Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma Corrigendum in /10.3892/or.2023.8581

Dai,Meng-Yuan; Fang,Fang; Zou,You; Yi,Xing; Ding,Yong-Jun; Chen,Chen; Tao,Ze-Zhang; Chen,Shi-Ming

doi:10.3892/or.2015.4274

Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma

Corrigendum in: /10.3892/or.2023.8581

Authors:
- Meng-Yuan Dai
- Fang Fang
- You Zou
- Xing Yi
- Yong-Jun Ding
- Chen Chen
- Ze-Zhang Tao
- Shi-Ming Chen
View Affiliations

Affiliations: Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P.R. China, Department of Medical Market, Renmin Hospital of Wuhan University, Wuhan 430060, P.R. China
Published online on: September 15, 2015 https://doi.org/10.3892/or.2015.4274
Pages: 3111-3119

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

Notch signaling plays a key role in a wide variety of human tumors; it can be an oncogene or a tumor-suppressor gene depending on the tissue context. The functions of Notch1 in laryngeal squamous cell carcinoma (LSCC) are largely unknown. We investigated the role of Notch1 in LSCC cell growth, apoptosis and metastasis. We analyzed Notch1 expression in clinical LSCC samples using quantum dot immunohistochemistry (QD-IHC) and conventional IHC. Human laryngeal carcinoma HEp-2 cells were transfected with Notch1-specific short hairpin RNA (shRNA), and cell proliferation, apoptosis, and migration and invasion were evaluated using the cell counting assay, flow cytometry and wound healing and Transwell assays, respectively; western blotting was used to validate the expression of Notch1 target genes. Compared with normal tissues, Notch1 was upregulated in LSCC tissues; compared with LSCC tissues without metastasis, Notch1 upregulation was enhanced in LSCC tissues with metastasis (P<0.05). Transfection downregulated Notch1 mRNA and protein expression levels in the Notch1 shRNA group. There was a significantly greater decrease in cell proliferation in the Notch1 shRNA group than cell proliferation in the non-transfected (P<0.05) and negative shRNA groups (P<0.05). Furthermore, Notch1 knockdown induced apoptosis in the HEp-2 cells. Additionally, the number of migrated and invasive cells in the Notch1 shRNA group was decreased (P<0.05). Notch1 knockdown in the HEp-2 cells greatly inhibited phosphorylated extracellular signal-related kinase (p-ERK), phosphorylated protein kinase B (p-AKT), c-Myc, Bcl-2, p21, cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin E expression levels and increased Bax expression. Altogether, our findings indicate that Notch1 expression is increased in human LSCC and correlates with tumorigenesis and metastasis, while in HEp-2 cells, Notch1 knockdown inhibited cell growth, induced apoptosis and inhibited migration and invasion by regulating Notch1 target genes, suggesting it may be a potential therapeutic target for treating LSCC.

