NGX6 expression improves the sensitivity of tamoxifen-resistant MCF-7 cells through modulation of the Smad signaling pathway

Zhao,Wen-Jing; Wang,Ke

doi:10.3892/ijo.2013.1886

NGX6 expression improves the sensitivity of tamoxifen-resistant MCF-7 cells through modulation of the Smad signaling pathway

Authors:
- Wen-Jing Zhao
- Ke Wang
View Affiliations

Affiliations: Department of Ultrasound, Τhe First Affiliated Hospital of China Medical University, Heping District, Shenyang, Liaoning 110001, P.R. China, Department of Cardiac Surgery, Shengjing Hospital of China Medical University, Heping District, Shenyang, Liaoning 110004, P.R. China
Published online on: April 8, 2013 https://doi.org/10.3892/ijo.2013.1886
Pages: 2060-2068

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

The effects of nasopharyngeal carcinoma-associated gene 6 (NGX6) in breast cancer was studied. We demonstrated that the levels of the NGX6 protein and mRNA were lower in patients with tamoxifen-resistant tumors compared to patients with tamoxifen-sensitive tumors. Tamoxifen was able to decrease proliferation, increase apoptosis and induce G1 arrest in NGX6-expressing TRM-7 cells in vitro. In order to detect the mechanism(s) of tamoxifen action, we first obtain the three-dimensional structure of the NGX6 protein by using Protein Homology/analogY Recognition Engine (PHYRE). Prediction of the docking between the NGX6 protein and tamoxifen was performed using SYBYL-X 1.3. Furthermore, we found that tamoxifen activated Smad2/3, and increased the expression of Smad4 in NGX6-expressing TRM-7 cells as evaluated by western blot analysis. Smad2/3-targeted siRNA was used to confirm the mechanism(s) of tamoxifen action in NGX6-expressing cells. These results indicated that NGX6 may increase the sensitivity of breast cancer cells to tamoxifen.

