MicroRNA-126 functions as a tumor suppressor in colorectal cancer cells by targeting CXCR4 via the AKT and ERK1/2 signaling pathways

Liu,Yaling; Zhou,Yu; Feng,Xiao; An,Ping; Quan,Xiaojing; Wang,Hao; Ye,Shicai; Yu,Caiyuan; He,Yanting; Luo,Hesheng

doi:10.3892/ijo.2013.2168

MicroRNA-126 functions as a tumor suppressor in colorectal cancer cells by targeting CXCR4 via the AKT and ERK1/2 signaling pathways

Authors:
- Yaling Liu
- Yu Zhou
- Xiao Feng
- Ping An
- Xiaojing Quan
- Hao Wang
- Shicai Ye
- Caiyuan Yu
- Yanting He
- Hesheng Luo
View Affiliations

Affiliations: Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China, Department of Gastroenterology, The Affiliated Hospital of Guangdong Medical College, Xiashan District, Zhanjiang, Guangdong, P.R. China
Published online on: November 5, 2013 https://doi.org/10.3892/ijo.2013.2168
Pages: 203-210

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

Recent evidence shows that altered microRNA-126 (miR-126) expression is implicated in the progression of colorectal cancer (CRC). However, the precise roles and mechanisms of miR-126 in CRC remain unclear. The aim of this study was to investigate the roles of miR-126 in CRC cells and to elucidate miR-126-mediated mechanisms in CRC cells. First, miR-126 expression was analyzed using qRT-PCR in 4 human CRC cell lines (SW480, SW620, HT-29 and HCT-116). Furthermore, the biological properties of miR-126 in CRC cells in vitro were examined by applying Cell Counting Kit 8, cell cycle, cell apoptosis and transwell assays. The mechanisms and pathways of miR-126-mediated in CRC cells were detected by using qRT-PCR, western blotting and luciferase reporter assay. We found that miR-126 overexpression inhibited cell proliferation, migration and invasion, and induced cell arrest in the G0/G1 phase of CRC cells, suggesting that miR-126 functions as a tumor suppressor in CRC cells. Furthermore, we identified the CXC chemokine receptor 4 (CXCR4) as a target of miR-126, and showed that it was negatively regulated by miR-126. We demonstrated that miR-126-mediated tumor suppression might be partly dependent on AKT and ERK1/2 signaling pathways. In conclusion, our data revealed that miR-126 functions as a tumor suppressor in CRC cells by regulating CXCR4 expression via the AKT and ERK1/2 signaling pathways and might be a novel target for therapeutic strategies in CRC.

