Production of interleukin‑4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth Retraction in /10.3892/mmr.2016.5732

Liu,Chun‑Tao; Xin,Ying; Tong,Chun‑Yan; Li,Bing; Bao,Hong‑Li; Zhang,Cai‑Yun; Wang,Xue‑Hui

doi:10.3892/mmr.2016.5195

Production of interleukin‑4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth

Retraction in: /10.3892/mmr.2016.5732

Authors:
- Chun‑Tao Liu
- Ying Xin
- Chun‑Yan Tong
- Bing Li
- Hong‑Li Bao
- Cai‑Yun Zhang
- Xue‑Hui Wang
View Affiliations

Affiliations: Department of Gynecology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
Published online on: April 27, 2016 https://doi.org/10.3892/mmr.2016.5195
Pages: 5068-5076
Copyright: © Liu 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

The cancer stem cell (CSC) theory suggests that cancer growth and invasion is dictated by the small population of CSCs within the heterogenous tumor. The aim of the present study was to elucidate the cause for chemotherapy failure and the resistance of CSCs to apoptosis. A total of ~2.3% cluster of differentiation (CD)133+ cancer stem‑like side population (SP) cells were identified in cases of uterine cervical cancer. These CD133+ SP cells were found to potently initiate tumor growth and invasion, as they exhibit transcriptional upregulation of stemness genes, including octamer‑binding transcription factor‑4, B‑cell‑specific Moloney murine leukemia virus insertion site‑1, epithelial cell adhesion molecule, (sex determining region Y)‑box 2, Nestin and anti‑apoptotic B cell lymphoma‑2. In addition, the CD133+ SP cells showed resistance to multi‑drug treatment and apoptosis. The present study further showed that the secretion of interleukin‑4 (IL‑4) in CD133+ cervical cancer SP cells promoted cell proliferation and prevented the SP cells from apoptosis. Following the neutralization of IL‑4 with anti‑IL‑4 antibody, the CD133+ SP cells were more sensitive to drug treatment and apoptosis. Therefore, the data obtained in the present study suggested that the autocrine secretion of IL‑4 promotes increased survival and resistance to cell death in CSCs.

