Positive Correlative over-Expression between eIF4E and Snail in Nasopharyngeal Carcinoma Promotes its Metastasis and Resistance to Cisplatin
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EIF4E is the rate-limiting factor in the mRNA translation of specific set of oncogenes. Snail is the core transcription factor of epithelial-mesenchymal transition (EMT), a key step of cancer metastasis. The connection between the two oncoproteins has not been well established in the human cancer tissues and in nasopharyngeal carcinoma (NPC). Here we showed that the positive correlative over-expression was seen between eIF4E and Snail in NPC tissues, and the expression was significantly higher in the metastatic NPC than in the un-metastatic NPC. In NPC cells, eIF4E knockdown significantly reduced Snail mRNA and protein levels, increased the mRNA level of E-cad (a direct downstream gene of Snail and a negative EMT marker), attenuated the invasive ability of the cells, and sensitized the cells to cisplatin in invasion. In contrast, enforced the expression of eIF4E significantly increased Snail mRNA and protein levels, and promoted the invasive ability in NPC cells. Under the condition of the high eIF4E expression, Snail knockdown significantly increased E-cad mRNA level and weaken the invasive ability of NPC cells. Finally, eIF4E directly bound Snail mRNA for translation initiation displayed by the RIP assay. Therefore, the results firstly suggested that eIF4E enhanced the Snail expression in both transcription and translation manner in human cancer tissues and targeting the eIF4E/Snail axis might intervene with the EMT and metastasis of NPC. This finding provided a new clue for further understanding the metastatic mechanism of human cancers and for preventing and treating NPC metastasis.
KeywordseIF4E Snail NPC EMT Invasion Metastasis
This work was funded by the Natural Science Fund of Guangdong Province (2015A030313519), the National Natural Science Fund of China (81572566) and the Science and Technology Planning Project of Guangdong Province (2016A020215146).
Compliance with Ethical Standards
Conflict of Interest
Authors Yunhong Yao, Tianyun Pang, Ying Cheng, Weiwei Yong, Haixian Kang, Yi Zhao, Sen Wang and Xinrong Hu declare that they have no conflict of interest.
- 1.Shair KHY, Reddy A, Cooper VS (2018) New insights from elucidating the role of LMP1 in nasopharyngeal carcinoma. Cancers (Basel) 10(4)Google Scholar
- 4.Zuo LL, Zhang J, Liu LZ, Zhou Q, Du SJ, Xin SY, Ning ZP, Yang J, Yu HB, Yue WX, Wang J, Zhu FX, Li GY, Lu JH (2017) Cadherin 6 is activated by Epstein-Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma. Oncogenesis 6(12):402CrossRefGoogle Scholar
- 5.Brzozowa M, Michalski M, Wyrobiec G, Piecuch A, Dittfeld A, Harabin-Słowińska M, Boroń D, Wojnicz R (2015) The role of Snail1 transcription factor in colorectal cancer progression and metastasis. Contemp Oncol (Pozn) 19(4):265–270Google Scholar
- 10.Ernst BP, Mikstas C, Stöver T, Stauber R, Strieth S (2018) Association of eIF4E and SPARC expression with lymphangiogenesis and lymph node metastasis in hypopharyngeal cancer. Anticancer Res 38(2):699–706Google Scholar
- 16.Wang W, Wen Q, Luo J, Chu S, Chen L, Xu L, Zang H, Alnemah MM, Li J, Zhou J, Fan S (2017) Suppression of β-catenin nuclear translocation by CGP57380 decelerates poor progression and potentiates radiation-induced apoptosis in nasopharyngeal carcinoma. Theranostics 7(7):2134–2149CrossRefGoogle Scholar
- 18.Zheng J, Zhang C, Zhang Y, Pei J, Fan S (2017) Over-expressions of p-eIF4E and p-4EBP1 are associated with poor prognosis in nasopharyngeal carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 33(4):531–535Google Scholar
- 20.Robichaud N, Del Rincon SV, Huor B, Alain T, Petruccelli LA, Hearnden J, Goncalves C, Grotegut S, Spruck CH, Furic L, Larsson O, Muller WJ, Miller WH, Sonenberg N (2015) Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 34(16):2032–2042CrossRefGoogle Scholar
- 21.Smith KA, Zhou B, Avdulov S, Benyumov A, Peterson M, Liu Y, Okon A, Hergert P, Braziunas J, Wagner CR, Borok Z, Bitterman PB (2015) Transforming growth factor-β1 induced epithelial mesenchymal transition is blocked by a chemical antagonist of translation factor eIF4E. Sci Rep 5:18233CrossRefGoogle Scholar
- 25.Tajirika T, Tokumaru Y, Taniguchi K, Sugito N, Matsuhashi N, Futamura M, Yanagihara K, Akao Y, Yoshida K. DEAD-box protein RNA-helicase DDX6 regulates the expression of HER2 and FGFR2 at the post-transcriptional step in gastric cancer cells. Int J Mol Sci. 2018; 19(7). pii: E2005Google Scholar
- 28.Herdy B, Jaramillo M, Svitkin YV, Rosenfeld AB, Kobayashi M, Walsh D, Alain T, Sean P, Robichaud N, Topisirovic I, Furic L, Dowling RJO, Sylvestre A, Rong L, Colina R, Costa-Mattioli M, Fritz JH, Olivier M, Brown E, Mohr I, Sonenberg N (2012) Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nat Immunol 13(6):543–550CrossRefGoogle Scholar
- 32.Zhai D, Cui C, Xie L, Cai L, Yu J (2018) Sterol regulatory element-binding protein 1 cooperates with c-Myc to promote epithelial-mesenchymal transition in colorectal cancer. Oncol Lett 15(4):5959–5965Google Scholar
- 33.Song R, Song H, Liang Y, Yin D, Zhang H, Zheng T, Wang J, Lu Z, Song X, Pei T, Qin Y, Li Y, Xie C, Sun B, Shi H, Li S, Meng X, Yang G, Pan S, Zhu J, Qi S, Jiang H, Zhang Z, Liu L (2014) Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology 60(5):1659–1673CrossRefGoogle Scholar
- 36.Evdokimova V, Tognon C, Ng T, Ruzanov P, Melnyk N, Fink D, Sorokin A, Ovchinnikov LP, Davicioni E, Triche TJ, Sorensen PH (2009) Translational activation of Snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell 15:402–415CrossRefGoogle Scholar