Activation of IL-8 Via PI3K/Akt-dependent Pathway is Involved in Leptin-mediated Epithelial-mesenchymal Transition in Human Breast Cancer Cells

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2015 Jun 30

PMID 26121010

Citations 78

Authors

Lin Wang

Cuiping Tang

Hong Cao

Kuangfa Li

Xueli Pang

Liang Zhong

Weiqi Dang

Hao Tang

Yunxiu Huang

Lan Wei

Min Su

Tingmei Chen

Affiliations

Soon will be listed here.

Abstract

Background Information: Previous studies have revealed that leptin may be involved in epithelial-mesenchymal transition (EMT), a crucial initiator of cancer progression to facilitate metastatic cascade, increase tumor recurrence, and ultimately cause poor prognosis. However, the underlying mechanism remains unclear. The aim of our present study was to investigate the effect of leptin on EMT of breast cancer cells and the underlying mechanism.

Results: Our data demonstrated that leptin significantly increased the phosphorylation of STAT3, Akt, and ERK1/2, elevated the expression of IL-8, and induced breast cancer cells to undergo EMT. The effect of leptin on IL-8 could visibly abolished by the inhibitor of PI3K LY294002. In addition, leptin-induced EMT of breast cancer cells was blocked by anti-IL-8 antibodies. Examination of the expression of ObR, leptin, IL-8 and EMT-related biomarkers in patient specimens demonstrated that malignant breast carcinoma with lymph node metastases (LNM), which represents poor prognosis, expressed higher levels of ObR, leptin, IL-8 than other types of breast cancer, and displayed more obvious EMT transversion. In vivo xenograft experiment revealed that leptin signally promoted tumor growth and metastasis and increased the expressions of IL-8 and EMT-related biomarkers.

Conclusions: Our results support that leptin-induced EMT in breast cancer cells requires IL-8 activation via the PI3K/Akt signal pathway.

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References

Nieto M . The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol. 2011; 27:347-76. DOI: 10.1146/annurev-cellbio-092910-154036. View

Liu Z, Bandyopadhyay A, Nichols R, Wang L, Hinck A, Wang S . Blockade of Autocrine TGF-β Signaling Inhibits Stem Cell Phenotype, Survival, and Metastasis of Murine Breast Cancer Cells. J Stem Cell Res Ther. 2013; 2(1):1-8. PMC: 3593047. DOI: 10.4172/2157-7633.1000116. View

Xie K . Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 2001; 12(4):375-91. DOI: 10.1016/s1359-6101(01)00016-8. View

Slattery M, John E, Torres-Mejia G, Stern M, Lundgreen A, Hines L . Matrix metalloproteinase genes are associated with breast cancer risk and survival: the Breast Cancer Health Disparities Study. PLoS One. 2013; 8(5):e63165. PMC: 3655963. DOI: 10.1371/journal.pone.0063165. View

de Azambuja E, McCaskill-Stevens W, Francis P, Quinaux E, Crown J, Vicente M . The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial. Breast Cancer Res Treat. 2009; 119(1):145-53. DOI: 10.1007/s10549-009-0512-0. View

Luboshits G, Shina S, Kaplan O, Engelberg S, Nass D, Chaitchik S . Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 1999; 59(18):4681-7. View

Zhang Y, Bellows C, Kolonin M . Adipose tissue-derived progenitor cells and cancer. World J Stem Cells. 2011; 2(5):103-13. PMC: 3097931. DOI: 10.4252/wjsc.v2.i5.103. View

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

Huang L, Li C . Leptin: a multifunctional hormone. Cell Res. 2000; 10(2):81-92. DOI: 10.1038/sj.cr.7290038. View

10.

Ray A, Cleary M . Obesity and breast cancer: a clinical biochemistry perspective. Clin Biochem. 2011; 45(3):189-97. DOI: 10.1016/j.clinbiochem.2011.11.016. View

11.

Lehrer S, Diamond E, Mamkine B, Stone N, Stock R . Serum interleukin-8 is elevated in men with prostate cancer and bone metastases. Technol Cancer Res Treat. 2004; 3(5):411. DOI: 10.1177/153303460400300501. View

12.

Hedges J, Singer C, Gerthoffer W . Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am J Respir Cell Mol Biol. 2000; 23(1):86-94. DOI: 10.1165/ajrcmb.23.1.4014. View

13.

Kushiro K, Nunez N . Ob/ob serum promotes a mesenchymal cell phenotype in B16BL6 melanoma cells. Clin Exp Metastasis. 2011; 28(8):877-86. DOI: 10.1007/s10585-011-9418-4. View

14.

Eiro N, Gonzalez L, Gonzalez L, Fernandez-Garcia B, Lamelas M, Marin L . Relationship between the inflammatory molecular profile of breast carcinomas and distant metastasis development. PLoS One. 2012; 7(11):e49047. PMC: 3493514. DOI: 10.1371/journal.pone.0049047. View

15.

Waugh D, Wilson C . The interleukin-8 pathway in cancer. Clin Cancer Res. 2008; 14(21):6735-41. DOI: 10.1158/1078-0432.CCR-07-4843. View

16.

Simpson E, Brown K . Obesity and breast cancer: role of inflammation and aromatase. J Mol Endocrinol. 2013; 51(3):T51-9. DOI: 10.1530/JME-13-0217. View

17.

Ishikawa M, Kitayama J, Nagawa H . Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res. 2004; 10(13):4325-31. DOI: 10.1158/1078-0432.CCR-03-0749. View

18.

Germano G, Allavena P, Mantovani A . Cytokines as a key component of cancer-related inflammation. Cytokine. 2008; 43(3):374-9. DOI: 10.1016/j.cyto.2008.07.014. View

19.

Wolin K, Carson K, Colditz G . Obesity and cancer. Oncologist. 2010; 15(6):556-65. PMC: 3227989. DOI: 10.1634/theoncologist.2009-0285. View

20.

Palena C, Hamilton D, Fernando R . Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment. Future Oncol. 2012; 8(6):713-22. PMC: 3462442. DOI: 10.2217/fon.12.59. View