View Figures

View References

1	Ponten J, Adami HO, Bergström R, Dillner J, Friberg LG, Guftafsson L, Miller AB, Parkin DM, Sparén P and Trichopoulos D: Strategies for global control of cervical cancer. Int J Cancer. 60:1–26. 1995. View Article : Google Scholar : PubMed/NCBI
2	Nair P, Nair MK, Jayaprakash PG and Pillai MR: Decreased programmed cell death in the uterine cervix associated with high risk human papilloma virus infection. Pathol Oncol Res. 5:95–103. 1999. View Article : Google Scholar
3	Madrigal M, Janicek MF, Sevin BU, Perras J, Estape R, Peñalver M and Averette HE: In vitro antigene therapy targeting HPV-16 E6 and E7 in cervical carcinoma. Gynecol Oncol. 64:18–25. 1997. View Article : Google Scholar : PubMed/NCBI
4	Harley BC and Sherwood WS: Telomerase, checkpoints and cancer. Cancer Surv. 29:263–284. 1997.PubMed/NCBI
5	Johnstone RW, Ruefli AA and Lowe SW: Apoptosis: A link between cancer genetics and chemotherapy. Cell. 108:153–164. 2002. View Article : Google Scholar : PubMed/NCBI
6	Dean M, Fojo T and Bates S: Tumor stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
7	Stassi G, Todaro M, Zerilli M, Ricci-Vitiani L, Di Liberto D, Patti M, Florena A, Di Gaudio F, Di Gesù G and De Maria R: Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res. 63:6784–6790. 2003.PubMed/NCBI
8	Todaro M, Zerilli M, Ricci-Vitiani L, Bini M, Perez Alea M, Maria Florena A, Miceli L, Condorelli G, Bonventre S, Di Gesù G, et al: Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells. Cancer Res. 66:1491–1499. 2006. View Article : Google Scholar : PubMed/NCBI
9	Conticello C, Pedini F, Zeuner A, Patti M, Zerilli M, Stassi G, Messina A, Peschle C and De Maria R: IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins. J Immunol. 172:5467–5477. 2004. View Article : Google Scholar : PubMed/NCBI
10	Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G and Sarfati M: Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med. 176:1319–1326. 1992. View Article : Google Scholar : PubMed/NCBI
11	Fan J, Li R, Zhang R, Liu HL, Zhang N, Zhang FQ and Dou KF: Effect of Bcl2 and Bax on survival of side population cells from hepatocellular carcinoma cells. World J Gastroenterol. 13:6053–6059. 2007. View Article : Google Scholar : PubMed/NCBI
12	Park JR, Kim RJ, Lee YK, Kim SR, Roh KJ, Oh SH, Kong G, Kang KS and Nam JS: Dysadherin can enhance tumorigenesis by conferring properties of stemlike cells to hepatocellular carcinoma cells. J Hepatol. 54:122–131. 2011. View Article : Google Scholar
13	Shimamura T, Yasuda J, Ino Y, Gotoh M, Tsuchiya A, Nakajima A, Sakamoto M, Kanai Y and Hirohashi S: Dysadherin expression facilitates cell motility and metastatic potential of human pancreatic cancer cells. Cancer Res. 64:6989–6995. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ståhlberg A, Zoric N, Åman P and Kubista M: Quantitative real-time PCR for cancer detection: The lymphoma case. Expert Review of Molecular Diagnostics. 5:221–230. 2005. View Article : Google Scholar : PubMed/NCBI
15	Shi Y, Fu X, Hua Y, Han Y, Lu Y and Wang J: The side population in human lung cancer cell line NCI-H460 Is enriched in stem-like cancer cells. PLoS One. 7:e333582012. View Article : Google Scholar : PubMed/NCBI
16	Ho MM, Ng AV, Lam S and Hung JY: Side population in human lung cancer celllines and tumors is enriched with stem-like cancer cells. Cancer Res. 67:4827–4833. 2007. View Article : Google Scholar : PubMed/NCBI
17	Ravi D, Ramdas K, Mathew BS, Nalinakumari KR, Nair MK and Pillai MR: Angiogenesis during tumor progression in the oral cavity is related to reduced apoptosis and high tumor cell proliferation. Oral Oncol. 34:543–548. 1998. View Article : Google Scholar
18	Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP and Stassi G: Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 1:389–402. 2007. View Article : Google Scholar
19	Grunewald SM, Werthmann A, Schnarr B, Klein CE, Bröcker EB, Mohrs M, Brombacher F, Sebald W and Duschl A: An antagonistic IL-4 mutant prevents type I allergy in the mouse: Inhibition of the IL-4/IL-13 receptor system completely abrogates humoral immune response to allergen and development of allergic symptoms in vivo. J Immunol. 160:4004–4009. 1998.PubMed/NCBI
20	Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, et al: Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 9:157–173. 2006. View Article : Google Scholar : PubMed/NCBI
21	Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C and De Maria R: Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 13:1238–1241. 2006. View Article : Google Scholar : PubMed/NCBI
22	Kieslinger M, Woldman I, Moriggl R, Hofmann J, Marine JC, Ihle JN, Beug H and Decker T: Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation. Genes Dev. 14:232–244. 2000.PubMed/NCBI
23	Morrison BW and Leder P: A receptor binding domain of mouse interleukin-4 defined by a solid-phase binding assay and in vitro mutagenesis. J Biol Chem. 267:11957–11963. 1992.PubMed/NCBI
24	Gooch JL, Christy B and Yee D: STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. Neoplasia. 4:324–331. 2002. View Article : Google Scholar : PubMed/NCBI
25	Roca H, Craig MJ, Ying C, Varsos ZS, Czarnieski P, Alva AS, Hernandez J, Fuller D, Daignault S, Healy PN and Pienta KJ: IL-4 induces proliferation in prostate cancer PC3 cells under nutrient-depletion stress through the activation of the JNK-pathway and survivin upregulation. J Cell Biochem. 113:1569–1580. 2012.
26	Joshi BH, Leland P, Lababidi S, Varrichio F and Puri RK: Interleukin-4 receptor alpha overexpression in human bladder cancer correlates with the pathological grade and stage of the disease. Cancer Med. 3:1615–1628. 2014. View Article : Google Scholar : PubMed/NCBI