Malignant ascites enhances migratory and invasive properties of ovarian cancer cells with membrane bound IL-6R in vitro

Soochi Kim; HyeRan Gwak; Hee Seung Kim; Boyun Kim; Danny N Dhanasekaran; Yong Sang Song

doi:10.18632/oncotarget.13074

Malignant ascites enhances migratory and invasive properties of ovarian cancer cells with membrane bound IL-6R in vitro

Oncotarget. 2016 Dec 13;7(50):83148-83159. doi: 10.18632/oncotarget.13074.

Authors

Soochi Kim^{1

2}, HyeRan Gwak^{2

3}, Hee Seung Kim^{2

4}, Boyun Kim^{2

5}, Danny N Dhanasekaran⁶, Yong Sang Song^{1

2

3

4}

Affiliations

¹ Interdisciplinary Program in Cancer Biology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
² Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
³ Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
⁴ Department of Obstetrics and Gynecology, Seoul National University, Seoul, Republic of Korea.
⁵ Nano System Institute, Seoul National University, Seoul, Korea.
⁶ Stephenson Cancer Center, University of Oklahoma Health Sciences Center, USA.

Abstract

Transcoelomic route is the most common and the earliest route of metastasis, causing the ascites formation in advanced epithelial ovarian cancer (EOC). We demonstrated that interleukin 6 (IL-6) is enriched in the malignant ascites from patients with ovarian cancer, which enhanced invasive properties of EOC cells. Interestingly, the expression of IL-6R on cell membrane of EOC cells correlated with ascites-induced invasion. Selective knockdown of IL-6R or inhibition with IL-6 neutralizing antibody, suppressed the stimulatory effects of ascites on EOC invasion. Moreover, the ascites treatment induced the phosphorylation of JAK2-STAT3 and use of selective inhibitors of JAK2 and STAT3, blocked the expression of epithelial-mesenchymal transition related proteins in parallel with the suppression of EOC invasion. Thus, IL-6/IL-6R mediated JAK2-STAT3 signaling pathway could be a promising therapeutic target for anticancer therapy in ovarian cancer patients with ascites.

Keywords: IL-6R; ascites; invasion; migration; ovarian cancer.

MeSH terms

Aged
Antibodies, Neutralizing / pharmacology
Antineoplastic Agents / pharmacology
Ascites*
Ascitic Fluid / metabolism*
Carcinoma, Ovarian Epithelial
Cell Line, Tumor
Cell Membrane / drug effects
Cell Membrane / metabolism*
Cell Movement* / drug effects
Epithelial-Mesenchymal Transition
Female
Humans
Interleukin-6 / metabolism*
Janus Kinase 2 / antagonists & inhibitors
Janus Kinase 2 / metabolism
Middle Aged
Neoplasm Invasiveness
Neoplasms, Glandular and Epithelial / drug therapy
Neoplasms, Glandular and Epithelial / genetics
Neoplasms, Glandular and Epithelial / metabolism*
Neoplasms, Glandular and Epithelial / pathology
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / pathology
Phosphorylation
Protein Kinase Inhibitors / pharmacology
RNA Interference
Receptors, Interleukin-6 / antagonists & inhibitors
Receptors, Interleukin-6 / genetics
Receptors, Interleukin-6 / metabolism*
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / metabolism
Signal Transduction
Time Factors
Transfection

Substances

Antibodies, Neutralizing
Antineoplastic Agents
IL6 protein, human
IL6R protein, human
Interleukin-6
Protein Kinase Inhibitors
Receptors, Interleukin-6
STAT3 Transcription Factor
STAT3 protein, human
JAK2 protein, human
Janus Kinase 2

Grants and funding

R01 CA116984/CA/NCI NIH HHS/United States