miR‑501‑3p promotes colorectal cancer progression via activation of Wnt/β‑catenin signaling

Wu,Fangxiong; Xing,Tongchao; Gao,Xiaopeng; Liu,Fengrui

doi:10.3892/ijo.2019.4852

miR‑501‑3p promotes colorectal cancer progression via activation of Wnt/β‑catenin signaling

Authors:
- Fangxiong Wu
- Tongchao Xing
- Xiaopeng Gao
- Fengrui Liu
View Affiliations

Affiliations: Department of Gastroenterology, First Affiliated Hospital of Xi'an Medical College, Xi'an, Shaanxi 710077, P.R. China, General Surgery, The Fourth People's Hospital of Shaanxi Province, Xi'an, Shaanxi 710000, P.R. China, Second Department of General Surgery, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China, Emergency Department, First Affiliated Hospital of Xi'an Medical College, Xi'an, Shaanxi 710077, P.R. China
Published online on: July 30, 2019 https://doi.org/10.3892/ijo.2019.4852
Pages: 671-683
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Aberrant activation of Wnt/β‑catenin signaling is observed in >90% of colorectal cancer cases. microRNAs (miRNAs) regulate the expression of key genes in Wnt/β‑catenin signaling. As a result, abnormal expression of miRNAs regulates the activation of Wnt/β‑catenin signaling in several types of cancer. In the current study, it was demonstrated that miR‑501‑3p was overexpressed in colorectal tumor tissues compared to the adjacent normal tissues. Downregulation of miR‑501‑3p inhibited cell proliferation and sphere formation, while it induced cell cycle arrest at the G1 phase in colorectal cancer cells. Bioinformatics analysis results predicted that adenomatous polyposis coli (APC), a negative regulator of Wnt/β‑catenin signaling, was a potential target gene of miR‑501‑3p. Inhibition of miR‑501‑3p increased APC expression in colorectal cancer cells. Additionally, β‑catenin was destabilized following miR‑501‑3p inhibition; immunofluorescence analysis revealed that β‑catenin translocated from nucleus to cytoplasm. In addition, cyclin D1 and c‑Myc, two well‑characterized target genes of Wnt/β‑catenin signaling, were downregulated following miR‑501‑3p inhibition. Transfection of APC small interfering RNA re‑activated β‑catenin and stimulated the expression of cyclin D1 and c‑Myc. Furthermore, silencing of APC reversed the miR‑501‑3p inhibitor‑induced cell cycle disruption, and the inhibition of cell proliferation and sphere formation in colorectal cancer cells. In conclusion, the present study identified miR‑501‑3p as a novel regulator of Wnt/β‑catenin signaling in colorectal cancer cells via targeting APC, suggesting that miR‑501‑3p may act as a novel oncogenic miRNA in colorectal cancer.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A and Jemal A: Colorectal cancer statistics, 2017. CA Cancer J Clin. 67:177–193. 2017. View Article : Google Scholar : PubMed/NCBI
3	Araghi M, Soerjomataram I, Jenkins M, Brierley J, Morris E, Bray F and Arnold M: Global trends in colorectal cancer mortality: Projections to the year 2035. Int J Cancer. 144:2992–3000. 2019. View Article : Google Scholar
4	Jiang S, Miao D, Wang M, Lv J, Wang Y and Tong J: MiR-30-5p suppresses cell chemoresistance and stemness in colorectal cancer through USP22/Wnt/β-catenin signaling axis. J Cell Mol Med. 23:630–640. 2019. View Article : Google Scholar
5	Claessen MM, Schipper ME, Oldenburg B, Siersema PD, Offerhaus GJ and Vleggaar FP: WNT-pathway activation in IBD-associated colorectal carcinogenesis: Potential biomarkers for colonic surveillance. Cell Oncol. 32:303–310. 2010.PubMed/NCBI
6	Cheng H, Sun X, Li J, He P, Liu W and Meng X: Knockdown of Uba2 inhibits colorectal cancer cell invasion and migration through downregulation of the Wnt/β-catenin signaling pathway. J Cell Biochem. 119:6914–6925. 2018. View Article : Google Scholar : PubMed/NCBI
