Skip to main content
  • Minireview
  • Published:

Recent insights into the role of NF-kappaB in ovarian carcinogenesis


The NF-κBs are a family of ubiquitously expressed transcription factors that have been described to be responsible for the establishment of an inflammatory response. Studies in the past decade have also demonstrated this family's role in the initiation and progression of hematological and solid tumors. Recently, research has uncovered a specific role for NF-κBs in the development and maintenance of ovarian cancer.

Clinical overview of epithelial ovarian cancer

Epithelial ovarian cancer (EOC) accounts for the majority of ovarian cancer and is the most lethal of all gynecological malignancies. It was expected that 21,550 new cases of EOC would be diagnosed in the US in 2009 and that 14,600 women would die from the disease [1]. Although ovarian cancer accounts for only 3% of all female cancers, it is the fifth most common cause of cancer deaths in women. Given that EOC usually presents with non-specific symptoms, such as bloating or abdominal discomfort, which can all be mistaken for a more benign condition, and because there is currently no means for early detection, patients with EOC are often diagnosed with late-stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III or IV). On initial diagnosis, patients undergo complete surgical debulking (resection whose only goal is to make subsequent therapy more effective) followed by combination chemotherapy usually consisting of carboplatin and paclitaxel. Approximately 80% of patients respond to this treatment regimen, which has been the standard for more than 10 years [2]. However, 60 to 80% of the responders present with recurrent disease between 6 months and 2 years after treatment. Unfortunately, disease recurrence is characterized by chemoresistance, resulting in disease progression and death. As a result, the 5-year survival rate for patients diagnosed with late-stage disease is only 15 to 20% [3].

NF-κB in ovarian cancer initiation and progression

Chronic inflammation has been associated with tumor initiation and progression. In the ovary, carcinogenesis has been linked to inflammatory processes, such as repeated ovulation, endometriosis and pelvic infections [4, 5]. The molecular link between inflammation and cancer is nuclear factor κ light chain enhancer of activated B cells (NF-κB) [6]. The NF-κB family of proteins, which has five members (Table 1), controls several key processes that are required for tumor development and progression, such as: activation of anti-apoptotic genes and genes involved in the progression of cell cycle [7, 8]; secretion of factors such as tumor necrosis factor (TNF) α and interleukin (IL)-6, which enhances cell growth [6]; promotion of a pro-angiogenic environment through enhanced production of IL-8 and vascular endothelial growth factor [9]; and creation of a microenvironment that may prevent immune surveillance [10] (Figure 1).

Table 1 Members of the NF-kB family of proteins
Figure 1
figure 1

The NF-κB pathway. In unstimulated cells, the NF-κB subunits p65 and p50 are sequestered in the cytoplasm by IκB. Ligand binding to receptors (such as TNFα and TLR4) leads to the activation of the IKK complex, which then phosphorylates IκB. Phosphorylated IκB is then ubiquitinated and degraded by the proteasome system, leading to the release of p65 and p50. The heterodimer then translocates to the nucleus and initiates the expression of genes that regulate proliferation, cell death, invasion, migration and immune regulation. This is the canonical pathway; there is also a non-canonical pathway involving other NF-κB family members. Most of the studies on EOC have looked at the members of the canonical pathway.

A correlation between NF-κB activation and EOC clinical profile has been described. Guo et al. [11] demonstrated that the expression of NF-κB p65 in EOC tumors is mainly nuclear and that the levels correlate with poor differentiation and late FIGO stage. Moreover, they showed that patients who were positive for NF-κB p65 subunit staining had lower cumulative survival rates and lower median survival (20% and 24 months, respectively) than patients that were negative (46.2% and 39 months, respectively). The correlation between NF-κB activation status (that is, levels of NF-κB p65 and RelB) and poor clinical outcome in EOC patients was corroborated in more recent studies by two other independent groups [12, 13].

