IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer

被引：69

作者：

Kachroo, Puja ^{[1
,2
,3
]}

Lee, Mi-Heon ^{[1
,3
]}

Zhang, Ling ^{[1
,3
]}

Baratelli, Felicita ^{[1
,2
]}

Lee, Gina ^{[1
,2
]}

Srivastava, Minu K. ^{[1
,4
]}

Wang, Gerald ^{[1
,2
]}

Walser, Tonya C. ^{[1
,2
]}

Krysan, Kostyantyn ^{[1
,2
]}

Sharma, Sherven ^{[1
,4
]}

Dubinett, Steven M. ^{[1
,2
,4
]}

Lee, Jay M. ^{[1
,2
,3
,5
]}

机构：

[1] Jonsson Comprehens Canc Ctr, Lung Canc Res Program, Los Angeles, CA 90034 USA

[2] Div Pulm & Crit Care Med, Los Angeles, CA USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Div Thorac Surg, Los Angeles, CA 90095 USA

[4] Vet Affair Greater Los Angeles Healthcare Syst, Mol Gene Med Lab, Los Angeles, CA USA

[5] Ronald Reagan UCLA Med Ctr, Div Thorac Surg, Los Angeles, CA 90095 USA

来源：

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH | 2013年 / 32卷

关键词：

IL-27; STAT1; STAT3; Epithelial-mesenchymal transition; Cytokine; Angiogenesis; RECOMBINANT HUMAN INTERLEUKIN-12; SIGNAL TRANSDUCER; CARCINOMA-CELLS; E-CADHERIN; CLINICAL-SIGNIFICANCE; TUMOR ANGIOGENESIS; INTERFERON-GAMMA; GENE-EXPRESSION; BETA-CATENIN; STAT3;

D O I：

10.1186/1756-9966-32-97

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Background: Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial-mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells. Methods: STAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, gamma-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors. Results: Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27-treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. Conclusion: IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1-dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27.

引用

页数：14

共 68 条

[1]

Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer [J].