JAK2 inhibitor blocks the inflammation and growth of esophageal squamous cell carcinoma in vitro through the JAK/STAT3 pathway

Fang,Juemin; Chu,Li; Li,Chunyan; Chen,Yijing; Hu,Fei; Zhang,Xi; Zhao,Huaxin; Liu,Zhuqing; Xu,Qing

doi:10.3892/or.2014.3609

JAK2 inhibitor blocks the inflammation and growth of esophageal squamous cell carcinoma in vitro through the JAK/STAT3 pathway

Authors:
- Juemin Fang
- Li Chu
- Chunyan Li
- Yijing Chen
- Fei Hu
- Xi Zhang
- Huaxin Zhao
- Zhuqing Liu
- Qing Xu
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Affiliations: Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, P.R. China
Published online on: November 14, 2014 https://doi.org/10.3892/or.2014.3609
Pages: 494-502

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Abstract

Recent research indicates that the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway may play an important role in chronic inflammation which promotes cancer progression, yet the mechanism is not clear. The present study aimed to investigate the role of the JAK/STAT3 pathway in the growth and cancer-related inflammation (CRI) of esophageal squamous cell carcinoma (ESCC) by studying the crosstalk between the JAK/STAT3 pathway and nuclear factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) which are important inflammatory factors associated with tumorigenesis. Cell growth and the cell cycle were assessed by CCK-8 assays and flow cytometry, respectively. The protein levels of STAT3, phosphorylated STAT3, VEGF, NF-κB p65, phosphorylated NF-κB p65 and COX-2 in ESCC cells following treatment with JAK2 inhibitor for 48 h or interleukin-6 (IL-6) for 24 h were detected. RT-PCR was performed to study the interaction among STAT3, NF-κB and COX-2 by transfection of siRNAs targeted at STAT3 and NF-κB. STAT3 was activated in 3 ESCC cell lines at different levels. Blocking the JAK/STAT3 pathway inhibited cancer growth through regulation of cell growth, cell cycle and angiogenesis. Likewise, abrogation of the JAK/STAT3 pathway decreased CRI by downregulating levels of NF-κB p65 phosphorylation, COX-2 and IL-6 concentration. In addition, CRI and cancer growth were accelerated by IL-6 through stimulation of the JAK/STAT3 and NF-κB p65 pathway. Moreover, STAT3 and NF-κB both regulated COX-2 as a downstream gene. The JAK/STAT3 pathway is an important pathway which links CRI and cancer growth through IL-6 and crosstalk with the NF-κB p65 subunit and COX-2. The STAT3 pathway could be a novel target both for cancer treatment and prevention in ESCC.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Wei WQ, Yang J, Zhang SW, Chen WQ and Qiao YL: Analysis of the esophageal cancer mortality in 2004–2005 and its trends during last 30 years in China. Zhonghua Yu Fang Yi Xue Za Zhi. 44:398–402. 2010.(In Chinese). PubMed/NCBI
3	Colotta F, Allavena P, Sica A, Garlanda C and Mantovani A: Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 30:1073–1081. 2009. View Article : Google Scholar : PubMed/NCBI
4	Suzuk L, Noffsinger AE, Hui YZ and Fenoglio-Preiser CM: Detection of human papillomavirus in esophageal squamous cell carcinoma. Cancer. 78:704–710. 1996. View Article : Google Scholar : PubMed/NCBI
5	Antunes LC, Prolla JC, de Barros Lopes A, da Rocha MP and Fagundes RB: No evidence of HPV DNA in esophageal squamous cell carcinoma in a population of Southern Brazil. World J Gastroenterol. 19:6598–6603. 2013. View Article : Google Scholar : PubMed/NCBI
6	Yang GZ, Li L, Ding HY and Zhou JS: Cyclooxygenase-2 is over-expressed in Chinese esophageal squamous cell carcinoma, and correlated with NF-κB: an immunohistochemical study. Exp Mol Pathol. 79:214–218. 2005. View Article : Google Scholar : PubMed/NCBI
7	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
8	Bollrath J and Greten FR: IKK/NF-κB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis. EMBO Rep. 10:1314–1319. 2009. View Article : Google Scholar : PubMed/NCBI
9	Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
10	Chung SS, Giehl N, Wu Y and Vadgama JV: STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits. Int J Oncol. 44:403–411. 2014.
11	Qu Y, Oyan AM, Liu R, et al: Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling. Cancer Res. 73:7090–7100. 2013. View Article : Google Scholar : PubMed/NCBI
12	Burke WM, Jin X, Lin HJ, et al: Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 20:7925–7934. 2001. View Article : Google Scholar : PubMed/NCBI
13	Huang C, Cao J, Huang KJ, et al: Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer Sci. 97:1417–1423. 2006. View Article : Google Scholar : PubMed/NCBI
14	Xiong H, Zhang ZG, Tian XQ, et al: Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 10:287–297. 2008.PubMed/NCBI
15	Turkson J and Jove R: STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 19:6613–6626. 2000. View Article : Google Scholar
16	Schindler C and Darnell JE Jr: Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem. 64:621–652. 1995. View Article : Google Scholar : PubMed/NCBI
17	Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI
18	Park EJ, Lee JH, Yu GY, et al: Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 140:197–208. 2010. View Article : Google Scholar : PubMed/NCBI
19	Grivennikov S, Karin E, Terzic J, et al: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 15:103–113. 2009. View Article : Google Scholar : PubMed/NCBI
20	Karin M: Nuclear factor-κB in cancer development and progression. Nature. 441:431–436. 2006. View Article : Google Scholar : PubMed/NCBI
21	Greten FR, Eckmann L, Greten TF, et al: IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 118:285–296. 2004. View Article : Google Scholar : PubMed/NCBI
22	He G and Karin M: NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res. 21:159–168. 2010. View Article : Google Scholar
23	Lo HW, Hsu SC, Xia W, et al: Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 67:9066–9076. 2007. View Article : Google Scholar : PubMed/NCBI
24	Coussens LM and Werb Z: Inflammation and cancer. Nature. 420:860–867. 2002. View Article : Google Scholar : PubMed/NCBI
25	Grivennikov SI and Karin M: Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21:11–19. 2010. View Article : Google Scholar :
26	Hao Q, Zhang C, Gao Y, et al: FOXP3 inhibits NF-κB activity and hence COX2 expression in gastric cancer cells. Cell Signal. 26:564–569. 2014. View Article : Google Scholar
27	von Rahden BH, Stein HJ, Pühringer F, et al: Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma. Cancer Res. 65:5038–5044. 2005. View Article : Google Scholar : PubMed/NCBI
28	Zhi H, Wang L, Zhang J, et al: Significance of COX-2 expression in human esophageal squamous cell carcinoma. Carcinogenesis. 27:1214–1221. 2006. View Article : Google Scholar