View Figures

View References

1	Zainuddin N, Jaafart H, Isa MN, et al: Loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in malays with malignant glioma. Neurol Res. 26:88–92. 2004. View Article : Google Scholar : PubMed/NCBI
2	Nishisaka T, Takeshima Y and Inai K: Evaluation of p53 gene mutation and loss of heterozygosity of 3p, 9p and 17p in precancerous lesions of 29 lung cancer patients. Hiroshima J Med Sci. 49:109–116. 2000.PubMed/NCBI
3	Wistuba II, Behrens C, Milchgrub S, et al: Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene. 18:643–650. 1999. View Article : Google Scholar : PubMed/NCBI
4	Perinchery G, Bukurov N, Nakajima K, et al: High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer. Int J Cancer. 83:610–614. 1999. View Article : Google Scholar : PubMed/NCBI
5	Partridge M, Emilion G, Pateromichelakis S, et al: Location of candidate tumour suppressor gene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. Int J Cancer. 83:318–325. 1999. View Article : Google Scholar : PubMed/NCBI
6	Calin GA, Dumitru CD, Shimizu M, et al: Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 99:15524–15529. 2002. View Article : Google Scholar : PubMed/NCBI
7	Peng S, Fan S, Li X, et al: The expression of ezrin in NPC and its interaction with NGX6, a novel candidate suppressor. Cancer Sci. 8:341–349. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ma J, Zhou J, Fan S, et al: Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion modulation in nasopharyngeal carcinoma cells. Carcinogenesis. 26:281–291. 2005. View Article : Google Scholar : PubMed/NCBI
9	Wang L, Ma J, Li J, et al: NGX6 gene inhibits cell proliferation and plays a negative role in EGFR pathway in nasopharyngeal carcinoma cells. J Cell Biochem. 95:64–73. 2005. View Article : Google Scholar : PubMed/NCBI
10	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 6:69–90. 2011. View Article : Google Scholar
11	Xiong J, Yu D, Wei N, et al: An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples. FEBS J. 277:1684–1694. 2010. View Article : Google Scholar
12	Hu Y, Fan L, Zheng J, et al: Detection of circulating tumor cells in breast cancer patients utilizing multiparameter flow cytometry and assessment of the prognosis of patients in different CTCs levels. Cytometry A. 77:213–219. 2010. View Article : Google Scholar : PubMed/NCBI
13	Zhou FF, Xia LP, Wang X, et al: Analysis of prognostic factors in male breast cancer: a report of 72 cases from a single institution. Chin J Cancer. 29:184–188. 2010. View Article : Google Scholar : PubMed/NCBI
14	Arpino G, De Angelis C, Giuliano M, et al: Molecular mechanism and clinical implications of endocrine therapy resistance in breast cancer. Oncology. 77(Suppl 1): 23–37. 2009. View Article : Google Scholar : PubMed/NCBI
15	Henry NL and Hayes DF: Can biology trump anatomy? Do all node-positive patients with breast cancer need chemotherapy? J Clin Oncol. 25:2501–2503. 2007. View Article : Google Scholar : PubMed/NCBI
16	Jaiyesimi IA, Buzdar AU, Decker DA, et al: Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 13:513–529. 1995.PubMed/NCBI
17	Kim MR, Choi HK, Cho KB, et al: Involvement of Pin1 induction in epithelial-mesenchymal transition of tamoxifen-resistant breast cancer cells. Cancer Sci. 100:1834–1841. 2009. View Article : Google Scholar : PubMed/NCBI
18	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.
19	Markaryan A, Nelson EG, Tretiakova M, et al: Technical report: immunofluorescence and TUNEL staining of celloidin embedded human temporal bone tissues. Hear Res. 241:1–6. 2008. View Article : Google Scholar : PubMed/NCBI
20	Hurst PR, Mora JM and Fenwick MA: Caspase-3, TUNEL and ultrastructural studies of small follicles in adult human ovarian biopsies. Hum Reprod. 21:1974–1980. 2006. View Article : Google Scholar : PubMed/NCBI
21	Bennett-Lovsey RM, Herbert AD, Sternberg MJ, et al: Exploring the extremes of sequence/structure space with ensemble fold recognition in the program Phyre. Proteins. 70:611–625. 2008. View Article : Google Scholar : PubMed/NCBI
22	Kelley LA and Sternberg MJ: Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc. 4:363–371. 2009. View Article : Google Scholar : PubMed/NCBI
23	Martí-Renom MA, Stuart AC, Fiser A, et al: Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct. 29:291–325. 2000.
24	Szklarczyk D, Franceschini A, Kuhn M, et al: The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 39(Database issue): D561–D568. 2011. View Article : Google Scholar : PubMed/NCBI
25	D’Arcangelo G, Miao GG, Chen SC, et al: A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature. 374:719–723. 1995.
26	Wang L, Xiang B, Yi M, et al: Identification of a new seven-span transmembrane protein: NGX6a is downregulated in nasopharyngeal carcinoma and is associated with tumor metastasis. J Histochem Cytochem. 58:41–51. 2010. View Article : Google Scholar : PubMed/NCBI
27	Guo Q, Shen S, Liao M, et al: NGX6 inhibits cell invasion and adhesion through suppression of Wnt/betacatenin signal pathway in colon cancer. Acta Biochim Biophys Sin. 42:450–456. 2010. View Article : Google Scholar : PubMed/NCBI
28	Xiao JD and Shen SR: Expression and significance of NGX6 gene in human hepatocellular carcinoma. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 33:937–941. 2008.PubMed/NCBI
29	Eskandari-Nasab E, Hashemi M, Rezaei H, et al: Evaluation of UDP-glucuronosyltransferase 2B17 (UGT2B17) and dihydrofolate reductase (DHFR) genes deletion and the expression level of NGX6 mRNA in breast cancer. Mol Biol Rep. 39:10531–10539. 2012. View Article : Google Scholar : PubMed/NCBI
30	Wang XY, Wu MH, Liu F, et al: Differential miRNA expression and their target genes between NGX6-positive and negative colon cancer cells. Mol Cell Biochem. 345:283–290. 2010. View Article : Google Scholar : PubMed/NCBI
31	Guo Q, Wu M, Lian P, et al: Synergistic effect of indomethacin and NGX6 on proliferation and invasion by human colorectal cancer cells through modulation of the Wnt/beta-catenin signaling pathway. Mol Cell Biochem. 330:71–81. 2009. View Article : Google Scholar : PubMed/NCBI
32	Peng Y, Li H, Wu M, et al: NGX6 inhibits AP-1 and Ets-1 expression and down-regulates cyclin D1 in human colorectal cancer. Acta Biochim Biophys Sin. 41:504–514. 2009. View Article : Google Scholar : PubMed/NCBI
33	Schmierer B and Hill CS: TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 8:970–982. 2007. View Article : Google Scholar : PubMed/NCBI
34	Jacob D, Davis J, Zhu H, et al: Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter. Clin Cancer Res. 10:3535–3541. 2004. View Article : Google Scholar