The microRNA-429/DUSP4 axis regulates the sensitivity of colorectal cancer cells to nintedanib

Cheng,Guohua; Li,Yarong; Liu,Zhaoyu; Song,Xiang

doi:10.3892/mmr.2021.11867

The microRNA-429/DUSP4 axis regulates the sensitivity of colorectal cancer cells to nintedanib

Authors:
- Guohua Cheng
- Yarong Li
- Zhaoyu Liu
- Xiang Song
View Affiliations

Affiliations: Department of Oncology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
Published online on: January 25, 2021 https://doi.org/10.3892/mmr.2021.11867
Article Number: 228
Copyright: © Cheng 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

Colorectal cancer (CRC) is recognized as one of the most common malignancies, which ranks third among all cancer-related deaths worldwide. Nintedanib is an orally available tyrosine kinase inhibitor that can treat CRC; however, drug resistance to nintedanib leads to unsatisfactory treatments for patients with CRC. The aim of the present study was to explore whether overexpression of miR-429 elevated the sensitivity of CRC cells to nintedanib by downregulating dual specificity protein phosphatase 4 (DUSP4). The nintedanib-resistant CRC cell model was established via the treatment of cells with nintedanib in a dose-dependent manner. Reverse transcription-quantitative PCR was used to detect the expression levels of miR-429 and DUSP4, and to confirm the transfection efficiency of miR-429 mimic and DUSP4 overexpression plasmid. Cell Counting Kit-8 assay was utilized to measure the inhibition rate of cells. Western blotting was conducted to observe the expression levels of DUSP4 protein, apoptosis-related proteins and proteins related to the JNK signaling pathway. Dual-luciferase reporter assay was performed to evaluate luciferase activity and TUNEL assay was conducted to detect the apoptosis of cells. The results revealed that miR-429 mimic elevated the sensitivity of CRC cells to nintedanib. Moreover, by ENCORI prediction, DUSP4 was identified as a target gene of miR-429, and overexpression of DUSP4 reversed the inducing effect of miR-429 overexpression on the sensitivity of CRC cells to nintedanib. In conclusion, overexpression of miR-429 may elevate the sensitivity of CRC cells to nintedanib through inhibition of the JNK signaling pathway by targeting DUSP4.These findings may aid in the prevention of drug resistance of CRC cells to nintedanib.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Fanali C, Lucchetti D, Farina M, Corbi M, Cufino V, Cittadini A and Sgambato A: Cancer stem cells in colorectal cancer from pathogenesis to therapy: Controversies and perspectives. World J Gastroenterol. 20:923–942. 2014. View Article : Google Scholar : PubMed/NCBI
3	Malapelle U: USP11 role in colorectal cancer growing and metastatisation. EBioMedicine. 48:5–6. 2019. View Article : Google Scholar : PubMed/NCBI
4	Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D and Bray F: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 49:1374–1403. 2013. View Article : Google Scholar : PubMed/NCBI
5	Rodríguez-Portal JA: Efficacy and safety of Nintedanib for the rreatment of idiopathic pulmonary fibrosis: An update. Drugs R D. 18:19–25. 2018. View Article : Google Scholar : PubMed/NCBI
6	Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, et al: Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 365:1079–1087. 2011. View Article : Google Scholar : PubMed/NCBI
7	Crestani B, Huggins JT, Kaye M, Costabel U, Glaspole I, Ogura T, Song JW, Stansen W, Quaresma M, Stowasser S, et al: Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: Results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 7:60–68. 2019. View Article : Google Scholar : PubMed/NCBI
8	Collard HR, Richeldi L, Kim DS, Taniguchi H, Tschoepe I, Luisetti M, Roman J, Tino G, Schlenker-Herceg R, Hallmann C, et al: Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis. Eur Respir J. 49:16013392017. View Article : Google Scholar : PubMed/NCBI
9	Xue H and Tian GY: MiR-429 regulates the metastasis and EMT of HCC cells through targeting RAB23. Arch Biochem Biophys. 637:48–55. 2018. View Article : Google Scholar : PubMed/NCBI
10	Nishijima N, Seike M, Soeno C, Chiba M, Miyanaga A, Noro R, Sugano T, Matsumoto M, Kubota K and Gemma A: miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. Int J Oncol. 48:937–944. 2016. View Article : Google Scholar : PubMed/NCBI
11	Tian X, Wei Z, Wang J, Liu P, Qin Y and Zhong M: MicroRNA-429 inhibits the migration and invasion of colon cancer cells by targeting PAK6/cofilin signaling. Oncol Rep. 34:707–714. 2015. View Article : Google Scholar : PubMed/NCBI
12	Low HB and Zhang Y: Regulatory roles of MAPK phosphatases in cancer. Immune Netw. 16:85–98. 2016. View Article : Google Scholar : PubMed/NCBI