7	Bienz M and Clevers H: Linking colorectal cancer to Wnt signaling. Cell. 103:311–320. 2000. View Article : Google Scholar : PubMed/NCBI
8	Clevers H and Nusse R: Wnt/β-catenin signaling and disease. Cell. 149:1192–1205. 2012. View Article : Google Scholar : PubMed/NCBI
9	Emons G, Spitzner M, Reineke S, Möller J, Auslander N, Kramer F, Hu Y, Beissbarth T, Wolff HA, Rave-Fränk M, et al: Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling. Mol Cancer Res. 15:1481–1490. 2017. View Article : Google Scholar : PubMed/NCBI
10	Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, Schwitalla S, Kalna G, Ogg EL, Athineos D, et al: ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell. 12:761–773. 2013. View Article : Google Scholar : PubMed/NCBI
11	Peifer M and Polakis P: Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science. 287:1606–1609. 2000. View Article : Google Scholar : PubMed/NCBI
12	Sparks AB, Morin PJ, Vogelstein B and Kinzler KW: Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 58:1130–1134. 1998.PubMed/NCBI
13	Sawa M, Masuda M and Yamada T: Targeting the Wnt signaling pathway in colorectal cancer. Expert Opin Ther Targets. 20:419–429. 2016. View Article : Google Scholar
14	Olsen AK, Coskun M, Bzorek M, Kristensen MH, Danielsen ET, Jørgensen S, Olsen J, Engel U, Holck S and Troelsen JT: Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells. Carcinogenesis. 34:1361–1369. 2013. View Article : Google Scholar : PubMed/NCBI
15	Shu Z, Chen L and Ding D: miR-582-5P induces colorectal cancer cell proliferation by targeting adenomatous polyposis coli. World J Surg Oncol. 14:2392016. View Article : Google Scholar : PubMed/NCBI
16	Lee RC, Feinbaum RL and Ambros V: The C. elegans heter-ochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 75:843–854. 1993. View Article : Google Scholar : PubMed/NCBI
17	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
18	Alvarez-Garcia I and Miska EA: MicroRNA functions in animal development and human disease. Development. 132:4653–4662. 2005. View Article : Google Scholar : PubMed/NCBI
19	Ha M and Kim VN: Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 15:509–524. 2014. View Article : Google Scholar : PubMed/NCBI
20	Thomas J, Ohtsuka M, Pichler M and Ling H: MicroRNAs: Clinical relevance in colorectal cancer. Int J Mol Sci. 16:28063–28076. 2015. View Article : Google Scholar : PubMed/NCBI
21	Iwaya T, Yokobori T, Nishida N, Kogo R, Sudo T, Tanaka F, Shibata K, Sawada G, Takahashi Y, Ishibashi M, et al: Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. Carcinogenesis. 33:2391–2397. 2012. View Article : Google Scholar : PubMed/NCBI
22	Slattery ML, Herrick JS, Pellatt DF, Stevens JR, Mullany LE, Wolff E, Hoffman MD, Samowitz WS and Wolff RK: MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: Variations in miRNA expression and disease progression. Carcinogenesis. 37:245–261. 2016. View Article : Google Scholar : PubMed/NCBI
23	Sanches JGP, Xu Y, Yabasin IB, Li M, Lu Y, Xiu X, Wang L, Mao L, Shen J, Wang B, et al: miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD. Chem Biol Interact. 285:85–95. 2018. View Article : Google Scholar : PubMed/NCBI
24	Liu Y, Chai Y, Zhang J and Tang J: A Function variant at miR-501 alters susceptibility to hepatocellular carcinoma in a Chinese Han population. Cell Physiol Biochem. 38:2500–2508. 2016. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Agarwal V, Bell GW, Nam JW and Bartel DP: Predicting effective microRNA target sites in mammalian mRNAs. Elife. 4:e050052015. View Article : Google Scholar :
27	Moreno-Bueno G, Hardisson D, Sánchez C, Sarrió D, Cassia R, García-Rostán G, Prat J, Guo M, Herman JG, Matías-Guiu X, et al: Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene. 21:7981–7990. 2002. View Article : Google Scholar : PubMed/NCBI
