Multidisciplinary Oncologic Centre Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium.
Phase I - Early Clinical Trials Unit & Center for Oncological Research (CORE), Antwerp University, Belgium.
Crit Rev Oncol Hematol. 2017 Dec;120:141-150. doi: 10.1016/j.critrevonc.2017.11.001. Epub 2017 Nov 7.
Background The Nuclear Factor kappaB (NF-kB) family consists of transcription factors that play a complex and essential role in the regulation of immune responses and inflammation. NF-kB has recently generated considerable interest as it has been implicated in human cancer initiation, progression and resistance to treatment. In the present comprehensive review the different aspects of NF-kB signaling in the carcinogenesis of cancer of the uterine cervix are discussed. NF-kB functions as part of a network, which determines the pattern of its effects on the expression of several other genes (such as crosstalks with reactive oxygen species, p53, STAT3 and miRNAS) and thus its function. Activation of NF-kB triggered by a HPV infection is playing an important role in the innate and adaptive immune response of the host. The virus induces down regulation of NF-kB to liquidate the inhibitory activity for its replication triggered by the immune system leading a status of persistant HPV infection. During the progression to high grade intraepithelial neoplasia and cervical cancer NF-KB becomes constitutionally activated again. Mutations in NF-kB genes are rare in solid tumors but mutations of upstream signaling molecules such as RAS, EGFR, PGF, HER2 have been implicated in elevated NF-kB signaling. NF-kB can stimulate transcription of proliferation regulating genes (eg. cyclin D1 and c-myc), genes involved in metastasis, VEGF dependent angiogenesis and cell immortality by telomerase. NF-kB activation can also induce the expression of activation-induced cytodine deaminase (AID) and the APOBEC proteins, providing a mechanistic link between the NF-kB pathway and mutagenic characteristic of cervical cancer. Inhibition of NF-kB has the potential to be used to reverse resistance to radiotherapy and systemic anti-cancer medication, but currently no clinicaly active NF-kB targeting strategies are available.
核因子 kappaB（NF-κB）家族由转录因子组成，在免疫反应和炎症的调节中发挥着复杂而重要的作用。NF-κB 最近引起了相当大的兴趣，因为它与人类癌症的发生、进展和对治疗的耐药性有关。在本综述中，讨论了 NF-κB 信号在宫颈癌发生中的不同方面。NF-κB 作为网络的一部分发挥作用，该网络决定了其对其他几个基因（如与活性氧、p53、STAT3 和 miRNAS 的交叉对话）表达的影响模式，从而决定了其功能。HPV 感染引发的 NF-κB 激活在宿主的先天和适应性免疫反应中起着重要作用。病毒诱导 NF-κB 的下调，以消除免疫系统触发的其复制的抑制活性，导致 HPV 持续感染。在向高级别上皮内瘤变和宫颈癌进展的过程中，NF-KB 再次被组成性激活。NF-κB 基因的突变在实体瘤中很少见，但上游信号分子（如 RAS、EGFR、PGF、HER2）的突变已被认为与 NF-κB 信号的升高有关。NF-κB 可以通过端粒酶刺激增殖调节基因（如 cyclin D1 和 c-myc）、参与转移的基因、VEGF 依赖性血管生成和细胞永生化的转录。NF-κB 的激活还可以诱导激活诱导的胞嘧啶脱氨酶（AID）和 APOBEC 蛋白的表达，为 NF-κB 途径与宫颈癌的致突变特征之间提供了一种机制联系。NF-κB 的抑制有可能用于逆转对放射治疗和全身抗癌药物的耐药性，但目前没有临床有效的 NF-κB 靶向策略。