In addition to these correlation studies [1113], the in vitro activation or specific inhibition of the NF-κB pathway using either small-molecule inhibitors or short interfering RNA (siRNA) was recently shown to affect the growth behavior of EOC cells. Using the ligand TNF-like weak inducer of apoptosis (TWEAK) to activate NF-κB in the highly metastatic human EOC cell line HO-8910PM, Dai et al. [14] showed that although TWEAK-induced nuclear translocation of NF-κB p65 does not enhance cell growth, treatment with TWEAK for 6 hours can significantly enhance adhesion and promote the migration and invasion capacity of these cells [14]. These effects were inhibited when cells were treated with TWEAK in the presence of the NF-κB inhibitor pyrrolidine dithiocarbamate.

In another study, which showed that microRNA-9 (miR-9) could control the levels of NF-κB1, the authors [15] showed that a decrease in NF-κB1 levels, as a result of overexpressing miR-9 or by using the siRNA expression vector pSilencer/si-NF-κB1, is associated with a reduction in cell growth and colony formation by the human EOC line ES-2.

In a more recent study using several EOC cell lines, Hernandez et al. [16] showed that inhibition of the NF-κB pathway through specific inhibition of inhibitor of NF-κB kinase β (IKKβ) can decrease the percentage of viable CAOV3, IGROV1 and A2780 cells. In addition, they showed that blocking IKKβ activity through either small-molecule inhibition or siRNA can inhibit anchorage-independent growth and the capacity of the cells to invade through a basement membrane. More importantly, the authors [16] identified the network of genes controlled by the IKKβ-NF-κB pathway in CAOV3 cells. Using the highly specific IKKβ small-molecule inhibitor ML120b or IKKβ siRNA to decrease IKKβ expression, gene expression microarray results showed that the IKKβ-NF-κB pathway controls genes associated with EOC cell proliferation, adhesion, invasion, angiogenesis and the creation of a pro-inflammatory microenvironment.

NF-κB signaling and ovarian cancer stem cells

Our group has identified a subpopulation of EOC cells that is responsive to the pathway involving Toll-like receptor 4 (TLR4) and NF-κB [17]. Treatment with the chemotherapy agent paclitaxel, which is a known TLR4 ligand, induced NF-κB activation, leading to enhanced cell proliferation. NF-κB is constitutively active in these cells, resulting in constitutive secretion of pro-inflammatory cytokines [17], and this is brought about by constitutive IKKβ activity [18]. These cells also express the cancer stem cell marker CD44 and are in fact the ovarian cancer stem cells (OCSCs) [19].

The CD44+ OCSCs are resistant to chemotherapeutic agents, and this resistance is partly regulated by the NF-κB pathway [19]. In our most recent study [20], we showed that the NF-κB inhibitor Eriocalyxin B can sensitize these cells to TNFα- and Fas-mediated apoptosis. The CD44+ OCSCs can also serve as tumor vascular progenitors in vitro and in vivo, an effect also regulated by the NF-κB pathway [21].


Research in the past 5 years has unraveled the multiple mechanisms that enable NF-κB to support ovarian carcinogenesis, including that this pathway confers some of the properties of OCSCs. These findings highlight the clinical potential for NF-κB inhibitors to prevent recurrence and improve survival in EOC patients. The fact that the main effectors of this pathway significantly correlate with disease activity suggests the feasibility of choosing patients that may benefit from targeting this molecular pathway.



epithelial ovarian cancer cells


inhibitor of NF-κB kinase α


inhibitor of NF-κB kinase β


inhibitor of NFκB




Nuclear factor kappa-light-chain-enhancer of activated B cells


ovarian cancer stem cells


short hairpin RNA


small interfering RNA


tumor necrosis factor α.


  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 2009, 59: 225-249. 10.3322/caac.20006.

    Article  PubMed  Google Scholar 

  2. Covens A, Carey M, Bryson P, Verma S, Fung Kee Fung M, Johnston M: Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol. 2002, 85: 71-80. 10.1006/gyno.2001.6552.

    Article  PubMed  CAS  Google Scholar 

  3. Schwartz PE: Current diagnosis and treatment modalities for ovarian cancer. Cancer Treat Res. 2002, 107: 99-118.

    PubMed  Google Scholar 

  4. Cramer DW, Welch WR: Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst. 1983, 71: 717-721.

    PubMed  CAS  Google Scholar 

  5. Mandai M, Yamaguchi K, Matsumura N, Baba T, Konishi I: Ovarian cancer in endometriosis: molecular biology, pathology, and clinical management. Int J Clin Oncol. 2009, 14: 383-391. 10.1007/s10147-009-0935-y.