View Figures

View References

1	Liu M, Wu H, Liu T, Li Y, Wang F, Wan H, Li X and Tang H: Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma. Cell Res. 19:828–837. 2009. View Article : Google Scholar : PubMed/NCBI
2	Zhu M, Yin F, Yang L, Chen S, Chen R, Zhou X, Jing W, Fan X, Jia R, Wang H, et al: Contribution of TIP30 to chemoresistance in laryngeal carcinoma. Cell Death Dis. 5:e14682014. View Article : Google Scholar : PubMed/NCBI
3	Capaccione KM and Pine SR: The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 34:1420–1430. 2013. View Article : Google Scholar : PubMed/NCBI
4	Ntziachristos P, Lim JS, Sage J and Aifantis I: From fly wings to targeted cancer therapies: A centennial for notch signaling. Cancer Cell. 25:318–334. 2014. View Article : Google Scholar : PubMed/NCBI
5	Su BH, Qu J, Song M, Huang XY, Hu XM, Xie J, Zhao Y, Ding LC, She L, Chen J, et al: NOTCH1 signaling contributes to cell growth, anti-apoptosis and metastasis in salivary adenoid cystic carcinoma. Oncotarget. 5:6885–6895. 2014. View Article : Google Scholar : PubMed/NCBI
6	Yu H, Zhao X, Huang S, Jian L, Qian G and Ge S: Blocking Notch1 signaling by RNA interference can induce growth inhibition in HeLa cells. Int J Gynecol Cancer. 17:511–516. 2007. View Article : Google Scholar : PubMed/NCBI
7	Wang L, Qin H, Chen B, Xin X, Li J and Han H: Overexpressed active Notch1 induces cell growth arrest of HeLa cervical carcinoma cells. Int J Gynecol Cancer. 17:1283–1292. 2007. View Article : Google Scholar : PubMed/NCBI
8	Zheng Q, Qin H, Zhang H, Li J, Hou L, Wang H, Zhang X, Zhang S, Feng L, Liang Y, et al: Notch signaling inhibits growth of the human lung adenocarcinoma cell line A549. Oncol Rep. 17:847–852. 2007.PubMed/NCBI
9	Ji X, Wang Z, Geamanu A, Sarkar FH and Gupta SV: Inhibition of cell growth and induction of apoptosis in non-small cell lung cancer cells by delta-tocotrienol is associated with notch-1 down-regulation. J Cell Biochem. 112:2773–2783. 2011. View Article : Google Scholar : PubMed/NCBI
10	Ito T, Udaka N, Okudela K, Yazawa T and Kitamura H: Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma. Endocr Pathol. 14:133–139. 2003. View Article : Google Scholar : PubMed/NCBI
11	Kunnimalaiyaan M and Chen H: Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist. 12:535–542. 2007. View Article : Google Scholar : PubMed/NCBI
12	Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J and Wang CY: Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 8:13–23. 2005. View Article : Google Scholar : PubMed/NCBI
13	Leethanakul C, Patel V, Gillespie J, Pallente M, Ensley JF, Koontongkaew S, Liotta LA, Emmert-Buck M and Gutkind JS: Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays. Oncogene. 19:3220–3224. 2000. View Article : Google Scholar : PubMed/NCBI
14	Hijioka H, Setoguchi T, Miyawaki A, Gao H, Ishida T, Komiya S and Nakamura N: Upregulation of Notch pathway molecules in oral squamous cell carcinoma. Int J Oncol. 36:817–822. 2010.PubMed/NCBI
15	Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, et al: Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 333:1154–1157. 2011. View Article : Google Scholar : PubMed/NCBI
16	Schacht V and Kern JS: Basics of immunohistochemistry. J Invest Dermatol. 135:e302015. View Article : Google Scholar : PubMed/NCBI
17	Yap L, Lee D, Khairuddin A, Pairan M, Puspita B, Siar C and Paterson I: The opposing roles of NOTCH signalling in head and neck cancer: A mini review. Oral Dis. Jan 7–2015.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
18	Sun W, Gaykalova DA, Ochs MF, Mambo E, Arnaoutakis D, Liu Y, Loyo M, Agrawal N, Howard J, Li R, et al: Activation of the NOTCH pathway in head and neck cancer. Cancer Res. 74:1091–1104. 2014. View Article : Google Scholar :
19	Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR and Carbone DP: Chromosome 19 trans-location, overexpression of Notch3, and human lung cancer. J Natl Cancer Inst. 92:1355–1357. 2000. View Article : Google Scholar : PubMed/NCBI
20	Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ and Powell MB: Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest. 118:3660–3670. 2008. View Article : Google Scholar : PubMed/NCBI
21	Sun JZ, Chen C, Jiang G, Tian WQ, Li Y and Sun SR: Quantum dot-based immunofluorescent imaging of Ki67 and identification of prognostic value in HER2-positive (non-luminal) breast cancer. Int J Nanomed. 9:1339–1346. 2014. View Article : Google Scholar
22	Abdel Aziz MT, Khaled HM, El Hindawi A, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, Taha F and Ali WI: Effect of mesenchymal stem cells and a novel curcumin derivative on Notch1 signaling in hepatoma cell line. Biomed Res Int. 2013:1296292013. View Article : Google Scholar : PubMed/NCBI
23	Moriyama M, Osawa M, Mak SS, Ohtsuka T, Yamamoto N, Han H, Delmas V, Kageyama R, Beermann F, Larue L, et al: Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol. 173:333–339. 2006. View Article : Google Scholar : PubMed/NCBI
24	Li Y, Takeshita K, Liu PY, Satoh M, Oyama N, Mukai Y, Chin MT, Krebs L, Kotlikoff MI, Radtke F, et al: Smooth muscle Notch1 mediates neointimal formation after vascular injury. Circulation. 119:2686–2692. 2009. View Article : Google Scholar : PubMed/NCBI
25	Czabotar PE, Lessene G, Strasser A and Adams JM: Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat Rev Mol Cell Biol. 15:49–63. 2014. View Article : Google Scholar
26	Cory S and Adams JM: Killing cancer cells by flipping the Bcl-2/Bax switch. Cancer Cell. 8:5–6. 2005. View Article : Google Scholar : PubMed/NCBI
27	Pelengaris S and Khan M: The many faces of c-MYC. Arch Biochem Biophys. 416:129–136. 2003. View Article : Google Scholar : PubMed/NCBI
28	Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB and Ball DW: Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 61:3200–3205. 2001.PubMed/NCBI
29	Li X, He X, Tian W and Wang J: Short hairpin RNA targeting Notch2 inhibits U87 human glioma cell proliferation by inducing cell cycle arrest and apoptosis in vitro and in vivo. Mol Med Rep. 10:2843–2850. 2014.PubMed/NCBI
30	Luo DH, Zhou Q, Hu SK, Xia YQ, Xu CC, Lin TS, Pan YT, Wu JS and Jin R: Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer. Oncol Lett. 7:471–478. 2014.PubMed/NCBI
31	Zhou L, Zhang N, Song W, You N, Li Q, Sun W, Zhang Y, Wang D and Dou K: The significance of Notch1 compared with Notch3 in high metastasis and poor overall survival in hepatocel-lular carcinoma. PLoS One. 8:e573822013. View Article : Google Scholar