CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma

Suzuki,Shigemasa; Yokobori,Takehiko; Tanaka,Naritaka; Sakai,Makoto; Sano,Akihiko; Inose,Takanori; Sohda,Makoto; Nakajima,Masanobu; Miyazaki,Tatsuya; Kato,Hiroyuki; Kuwano,Hiroyuki

doi:10.3892/or.2012.1831

CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma

Authors:
- Shigemasa Suzuki
- Takehiko Yokobori
- Naritaka Tanaka
- Makoto Sakai
- Akihiko Sano
- Takanori Inose
- Makoto Sohda
- Masanobu Nakajima
- Tatsuya Miyazaki
- Hiroyuki Kato
- Hiroyuki Kuwano
View Affiliations

Affiliations: Department of General Surgical Science, Gunma University, Graduate School of Medicine, Gunma 371-8511, Japan, Department of Surgical Oncology, Dokkyo Medical University, Tochigi 321-0293, Japan
Published online on: May 24, 2012 https://doi.org/10.3892/or.2012.1831
Pages: 465-472

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

CD47 inhibits phagocytosis and its overexpression is correlated with poor prognosis in patients with several types of cancer. It has also been reported that CD47 expression in multiple sclerosis is regulated by microRNAs. However, the regulatory mechanism of CD47 in cancer tissues has not been yet clarified. Re-analysis of a public microarray database revealed that miR-133a is downregulated in esophageal squamous cell carcinoma (ESCC). Moreover, in silico algorithms predicted that miR-133a is a regulator of CD47. The purpose of this study was to clarify the clinical significance of CD47 and its regulatory mechanism by miR-133a in ESCC. Quantitative real-time RT-PCR was used to evaluate CD47 and miR-133a expression in 102 cases of curative resected ESCC and adjacent non-cancerous tissue. The regulation of CD47 by miR-133a was examined with precursor miR-133a-transfected cells. A mouse xenograft model was used to investigate the ability of miR-133a to suppress tumor progression. High expression levels of CD47 were associated with lymph node metastasis (P=0.049). Multivariate analysis showed that CD47 expression was an independent prognostic factor (P=0.045). miR-133a expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P<0.001). In vitro assays showed that miR-133a is a direct regulator of CD47. miR‑133a significantly inhibited tumorigenesis and growth in vivo. CD47 expression is a novel prognostic marker in ESCC that is directly inhibited by the miR-133a tumor suppressor. This correlation could provide new insight into the mechanism of cancer progression and a promising candidate for target therapy in ESCC.