28	Gumbiner BM: Carcinogenesis: A balance between beta-catenin and APC. Curr Biol. 7:R443–R446. 1997. View Article : Google Scholar : PubMed/NCBI
29	Tetsu O and McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 398:422–426. 1999. View Article : Google Scholar : PubMed/NCBI
30	Gomase VS and Parundekar AN: MicroRNA: Human disease and development. Int J Bioinform Res Appl. 5:479–500. 2009. View Article : Google Scholar : PubMed/NCBI
31	Bailey ST, Westerling T and Brown M: Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res. 75:436–445. 2015. View Article : Google Scholar :
32	Wang Y, Gu J, Roth JA, Hildebrandt MA, Lippman SM, Ye Y, Minna JD and Wu X: Pathway-based serum microRNA profiling and survival in patients with advanced stage non-small cell lung cancer. Cancer Res. 73:4801–4809. 2013. View Article : Google Scholar : PubMed/NCBI
33	Yokoi A, Matsuzaki J, Yamamoto Y, Yoneoka Y, Takahashi K, Shimizu H, Uehara T, Ishikawa M, Ikeda SI, Sonoda T, et al: Integrated extracellular microRNA profiling for ovarian cancer screening. Nat Commun. 9:43192018. View Article : Google Scholar : PubMed/NCBI
34	Liu C, Liu R, Zhang D, Deng Q, Liu B, Chao HP, Rycaj K, Takata Y, Lin K, Lu Y, et al: MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes. Nat Commun. 8:142702017. View Article : Google Scholar : PubMed/NCBI
35	Yu J, Lei R, Zhuang X, Li X, Li G, Lev S, Segura MF, Zhang X and Hu G: MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells. Nat Commun. 7:138842016. View Article : Google Scholar
36	Hara N, Kikuchi M, Miyashita A, Hatsuta H, Saito Y, Kasuga K, Murayama S, Ikeuchi T and Kuwano R: Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer's disease. Acta Neuropathol Commun. 5:102017. View Article : Google Scholar : PubMed/NCBI
37	James MI, Iwuji C, Irving G, Karmokar A, Higgins JA, Griffin-Teal N, Thomas A, Greaves P, Cai H, Patel SR, et al: Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett. 364:135–141. 2015. View Article : Google Scholar : PubMed/NCBI
38	Boman BM, Fields JZ, Bonham-Carter O and Runquist OA: Computer modeling implicates stem cell overproduction in colon cancer initiation. Cancer Res. 61:8408–8411. 2001.PubMed/NCBI
39	Novellasdemunt L, Antas P and Li VS: Targeting Wnt signaling in colorectal cancer. A review in the theme: Cell signaling: Proteins, pathways and mechanisms. Am J Physiol Cell Physiol. 309:C511–C521. 2015. View Article : Google Scholar : PubMed/NCBI
40	Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MT, Wang H, Chen J, Ng SS, Chen M, et al: microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene. 32:5078–5088. 2013. View Article : Google Scholar
41	Zhang H, Hao Y, Yang J, Zhou Y, Li J, Yin S, Sun C, Ma M, Huang Y and Xi JJ: Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis. Nat Commun. 2:5542011. View Article : Google Scholar : PubMed/NCBI
42	Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JA, Bolijn A, Meijer GA and Agami R: Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res. 68:5795–5802. 2008. View Article : Google Scholar : PubMed/NCBI
43	Lin Y, Gu Q, Sun Z, Sheng B, Qi C, Liu B, Fu T, Liu C and Zhang Y: Upregulation of miR-3607 promotes lung adenocar-cinoma proliferation by suppressing APC expression. Biomed Pharmacother. 95:497–503. 2017. View Article : Google Scholar : PubMed/NCBI
44	Liu L, Zhang H, Shi L, Zhang W, Yuan J, Chen X, Liu J, Zhang Y and Wang Z: Inhibition of Rac1 activity induces G1/S phase arrest through the GSK3/cyclin D1 pathway in human cancer cells. Oncol Rep. 32:1395–1400. 2014. View Article : Google Scholar : PubMed/NCBI
45	Lee SH, Chen TY, Dhar SS, Gu B, Chen K, Kim YZ, Li W and Lee MG: A feedback loop comprising PRMT7 and miR-24-2 interplays with Oct4, Nanog, Klf4 and c-Myc to regulate stemness. Nucleic Acids Res. 44:10603–10618. 2016. View Article : Google Scholar : PubMed/NCBI