Regulation of IKKβ by miR-199a affects NF-κB activity in ovarian cancer cells

被引:261
作者
Chen, R. [2 ]
Alvero, A. B.
Silasi, D. A.
Kelly, M. G.
Fest, S.
Visintin, I.
Leiser, A.
Schwartz, P. E.
Rutherford, T.
Mor, G. [1 ]
机构
[1] Yale Univ, Sch Med, Reprod Immunol Unit, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA
[2] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA
关键词
inflammation; ovarian cancer; IKK beta; MyD88; chemoresistance;
D O I
10.1038/onc.2008.112
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cancer progression is an abnormal form of tissue repair characterized by chronic inflammation. I kappa B kinase-beta (IKK beta) required for nuclear factor-kappa B (NF-kappa B) activation plays a critical role in this process. Using EOC cells isolated from malignant ovarian cancer ascites and solid tumors, we identified IKKb as a major factor promoting a functional TLR-MyD88-NF-kappa B pathway that confers to EOC cell the capacity to constitutively secrete proinflammatory/protumor cytokines and therefore promoting tumor progression and chemoresistance. Furthermore, we describe for the first time the identification of the microRNA hsa-miR-199a as a regulator of IKK beta expression. Our study describes the property of ovarian cancer cells to enhance the inflammatory microenvironment as a result of the expression of an active IKKb pathway. Identification of these markers in patients' tumor samples may facilitate the adequate selection of treatment and open new venues for the development of effective therapy for chemoresistant ovarian cancers.
引用
收藏
页码:4712 / 4723
页数:12
相关论文
共 43 条
[1]   Signalling pathways of the TNF superfamily: A double-edged sword [J].
Aggarwal, BB .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (09) :745-756
[2]   Cancer and the chemokine network [J].
Balkwill, F .
NATURE REVIEWS CANCER, 2004, 4 (07) :540-550
[3]   Cancer - An inflammatory link [J].
Balkwill, F ;
Coussens, LM .
NATURE, 2004, 431 (7007) :405-406
[4]   The TNF receptor 1: A split personality complex [J].
Barnhart, BC ;
Peter, ME .
CELL, 2003, 114 (02) :148-150
[5]   Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts [J].
Baumgartner, B ;
Weber, M ;
Quirling, M ;
Fischer, C ;
Page, S ;
Adam, M ;
von Schilling, C ;
Waterhouse, C ;
Schmid, C ;
Neumeier, D ;
Brand, K .
LEUKEMIA, 2002, 16 (10) :2062-2071
[6]   Inflammation, cancer and chemoresistance: Taking advantage of the toll-like receptor signaling pathway [J].
Chen, Rui ;
Alvero, Ayesha B. ;
Silasi, Dan-Arin ;
Mor, Gil .
AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 2007, 57 (02) :93-107
[7]   Inflammation and cancer [J].
Coussens, LM ;
Werb, Z .
NATURE, 2002, 420 (6917) :860-867
[8]   Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-20S human osteosarcoma cells [J].
Duan, Z ;
Lamendola, DE ;
Penson, RT ;
Kronish, KM ;
Seide, MV .
CYTOKINE, 2002, 17 (05) :234-242
[9]   Apoptosis-based evaluation of chemosensitivity in ovarian cancer patients [J].
Flick, MB ;
O'Malley, D ;
Rutherford, T ;
Rodov, S ;
Kamsteeg, M ;
Hao, XY ;
Schwartz, P ;
Kacinski, BM ;
Mor, G .
JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION, 2004, 11 (04) :252-259
[10]   Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis [J].
Fukata, M ;
Michelsen, KS ;
Eri, R ;
Thomas, LS ;
Hu, B ;
Lukasek, K ;
Nast, CC ;
Lechago, J ;
Xu, RL ;
Naiki, Y ;
Soliman, A ;
Arditi, M ;
Abreu, MT .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2005, 288 (05) :G1055-G1065