Upregulated NTF4 in Colorectal Cancer Promotes Tumor Development Via Regulating Autophagy

Overview

Journal Int J Oncol

Specialty Oncology

Date 2020 Apr 3

PMID 32236587

Citations 9

Authors

Zhou Yang

Yusheng Chen

Xiyi Wei

Dejun Wu

Zhijun Min

Yingjun Quan

Affiliations

Soon will be listed here.

Abstract

Autophagy plays a key role in colorectal cancer (CRC) development and reduces the sensitivity of CRC cells to treatment. The present study reported a novel tumor‑suppressive role for autophagy, which was demonstrated to be regulated through the novel oncogene neurotrophin‑4 (NTF4). NTF4 was significantly overexpressed in tumor tissue compared with non‑tumor mucosa, and the upregulation of NTF4 in CRC was associated with poor overall survival and advanced TNM stage. The genetic knockdown of NTF4 using short hairpin RNA in CRC cells prevented epithelial‑to‑mesenchymal transition and activated autophagy; this was regulated through the interaction between autophagy‑associated gene 5 (Atg5) and the mitogen‑activated protein kinase pathway. In addition, the knockdown of NTF4 inhibited cell invasion, migration, proliferation and colony formation, and promoted cell cycle arrest. Treatment of the cells with the autophagy inhibitor chloroquine (CQ) rescued these functions and promoted cell invasion, migration, proliferation and colony formation. Finally, the knockdown of NTF4 inhibited the growth of subcutaneous xenografts in Balb/c‑nu mice. In conclusion, these findings suggested that NTF4 may be a diagnostic marker associated with the overall survival and progression of patients with CRC. NTF4 was found to promote tumorigenesis and CRC development through autophagy regulation.

Citing Articles

Integration analysis of - and -regulatory long non-coding RNAs associated with immune-related pathways in non-small cell lung cancer.

Liu Y, Yang H, Lv G, Duan J, Zhao W, Shi Y Biochem Biophys Rep. 2024; 40:101832.

PMID: 39539669 PMC: 11558640. DOI: 10.1016/j.bbrep.2024.101832.

Transcriptomic insights into adenoid cystic carcinoma via RNA sequencing.

Tang Y, An P, Gu B, Yi S, Hu X, Wu W Front Genet. 2023; 14:1144945.

PMID: 37152992 PMC: 10160386. DOI: 10.3389/fgene.2023.1144945.

Peroxidase is a novel potential marker in glioblastoma through bioinformatics method and experimental validation.

Shi W, Ding W, Zhao Z, Wang R, Wang F, Tang Y Front Genet. 2022; 13:990344.

PMID: 36118855 PMC: 9471987. DOI: 10.3389/fgene.2022.990344.

The Role of Neurotrophin-4/Forkhead Box L1 in the Development of Nonsmall-Cell Lung Cancer.

Mu L, Zhao H, Zhang Y, Xiao C Contrast Media Mol Imaging. 2022; 2022:9078012.

PMID: 36034210 PMC: 9381233. DOI: 10.1155/2022/9078012.

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy.

Vitto V, Bianchin S, Zolondick A, Pellielo G, Rimessi A, Chianese D Biomedicines. 2022; 10(7).

PMID: 35884904 PMC: 9313210. DOI: 10.3390/biomedicines10071596.

References

Vanhecke E, Adriaenssens E, Verbeke S, Meignan S, Germain E, Berteaux N . Brain-derived neurotrophic factor and neurotrophin-4/5 are expressed in breast cancer and can be targeted to inhibit tumor cell survival. Clin Cancer Res. 2011; 17(7):1741-52. DOI: 10.1158/1078-0432.CCR-10-1890. View

Yang Z, Chen Y, Wu D, Min Z, Quan Y . Analysis of risk factors for colon cancer progression. Onco Targets Ther. 2019; 12:3991-4000. PMC: 6535430. DOI: 10.2147/OTT.S207390. View

Galluzzi L, Baehrecke E, Ballabio A, Boya P, Bravo-San Pedro J, Cecconi F . Molecular definitions of autophagy and related processes. EMBO J. 2017; 36(13):1811-1836. PMC: 5494474. DOI: 10.15252/embj.201796697. View

Ye Y, Yu L, Wang H, Tashiro S, Onodera S, Ikejima T . TNFα-induced necroptosis and autophagy via supression of the p38-NF-κB survival pathway in L929 cells. J Pharmacol Sci. 2011; 117(3):160-9. DOI: 10.1254/jphs.11105fp. View

Zhang H, Tang J, Li C, Kong J, Wang J, Wu Y . MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells. Cancer Lett. 2014; 356(2 Pt B):781-90. DOI: 10.1016/j.canlet.2014.10.029. View

Yatsuoka T, Nishimura Y, Sakamoto H, Tanaka Y, Kurozumi M . [Lymph node metastasis of colorectal cancer with submucosal invasion]. Gan To Kagaku Ryoho. 2014; 40(12):2041-3. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Huang S, Sinicrope F . Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy. 2010; 6(2):256-69. PMC: 2948490. DOI: 10.4161/auto.6.2.11124. View

Ouyang L, Shi Z, Zhao S, Wang F, Zhou T, Liu B . Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 2012; 45(6):487-98. PMC: 6496669. DOI: 10.1111/j.1365-2184.2012.00845.x. View

10.

Shi Y, Huang X, Chen G, Wang Y, Zhi Q, Liu Y . Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells. Oncotarget. 2016; 7(30):48027-48037. PMC: 5216997. DOI: 10.18632/oncotarget.10338. View

11.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

12.

Yang Z, Wu D, Chen Y, Min Z, Quan Y . GRHL2 inhibits colorectal cancer progression and metastasis via oppressing epithelial-mesenchymal transition. Cancer Biol Ther. 2019; 20(9):1195-1205. PMC: 6741563. DOI: 10.1080/15384047.2019.1599664. View

13.

Shinojima N, Yokoyama T, Kondo Y, Kondo S . Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 2007; 3(6):635-7. DOI: 10.4161/auto.4916. View

14.

Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y . Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 2007; 67(20):9677-84. DOI: 10.1158/0008-5472.CAN-07-1462. View

15.

Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H . Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2017; 57(2):193-200. PMC: 5814919. DOI: 10.1002/mc.22746. View

16.

Chandrashekar D, Bashel B, Balasubramanya S, Creighton C, Ponce-Rodriguez I, Chakravarthi B . UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia. 2017; 19(8):649-658. PMC: 5516091. DOI: 10.1016/j.neo.2017.05.002. View

17.

Cunningham D, Atkin W, Lenz H, Lynch H, Minsky B, Nordlinger B . Colorectal cancer. Lancet. 2010; 375(9719):1030-47. DOI: 10.1016/S0140-6736(10)60353-4. View

18.

Morrison C, Parvani J, Schiemann W . The relevance of the TGF-β Paradox to EMT-MET programs. Cancer Lett. 2013; 341(1):30-40. PMC: 3752409. DOI: 10.1016/j.canlet.2013.02.048. View

19.

Lamouille S, Xu J, Derynck R . Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15(3):178-96. PMC: 4240281. DOI: 10.1038/nrm3758. View

20.

Sanchez-Tillo E, Liu Y, de Barrios O, Siles L, Fanlo L, Cuatrecasas M . EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci. 2012; 69(20):3429-56. PMC: 11115078. DOI: 10.1007/s00018-012-1122-2. View