13	Gaggianesi M, Turdo A, Chinnici A, Lipari E, Apuzzo T, Benfante A, Sperduti I, Di Franco S, Meraviglia S, Lo Presti E, et al: IL4 primes the dynamics of breast cancer progression via DUSP4 inhibition. Cancer Res. 77:3268–3279. 2017. View Article : Google Scholar : PubMed/NCBI
14	Kang X, Li M, Zhu H, Lu X, Miao J, Du S, Xia X and Guan W: DUSP4 promotes doxorubicin resistance in gastric cancer through epithelial-mesenchymal transition. Oncotarget. 8:94028–94039. 2017. View Article : Google Scholar : PubMed/NCBI
15	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 : PubMed/NCBI
16	Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S and Kolb M: Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 45:1434–1445. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S, Hallmann C and du BoisRM: Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 72:340–346. 2017. View Article : Google Scholar : PubMed/NCBI
18	Zhao YY, Feng JB, Peng J, Meng LH, Zhang HX and Wu ML: Signal mining and post-marketing evaluation of adverse drug reactions of nintedanib. Zhongguo Yiyuan Yaoxue Zazhi. 39:1655–1658. 2019.(In Chinese).
19	Januszyk P, Januszyk K, Wierzbik-Strońsk M, Boroń D and Grabarek B: Analysis of the differences in the expression of mRNAs and miRNAs associated with drug resistance in endometrial cancer cells treated with salinomycin. Curr Pharm Biotechnol. June 29–2020.https://doi.org/10.2174/1389201021666200629151008
20	Lagos-Quintana M, Rauhut R, Lendeckel W and Tuschl T: Identification of novel genes coding for small expressed RNAs. Science. 294:853–858. 2001. View Article : Google Scholar : PubMed/NCBI
21	Ambros V: MicroRNA pathways in flies and worms: Growth, death, fat, stress, and timing. Cell. 113:673–676. 2003. View Article : Google Scholar : PubMed/NCBI
22	Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
23	Wu CL, Ho JY, Hung SH and Yu DS: miR-429 expression in bladder cancer and its correlation with tumor behavior and clinical outcome. Kaohsiung J Med Sci. 34:335–340. 2018. View Article : Google Scholar : PubMed/NCBI
24	Zhang M, Dong BB, Lu M, Zheng MJ, Chen H, Ding JZ, Xu AM and Xu YH: miR-429 functions as a tumor suppressor by targeting FSCN1 in gastric cancer cells. Onco Targets Ther. 9:1123–1133. 2016.PubMed/NCBI
25	Guo C, Zhao D, Zhang Q, Liu S and Sun MZ: miR-429 suppresses tumor migration and invasion by targeting CRKL in hepatocellular carcinoma via inhibiting Raf/MEK/ERK pathway and epithelial-mesenchymal transition. Sci Rep. 8:23752018. View Article : Google Scholar : PubMed/NCBI
26	Wang F, Jiang C, Sun Q, Yan F, Wang L, Fu Z, Liu T and Hu F: Downregulation of miR-429 and inhibition of cell migration and invasion in nasopharyngeal carcinoma. Mol Med Rep. 13:3236–3242. 2016. View Article : Google Scholar : PubMed/NCBI
27	Han Y, Zhao Q, Zhou J and Shi R: miR-429 mediates tumor growth and metastasis in colorectal cancer. Am J Cancer Res. 7:218–233. 2017.PubMed/NCBI
28	Xiao P, Liu W and Zhou H: miR-429 promotes the proliferation of non-small cell lung cancer cells via targeting DLC-1. Oncol Lett. 12:2163–2168. 2016. View Article : Google Scholar : PubMed/NCBI
29	Wang Z, Zhu Z, Lin Z, Luo Y, Liang Z, Zhang C, Chen J and Peng P: miR-429 suppresses cell proliferation, migration and invasion in nasopharyngeal carcinoma by downregulation of TLN1. Cancer Cell Int. 19:1152019. View Article : Google Scholar : PubMed/NCBI
30	Ha J, Kang E, Seo J and Cho S: Phosphorylation dynamics of JNK signaling: Effects of dual-specificity phosphatases (DUSPs) on the JNK pathway. Int J Mol Sci. 20:61572019.doi: 10.3390/ijms20246157. View Article : Google Scholar
31	Chen P, Hutter D, Yang X, Gorospe M, Davis RJ and Liu Y: Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically. J Biol Chem. 276:29440–29449. 2001. View Article : Google Scholar : PubMed/NCBI
32	Muhammad T, Zhang J, Ma Y, Li Y, Zhang F, Zhang Y and Liang Y: Overexpression of a mitogen-activated protein kinase SlMAPK3 positively regulates tomato tolerance to cadmium and drought stress. Molecules. 24:5562019.https://doi.org/10.3390/molecules24030556 View Article : Google Scholar
33	Wagner EF and Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009. View Article : Google Scholar : PubMed/NCBI
34	Raitano AB, Halpern JR, Hambuch TM and Sawyers CL: The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci USA. 92:11746–11750. 1995. View Article : Google Scholar : PubMed/NCBI
35	Siddiqui MA and Reddy PA: Small molecule JNK (c-Jun N-terminal kinase) inhibitors. J Med Chem. 53:3005–3012. 2010. View Article : Google Scholar : PubMed/NCBI
36	Davis RJ: Signal transduction by the JNK group of MAP kinases. Cell. 103:239–252. 2000. View Article : Google Scholar : PubMed/NCBI