–1824. 2013. View Article : Google Scholar : PubMed/NCBI
30	Malinowsky K, Nitsche U, Janssen KP, Bader FG, Späth C, Drecoll E, Keller G, Höfler H, Slotta-Huspenina J and Becker KF: Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer. Br J Cancer. 110:2081–2089. 2014. View Article : Google Scholar : PubMed/NCBI
31	Uesugi A, Kozaki K, Tsuruta T, Furuta M, Morita K, Imoto I, Omura K and Inazawa J: The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 71:5765–5778. 2011. View Article : Google Scholar : PubMed/NCBI
32	Fan R, Zhong J, Zheng S, Wang Z, Xu Y, Li S, Zhou J and Yuan F: microRNA-218 increase the sensitivity of gastrointestinal stromal tumor to imatinib through PI3K/AKT pathway. Clin Exp Med. Apr 5–2014.Epub ahead of print. View Article : Google Scholar
33	Hadler-Olsen E, Winberg JO and Uhlin-Hansen L: Matrix metalloproteinases in cancer: Their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol. 34:2041–2051. 2013. View Article : Google Scholar : PubMed/NCBI
34	Stellas D and Patsavoudi E: Inhibiting matrix metalloproteinases, an old story with new potentials for cancer treatment. Anticancer Agents Med Chem. 12:707–717. 2012. View Article : Google Scholar : PubMed/NCBI
35	Shuman Moss LA, Jensen-Taubman S and Stetler-Stevenson WG: Matrix metalloproteinases: Changing roles in tumor progression and metastasis. Am J Pathol. 181:1895–1899. 2012. View Article : Google Scholar : PubMed/NCBI
36	Tie J, Pan Y, Zhao L, et al: MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 6:e10008792010. View Article : Google Scholar : PubMed/NCBI
37	Xin SY, Feng XS, Zhou LQ, Sun JJ, Gao XL and Yao GL: Reduced expression of circulating microRNA-218 in gastric cancer and correlation with tumor invasion and prognosis. World J Gastroenterol. 20:6906–6911. 2014. View Article : Google Scholar : PubMed/NCBI
38	Kinoshita T, Hanazawa T, Nohata N, et al: Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion through targeting laminin-332 in head and neck squamous cell carcinoma. Oncotarget. 3:1386–1400. 2012.PubMed/NCBI
39	Yamamoto N, Kinoshita T, Nohata N, Itesako T, Yoshino H, Enokida H, Nakagawa M, Shozu M and Seki N: Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma. Int J Oncol. 42:1523–1532. 2013.PubMed/NCBI
40	Hassan MQ, Maeda Y, Taipaleenmaki H, et al: miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem. 287:42084–42092. 2012. View Article : Google Scholar : PubMed/NCBI
41	Guo F, Carter DE and Leask A: miR-218 regulates focal adhesion kinase-dependent TGFβ signaling in fibroblasts. Mol Biol Cell. 25:1151–1158. 2014. View Article : Google Scholar : PubMed/NCBI
42	Knight ZA, Gonzalez B, Feldman ME, et al: A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 125:733–747. 2006. View Article : Google Scholar : PubMed/NCBI
43	Hales EC, Taub JW and Matherly LH: New insights into Notch1 regulation of the PI3K-AKT-mTOR1 signaling axis: Targeted therapy of γ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia. Cell Signal. 26:149–161. 2014. View Article : Google Scholar
44	Serrano-Nascimento C, da Silva Teixeira S, Nicola JP, Nachbar RT, Masini-Repiso AM and Nunes MT: The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway. Endocrinology. 155:1145–1156. 2014. View Article : Google Scholar : PubMed/NCBI
45	Kim SM, Park JH, Kim KD, Nam D, Shim BS, Kim SH and Ahn KS, Choi SH and Ahn KS: Brassinin induces apoptosis in PC-3 human prostate cancer cells through the suppression of PI3K/Akt/mTOR/S6K1 signaling cascades. Phytother Res. 28:423–431. 2014. View Article : Google Scholar
46	Jung KH, Yan HH, Fang Z, Son MK, Lee H, Hong S and Hong SS: HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer. Int J Oncol. 45:311–321. 2014.PubMed/NCBI
47	Slotkin EK, Patwardhan PP, Vasudeva SD, de Stanchina E, Tap WD and Schwartz GK: MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma. Mol Cancer Ther. 14:395–406. 2015. View Article : Google Scholar
48	Yuan H, Yang P, Zhou D, Gao W, Qiu Z, Fang F, Ding S and Xiao W: Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid arthritis fibroblast-like synoviocytes by down-regulating the PI3K/AKT activation and MMP-2/9 production in vitro. Mol Biol Rep. 41:5157–5165. 2014. View Article : Google Scholar : PubMed/NCBI
49	Yang N, Hui L, Wang Y, Yang H and Jiang X: SOX2 promotes the migration and invasion of laryngeal cancer cells by induction of MMP-2 via the PI3K/Akt/mTOR pathway. Oncol Rep. 31:2651–2659. 2014.PubMed/NCBI
50	Su Y, Gao L, Teng L, Wang Y, Cui J, Peng S and Fu S: Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways. J Transl Med. 11:1322013. View Article : Google Scholar
51	Li X, Yang Z, Song W, et al: Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. Int J Oncol. 43:793–802. 2013.PubMed/NCBI