**1.2 Important role of NF-κB in cancer**

NF-κB was first discovered by Dr. Ranjan Sen in 1986 [3]. This family of transcription factors plays important roles in the regulation of apoptosis, proliferation, inflammation, and immune response in both normal and cancer cells. Generally, in normal cells, the central transcription factor NF-κB is transiently activated in response to certain stimuli. However, cancer cells usually exhibit sustained activation of NF-κB [4, 5] which significantly contributes to their survival. Moreover, NF-κB activity plays critical roles in many of the well-known "hallmarks" of cancer, via its regulation of target genes involved in tumor cell proliferation, suppression of apoptosis, activation of angiogenesis as well as induction of the epithelial-to-mesenchymal transition (EMT) phenotype, a critical step in metastasis [6]. Constitutively active NF-κB has been found in many types of cancer. For instance, in thyroid cancer, oncogenic proteins including "rearranged during transfection" (RET), "Rat Sarcoma" (RAS), and "v-Raf murine sarcoma viral oncogene homolog B" (BRAF) were shown to induce NF-κB activation, which in turn activated proliferative and antiapoptotic signaling pathways [7]. Moreover, in renal cell carcinoma (RCC), NF-κB is constitutively activated. The phosphorylated p65, a major subunit of NF-κB, exhibited a significant increase in the RCC samples compared with corresponding normal tissues [8]. Furthermore, Nogueira et al. showed that in glioblastoma (GBM), deletion of IκB showed a phenotype similar to that of epidermal growth factor receptor (EGFR) amplification in the pathogenesis of GBM. This was also correlated with low survival rates in affected patients [2].

Importantly, our laboratory also found that in colon cancer, NF-κB can be activated by the Y-box protein 1 (YBX1), a critical event correlated with increased colon cancer cell proliferation and anchorage-independent growth [9, 10]. Additionally, in pancreatic cancer, a mutant oncogenic KrasG12D (glycine to aspartic acid) mutation induced positive feedback loops of interleukin 1α (IL-1α) and p62 expression to sustain constitutive IKKβ (inhibitor of NF-κB kinase subunit β)/NF-κB activation [11]. In breast cancer, moderately elevated NF-κB led to chronic inflammatory conditions that result in some cells escaping immune surveillance [12]. Additionally, NF-κB activation was shown to upregulate the expression of cyclin D1, cyclin-dependent kinase 2 (CDK2), and c-Myc, which drives cell cycle progression and causes uncontrolled cell proliferation [13]. Moreover, in breast cancer, NF-κB has been shown to induce and stabilize the expression of EMT markers (Snail and twist-related protein1) [14], a pivotal process in tumor metastasis. In addition to the role of NF-κB in solid tumors as described thus far, Gasparini et al. has thoroughly reviewed the important tumorgenic role of NF-κB in hematological malignancies, including acute lymphocytic lymphoma (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chromic myeloid leukemia (CML), B lymphomas, diffuse large B-cell lymphomas (DLBCLs), Hodgkin's lymphoma, adult T-cell lymphomas (ATLL), anaplastic large-cell lymphomas (ALCL), and multiple myeloma, which will not be further discussed in this chapter [15]. Overall, these studies highlight a prominent role of dysregulated NF-κB in multiple aspects of cancer progression in both solid tumors and hematological malignancies.
