NF-κB Signaling in Ovarian Cancer

Abstract

The NF-κB signaling pathway is a master and commander in ovarian cancer (OC) that promotes chemoresistance, cancer stem cell maintenance, metastasis and immune evasion. Many signaling pathways are dysregulated in OC and can activate NF-κB signaling through canonical or non-canonical pathways which have both overlapping and distinct roles in tumor progression. The activation of canonical NF-κB signaling has been well established for anti-apoptotic and immunomodulatory functions in response to the tumor microenvironment and the non-canonical pathway in cancer stem cell maintenance and tumor re-initiation. NF-κB activity in OC cells helps to create an immune-evasive environment and to attract infiltrating immune cells with tumor-promoting phenotypes, which in turn, drive constitutive NF-κB activation in OC cells to promote cell survival and metastasis. For these reasons, NF-κB is an attractive target in OC, but current strategies are limited and broad inhibition of this major signaling pathway in normal physiological and immunological functions may produce unwanted side effects. There are some promising pre-clinical outcomes from developing research to target and inhibit NF-κB only in the tumor-reinitiating cancer cell population of OC and concurrently activate canonical NF-κB signaling in immune cells to promote anti-tumor immunity.

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis

“…While this is the first study to demonstrate an association with clinical disease prognosis, several additional lines of mechanistic evidence support a pro-tumorigenic role for non-canonical NF-κB signaling independent of the canonical pathway [ 35 ]. We previously found that downregulation of cyclooxygenase-1 (COX-1) expression, an established pro-tumor mediator in ovarian cancer, resulted in reduced expression of multiple non-canonical NF-κB signaling components, including RELB , NFKB2 (p100/p52), CHUK (IKKα), and MAP3K14 (NF-κB-inducing kinase); in contrast, expression of canonical NF-κB pathway members was not changed by COX-1 knockdown [ 57 ].…”

“…Moreover, overexpression of p52 promotes lung tumorigenesis in mice, and associations have been demonstrated between non-canonical NF-κB signaling, p52-gene targets, and worse prognosis in human lung adenocarcinoma cases [ 33 ]. Further studies of in vitro and in vivo models of ovarian cancer have shown that non-canonical NF-κB signaling promotes cell growth and tumorigenicity as well as cancer stem cell self-renewal [ 31 , 32 , 34 , 35 ]. Aberrant expression of tissue transglutaminase in ovarian tumors has been implicated as an upstream regulator of p52 expression and non-canonical signaling, ultimately contributing to disease progression and intraperitoneal metastasis [ 31 ].…”

“…Prior studies have demonstrated increased activation of p52 in breast, lung, prostate, pancreatic, and ovarian cancers [ 26 – 32 ], and increased expression has been linked to worse prognosis in lung cancer [ 33 ]. While pre-clinical in vitro and in vivo studies have demonstrated a variety of mechanisms by which non-canonical NF-κB signaling may contribute to ovarian cancer carcinogenesis and progression, no studies to date have reported associations between non-canonical NF-κB transcription factors and ovarian cancer clinical prognosis [ 31 , 32 , 34 , 35 ]. Thus, we undertook this study to evaluate if variation in expression of NF-κB transcription factors, specifically tumor expression of p65 (a major contributor to canonical signaling) and p52 (a major contributor to non-canonical signaling), was associated with survival outcomes among a retrospective cohort of ovarian cancer cases.…”

miR-103 promotes the progression of non-Hodgkins lymphoma by inhibiting OTUD7B expression

“…Nuclear factor-Kappa B (NF-κB) is a well known transcription factor associated with almost all aspects of life activity (18). It consists of five subunits, namely c-Rel, Rel A (p65), Rel B, NF-κB1 (p105/p50), and NF-κB2 (p100/p52) (19). NF-κB plays a very important role in the progression of tumors by regulating multiple downstream targeted genes (19).…”

“…It consists of five subunits, namely c-Rel, Rel A (p65), Rel B, NF-κB1 (p105/p50), and NF-κB2 (p100/p52) (19). NF-κB plays a very important role in the progression of tumors by regulating multiple downstream targeted genes (19). A lot of studies indicated that NF-κB signaling is abnormally activated in NHL (20)(21)(22).…”