    Article  PubMed  Google Scholar 

  6. Karin M: Nuclear factor-kappaB in cancer development and progression. Nature. 2006, 441: 431-436. 10.1038/nature04870.

    Article  PubMed  CAS  Google Scholar 

  7. Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol. 2002, 3: 221-227. 10.1038/ni0302-221.

    Article  PubMed  CAS  Google Scholar 

  8. Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG: NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev. 2001, 12: 73-90. 10.1016/S1359-6101(00)00018-6.

    Article  PubMed  CAS  Google Scholar 

  9. Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ: Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res. 2000, 60: 5334-5339.

    PubMed  CAS  Google Scholar 

  10. Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005, 5: 749-759. 10.1038/nri1703.

    Article  PubMed  CAS  Google Scholar 

  11. Guo RX, Qiao YH, Zhou Y, Li LX, Shi HR, Chen KS: Increased staining for phosphorylated AKT and nuclear factor-kappaB p65 and their relationship with prognosis in epithelial ovarian cancer. Pathol Int. 2008, 58: 749-756. 10.1111/j.1440-1827.2008.02306.x.

    Article  PubMed  CAS  Google Scholar 

  12. Annunziata CM, Stavnes HT, Kleinberg L, Berner A, Hernandez LF, Birrer MJ, Steinberg SM, Davidson B, Kohn EC: Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Cancer. 2010, 116: 3276-3284. 10.1002/cncr.25190.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Darb-Esfahani S, Sinn BV, Weichert W, Budczies J, Lehmann A, Noske A, Buckendahl AC, Muller BM, Sehouli J, Koensgen D, Gyorffy B, Dietel M, Denkert C: Expression of classical NF-kappaB pathway effectors in human ovarian carcinoma. Histopathology. 2010, 56: 727-739. 10.1111/j.1365-2559.2010.03544.x.

    Article  PubMed  Google Scholar 

  14. Dai L, Gu L, Ding C, Qiu L, Di W: TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression. Cancer Lett. 2009, 283: 159-167. 10.1016/j.canlet.2009.03.036.

    Article  PubMed  CAS  Google Scholar 

  15. Guo LM, Pu Y, Han Z, Liu T, Li YX, Liu M, Li X, Tang H: MicroRNA-9 inhibits ovarian cancer cell growth through regulation of NF-kappaB1. FEBS J. 2009, 276: 5537-5546. 10.1111/j.1742-4658.2009.07237.x.

    Article  PubMed  CAS  Google Scholar 

  16. Hernandez L, Hsu SC, Davidson B, Birrer MJ, Kohn EC, Annunziata CM: Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer. Cancer Res. 2010, 70: 4005-4014. 10.1158/0008-5472.CAN-09-3912.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, Visintin I, Rutherford T, Mor G: TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006, 66: 3859-3868. 10.1158/0008-5472.CAN-05-3948.

    Article  PubMed  CAS  Google Scholar 

  18. Chen R, Alvero AB, Silasi DA, Kelly MG, Fest S, Visintin I, Leiser A, Schwartz PE, Rutherford T, Mor G: Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells. Oncogene. 2008, 27: 4712-4723. 10.1038/onc.2008.112.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, Rutherford T, Silasi DA, Steffensen KD, Waldstrom M, Visintin I, Mor G: Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle. 2009, 8: 158-166.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Leiser A, Alvero AB, Fu H, Holmberg J, Cheng YC, Silasi D, Rutherford R, Mor G: Regulation of inflammation by the NFκB pathway in the ovarian cancer stem cells. Am J Reprod Immunol. 2010,

    Google Scholar 

  21. Alvero AB, Fu HH, Holmberg J, Visintin I, Mor L, Marquina CC, Oidtman J, Silasi DA, Mor G: Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells. 2009, 27: 2405-2413. 10.1002/stem.191.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Ayesha B Alvero.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alvero, A.B. Recent insights into the role of NF-kappaB in ovarian carcinogenesis. Genome Med 2, 56 (2010).

Download citation

  • Published:

  • DOI: