Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy

Yang,Zhou; Chen,Yusheng; Wei,Xiyi; Wu,Dejun; Min,Zhijun; Quan,Yingjun

doi:10.3892/ijo.2020.5027

Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy

Authors:
- Zhou Yang
- Yusheng Chen
- Xiyi Wei
- Dejun Wu
- Zhijun Min
- Yingjun Quan
View Affiliations

Affiliations: Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China, First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: March 26, 2020 https://doi.org/10.3892/ijo.2020.5027
Pages: 1442-1454
Copyright: © Yang 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

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.

View Figures

View References

1	Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B and Starling N: Colorectal cancer. Lancet. 375:1030–1047. 2010. View Article : Google Scholar : PubMed/NCBI
2	Long AG, Lundsmith ET and Hamilton KE: Inflammation and colorectal Cancer. Curr Colorectal Cancer Rep. 13:341–351. 2017. View Article : Google Scholar : PubMed/NCBI
3	Yatsuoka T, Nishimura Y, Sakamoto H, Tanaka Y and Kurozumi M: Lymph node metastasis of colorectal cancer with submucosal invasion. Gan To Kagaku Ryoho. 40:2041–2043. 2013.In Japanese.
4	Shi Y, Huang XX, Chen GB, Wang Y, Zhi Q, Liu YS, Wu XL, Wang LF, Yang B, Xiao CX, et al: Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells. Oncotarget. 7:48027–48037. 2016. View Article : Google Scholar : PubMed/NCBI
5	Minichiello L, Casagranda F, Tatche RS, Stucky CL, Postigo A, Lewin GR, Davies AM and Klein R: Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. Neuron. 21:335–345. 1998. View Article : Google Scholar : PubMed/NCBI
6	Shen Y, Inoue N and Heese K: Neurotrophin-4 (ntf4) mediates neurogenesis in mouse embryonic neural stem cells through the inhibition of the signal transducer and activator of transcription-3 (stat3) and the modulation of the activity of protein kinase B. Cell Mol Neurobiol. 30:909–916. 2010. View Article : Google Scholar : PubMed/NCBI
7	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
8	Morrison CD, Parvani JG and Schiemann WP: The relevance of the TGF-β Paradox to EMT-MET programs. Cancer Lett. 341:30–40. 2013. View Article : Google Scholar : PubMed/NCBI
9	Sánchez-Tilló E, Liu Y, de Barrios O, Siles L, Fanlo L, Cuatrecasas M, Darling DS, Dean DC, Castells A and Postigo A: EMT-activating transcription factors in cancer: Beyond EMT and tumor invasiveness. Cell Mol Life Sci. 69:3429–3456. 2012. View Article : Google Scholar : PubMed/NCBI
10	Yang Z, Wu D, Chen Y, Min Z and Quan Y: GRHL2 inhibits colorectal cancer progression and metastasis via oppressing epithelial-mesenchymal transition. Cancer Biol Ther. 20:1195–1205. 2019. View Article : Google Scholar : PubMed/NCBI
11	Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, et al: Molecular definitions of autophagy and related processes. Embo J. 36:1811–1836. 2017. View Article : Google Scholar : PubMed/NCBI
12	Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B and Bao JK: Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45:487–498. 2012. View Article : Google Scholar : PubMed/NCBI
13	Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, Ueno T, Ochiai A and Esumi H: Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 67:9677–9684. 2007. View Article : Google Scholar : PubMed/NCBI
14	Huang S and Sinicrope FA: Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy. 6:256–269. 2010. View Article : Google Scholar : PubMed/NCBI
15	Zhang H, Tang J, Li C, Kong J, Wang J, Wu Y, Xu E and Lai M: MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells. Cancer Lett. 356:781–790. 2015. View Article : Google Scholar
16	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
17	Yang Z, Yu W, Huang R, Ye M and Min Z: SIRT6/HIF-1α axis promotes papillary thyroid cancer progression by inducing epithelial-mesenchymal transition. Cancer Cell Int. 19:172019. View Article : Google Scholar
18	Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45:W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI
19	Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK and Varambally S: UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 19:649–658. 2017. View Article : Google Scholar : PubMed/NCBI
20	Vanhecke E, Adriaenssens E, Verbeke S, Meignan S, Germain E, Berteaux N, Nurcombe V, Le Bourhis X and Hondermarck H: 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. 17:1741–1752. 2011. View Article : Google Scholar : PubMed/NCBI
21	Yang Z, Chen Y, Wu D, Min Z and Quan Y: Analysis of risk factors for colon cancer progression. Onco Targets Ther. 12:3991–4000. 2019. View Article : Google Scholar : PubMed/NCBI
22	Zhao W, Shi F, Guo Z, Zhao J, Song X and Yang H: Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 57:193–200. 2018. View Article : Google Scholar :
23	Wang H, Wang Y, Qian L, Wang X, Gu H, Dong X, Huang S, Jin M, Ge H, Xu C and Zhang Y: RNF216 contributes to proliferation and migration of colorectal cancer via suppressing BECN1-dependent autophagy. Oncotarget. 7:51174–51183. 2016.PubMed/NCBI
24	Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T and Simon HU: Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol. 8:1124–1132. 2006. View Article : Google Scholar : PubMed/NCBI
25	Shinojima N, Yokoyama T, Kondo Y and Kondo S: Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 3:635–637. 2007. View Article : Google Scholar : PubMed/NCBI
26	Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, White M, Reichelt J and Levine B: Akt-mediated regulation of autophagy and tumorigenesis through beclin 1 phosphorylation. Science. 338:956–959. 2012. View Article : Google Scholar : PubMed/NCBI
27	Cui Q, Tashiro S, Onodera S, Minami M and Ikejima T: Oridonin induced autophagy in human cervical carcinoma hela cells through ras, JNK, and P38 regulation. J Pharmacol Sci. 105:317–325. 2007. View Article : Google Scholar : PubMed/NCBI
28	Ye YC, Yu L, Wang HJ, Tashiro S, Onodera S and Ikejima T: TNFα-induced necroptosis and autophagy via supression of the p38-NF-κB survival pathway in L929 ells. J Pharmacol Sci. 117:160–169. 2011. View Article : Google Scholar
29	Lee B, Kim CH and Moon SK: Honokiol causes the p21WAF1-mediated G(1)-phase arrest of the cell cycle through inducing p38 mitogen activated protein kinase in vascular smooth muscle cells. FEBS Lett. 580:5177–5184. 2006. View Article : Google Scholar : PubMed/NCBI