View Figures

View References

1	Enzinger PC and Mayer RJ: Esophageal cancer. N Engl J Med. 349:2241–2252. 2003. View Article : Google Scholar : PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
3	Malthaner RA, Wong RK, Rumble RB and Zuraw L: Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis. BMC Med. 2:352004. View Article : Google Scholar : PubMed/NCBI
4	Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J and Simes J: Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 8:226–234. 2007. View Article : Google Scholar : PubMed/NCBI
5	Tepper J, Krasna MJ, Niedzwiecki D, et al: Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 26:1086–1092. 2008. View Article : Google Scholar : PubMed/NCBI
6	Shinohara M, Ohyama N, Murata Y, et al: CD47 regulation of epithelial cell spreading and migration, and its signal transduction. Cancer Sci. 97:889–895. 2006. View Article : Google Scholar : PubMed/NCBI
7	Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD and Lindberg FP: Role of CD47 as a marker of self on red blood cells. Science. 288:2051–2054. 2000. View Article : Google Scholar : PubMed/NCBI
8	Okazawa H, Motegi S, Ohyama N, et al: Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. J Immunol. 174:2004–2011. 2005. View Article : Google Scholar : PubMed/NCBI
9	van den Berg TK and van der Schoot CE: Innate immune ‘self’ recognition: a role for CD47-SIRPalpha interactions in hematopoietic stem cell transplantation. Trends Immunol. 29:203–206. 2008.
10	Oldenborg PA, Gresham HD, Chen Y, Izui S and Lindberg FP: Lethal autoimmune hemolytic anemia in CD47-deficient nonobese diabetic (NOD) mice. Blood. 99:3500–3504. 2002. View Article : Google Scholar : PubMed/NCBI
11	Jaiswal S, Chao MP, Majeti R and Weissman IL: Macrophages as mediators of tumor immunosurveillance. Trends Immunol. 31:212–219. 2010. View Article : Google Scholar : PubMed/NCBI
12	Majeti R, Chao MP, Alizadeh AA, et al: CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 138:286–299. 2009. View Article : Google Scholar : PubMed/NCBI
13	Chao MP, Alizadeh AA, Tang C, et al: Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 71:1374–1384. 2011. View Article : Google Scholar : PubMed/NCBI
14	Nagahara M, Mimori K, Kataoka A, et al: Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clin Cancer Res. 16:4625–4635. 2010. View Article : Google Scholar : PubMed/NCBI
15	Junker A, Krumbholz M, Eisele S, et al: MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain. 132:3342–3352. 2009. View Article : Google Scholar : PubMed/NCBI
16	Valencia-Sanchez MA, Liu J, Hannon GJ and Parker R: Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20:515–524. 2006. View Article : Google Scholar : PubMed/NCBI
17	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
18	Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
19	Lu J, Getz G, Miska EA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
20	Volinia S, Calin GA, Liu CG, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
21	Guo Y, Chen Z, Zhang L, et al: Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res. 68:26–33. 2008. View Article : Google Scholar : PubMed/NCBI
22	Childs G, Fazzari M, Kung G, et al: Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol. 174:736–745. 2009. View Article : Google Scholar : PubMed/NCBI
23	Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP and Wei WI: Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res. 14:2588–2592. 2008. View Article : Google Scholar : PubMed/NCBI
24	Nohata N, Hanazawa T, Kikkawa N, et al: Caveolin-1 mediates tumor cell migration and invasion and its regulation by miR-133a in head and neck squamous cell carcinoma. Int J Oncol. 38:209–217. 2011.PubMed/NCBI
25	Chiyomaru T, Enokida H, Tatarano S, et al: miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer. 102:883–891. 2010. View Article : Google Scholar : PubMed/NCBI
26	Song T, Xia W, Shao N, et al: Differential miRNA expression profiles in bladder urothelial carcinomas. Asian Pac J Cancer Prev. 11:905–911. 2010.PubMed/NCBI
27	Bandres E, Cubedo E, Agirre X, et al: Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 5:292006. View Article : Google Scholar : PubMed/NCBI
28	Missiaglia E, Shepherd CJ, Patel S, et al: MicroRNA-206 expression levels correlate with clinical behaviour of rhabdomyosarcomas. Br J Cancer. 102:1769–1777. 2010. View Article : Google Scholar : PubMed/NCBI
29	Rao PK, Missiaglia E, Shields L, et al: Distinct roles for miR-1 and miR-133a in the proliferation and differentiation of rhabdomyosarcoma cells. FASEB J. 24:3427–3437. 2010. View Article : Google Scholar : PubMed/NCBI
30	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
31	Kano M, Seki N, Kikkawa N, et al: miR-145, miR-133a and miR-133b: Tumor suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 127:2804–2814. 2010. View Article : Google Scholar : PubMed/NCBI
32	Hashimoto Y, Ito T, Inoue H, et al: Prognostic significance of fascin overexpression in human esophageal squamous cell carcinoma. Clin Cancer Res. 11:2597–2605. 2005. View Article : Google Scholar : PubMed/NCBI
33	Wang H, Madariaga ML, Wang S, Van Rooijen N, Oldenborg PA and Yang YG: Lack of CD47 on non-hematopoietic cells induces split macrophage tolerance to CD47null cells. Proc Natl Acad Sci USA. 104:13744–13749. 2007. View Article : Google Scholar : PubMed/NCBI
34	Kuwano H, Nakajima M, Miyazaki T and Kato H: Distinctive clinicopathological characteristics in esophageal squamous cell carcinoma. Ann Thorac Cardiovasc Surg. 9:6–13. 2003.PubMed/NCBI
35	Nagata H, Arai T, Soejima Y, Suzuki H, Ishii H and Hibi T: Limited capability of regional lymph nodes to eradicate metastatic cancer cells. Cancer Res. 64:8239–8248. 2004. View Article : Google Scholar : PubMed/NCBI
36	Asano K, Nabeyama A, Miyake Y, et al: CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 34:85–95. 2011. View Article : Google Scholar : PubMed/NCBI
37	Soifer HS, Rossi JJ and Saetrom P: MicroRNAs in disease and potential therapeutic applications. Mol Ther. 15:2070–2079. 2007. View Article : Google Scholar : PubMed/NCBI
38	Elmen J, Lindow M, Schutz S, Lawrence M, et al: LNA-mediated microRNA silencing in non-human primates. Nature. 452:896–899. 2008. View Article : Google Scholar : PubMed/NCBI
39	Silvestri P, Di Russo C, Rigattieri S, et al: MicroRNAs and ischemic heart disease: towards a better comprehension of pathogenesis, new diagnostic tools and new therapeutic targets. Recent Pat Cardiovasc Drug Discov. 4:109–118. 2009. View Article : Google Scholar : PubMed/NCBI
40	Chan KS, Espinosa I, Chao M, et al: Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci USA. 106:14016–14021. 2009. View Article : Google Scholar
41	Chao MP, Alizadeh AA, Tang C, et al: Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 142:699–713. 2010. View Article : Google Scholar : PubMed/NCBI
42	Chao MP, Alizadeh AA, Tang C, et al: Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 71:1374–1384. 2010. View Article : Google Scholar : PubMed/NCBI