View Figures

View References

1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
2.	Lan YT, Yang SH, Chang SC, et al: Analysis of the seventh edition of American Joint Committee on colon cancer staging. Int J Colorectal Dis. 27:657–663. 2012. View Article : Google Scholar : PubMed/NCBI
3.	Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Pasquinelli AE: MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 13:271–282. 2012.PubMed/NCBI
5.	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
6.	Asangani IA, Rasheed SA, Nikolova DA, et al: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 27:2128–2136. 2008. View Article : Google Scholar : PubMed/NCBI
7.	Ozen M, Creighton CJ, Ozdemir M and Ittmann M: Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 27:1788–1793. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Wang X, Tang S, Le SY, et al: Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One. 3:e25572008. View Article : Google Scholar : PubMed/NCBI
10.	Babashah S and Soleimani M: The oncogenic and tumour suppressive roles of microRNAs in cancer and apoptosis. Eur J Cancer. 47:1127–1137. 2011. View Article : Google Scholar : PubMed/NCBI
11.	Li XM, Wang AM, Zhang J and Yi H: Down-regulation of miR-126 expression in colorectal cancer and its clinical significance. Med Oncol. 28:1054–1057. 2011. View Article : Google Scholar : PubMed/NCBI
12.	Tavazoie SF, Alarcon C, Oskarsson T, et al: Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 451:147–152. 2008. View Article : Google Scholar : PubMed/NCBI
13.	Feng R, Chen X, Yu Y, et al: miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett. 298:50–63. 2010. View Article : Google Scholar : PubMed/NCBI
14.	Guo C, Sah JF, Beard L, Willson JK, Markowitz SD and Guda K: The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer. 47:939–946. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Liu B, Peng XC, Zheng XL, Wang J and Qin YW: MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer. 66:169–175. 2009. View Article : Google Scholar : PubMed/NCBI
16.	Zhang J, Du YY, Lin YF, et al: The cell growth suppressor, mir-126, targets IRS-1. Biochem Biophys Res Commun. 377:136–140. 2008. View Article : Google Scholar : PubMed/NCBI
17.	Hamada S, Satoh K, Fujibuchi W, et al: MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. Mol Cancer Res. 10:3–10. 2012. View Article : Google Scholar : PubMed/NCBI
18.	Zhang Y, Yang P, Sun T, et al: miR-126 and miR-126^* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol. 15:284–294. 2013.
19.	Zhang Y, Wang X, Xu B, et al: Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer. Oncol Rep. 30:1976–1984. 2013.PubMed/NCBI
20.	Miko E, Margitai Z, Czimmerer Z, et al: miR-126 inhibits proliferation of small cell lung cancer cells by targeting SLC7A5. FEBS Lett. 585:1191–1196. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Li N, Tang A, Huang S, et al: MiR-126 suppresses colon cancer cell proliferation and invasion via inhibiting RhoA/ROCK signaling pathway. Mol Cell Biochem. 380:107–119. 2013. View Article : Google Scholar : PubMed/NCBI
22.	Li Z, Lu J, Sun M, et al: Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA. 105:15535–15540. 2008. View Article : Google Scholar : PubMed/NCBI
23.	Fish JE, Santoro MM, Morton SU, et al: miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 15:272–284. 2008. View Article : Google Scholar : PubMed/NCBI
24.	Wang S, Aurora AB, Johnson BA, et al: The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 15:261–271. 2008. View Article : Google Scholar : PubMed/NCBI
25.	Otsubo T, Akiyama Y, Hashimoto Y, Shimada S, Goto K and Yuasa Y: MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One. 6:e166172011. View Article : Google Scholar : PubMed/NCBI
26.	Oberlin E, Amara A, Bachelerie F, et al: The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 382:833–835. 1996. View Article : Google Scholar : PubMed/NCBI
27.	Kim J, Takeuchi H, Lam ST, et al: Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol. 23:2744–2753. 2005. View Article : Google Scholar : PubMed/NCBI
28.	Murakami T, Kawada K, Iwamoto M, et al: The role of CXCR3 and CXCR4 in colorectal cancer metastasis. Int J Cancer. 132:276–287. 2013. View Article : Google Scholar : PubMed/NCBI
29.	Punj V, Matta H, Schamus S, Tamewitz A, Anyang B and Chaudhary PM: Kaposi’s sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a. Oncogene. 29:1835–1844. 2010.
30.	Tano N, Kim HW and Ashraf M: microRNA-150 regulates mobilization and migration of bone marrow-derived mononuclear cells by targeting Cxcr4. PLoS One. 6:e231142011. View Article : Google Scholar : PubMed/NCBI
31.	Labbaye C, Spinello I, Quaranta MT, et al: A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat Cell Biol. 10:788–801. 2008. View Article : Google Scholar : PubMed/NCBI
32.	Yasumoto K, Koizumi K, Kawashima A, et al: Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 66:2181–2187. 2006. View Article : Google Scholar : PubMed/NCBI
33.	Wendt MK, Drury LJ, Vongsa RA and Dwinell MB: Constitutive CXCL12 expression induces anoikis in colorectal carcinoma cells. Gastroenterology. 135:508–517. 2008. View Article : Google Scholar : PubMed/NCBI
34.	Shen X, Artinyan A, Jackson D, Thomas RM, Lowy AM and Kim J: Chemokine receptor CXCR4 enhances proliferation in pancreatic cancer cells through AKT and ERK dependent pathways. Pancreas. 39:81–87. 2010. View Article : Google Scholar : PubMed/NCBI
35.	Brand S, Dambacher J, Beigel F, et al: CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. Exp Cell Res. 310:117–130. 2005. View Article : Google Scholar : PubMed/NCBI