Nf kb and cancer how intimate is this relationship right

Downregulation of miRa-3p activates the NIK-dependent NF-κB pathway in colorectal cancer

nf kb and cancer how intimate is this relationship right

Previously, we have shown that YBX1 could function as a tumor promoter .. ( right panel), whereas the SA mutant showed decreased NF-κB DNA binding () NF-κB and cancer: how intimate is this relationship. Nuclear factor-κB (NF-κB) is a transcription factor that plays a crucial role in . The noncanonical pathway (right) engaged in by members of the TNF-like .. Aggarwal B.B. NF-κB and cancer: How intimate is this relationship. Nuclear factor kappa B (NF-κB) is a family of transcription factors that have an essential . 2B, Right). p53 loss was confirmed in these cells by qPCR (Fig. . Current insight into the relationship between p53 and GR is unclear. . () Rel/NF-κ B/I κ B family: Intimate tales of association and dissociation.

NF-kappaB and cancer: how intimate is this relationship.

In this study, we provide strong evidence regarding the discovery of the novel phosphorylation of Ser on YBX1. Furthermore, SA mutant protein is mainly restricted to the cytoplasm, whereas WT-YBX1 is located in both the cytoplasm and nucleus, indicating the importance of Ser phosphorylation for YBX1 translocation to the nucleus.

Both Ser and Ser phosphorylation differentially or collaboratively regulate different subgroups of genes that are associated with different networks of functions Fig. It was reported that the highly conserved and ubiquitously expressed pleiotropic CKI family plays critical regulatory roles in many cellular processes, including DNA processing and repair, proliferation, and cell differentiation.

In addition, CKI also can phosphorylate and activate Wnt signaling It is important to note that Wnt is known to play an important role in the epithelial-mesenchymal transition EMTan important process that contributes to cancer development Interestingly, YBX1 has also been implicated in interacting with promoters of a number of Wnt pathway proteins Mutations and genetic alterations of CKI are often detected in various cancers.

Therefore, CKI is considered a highly attractive therapeutic target in cancer On the other hand, although belonging to a different family, CKII is also involved in various important cellular processes, including cell cycle control, apoptosis, and circadian rhythm.

It is well known that CKII plays an important role in tumorigenesis and angiogenesis processes 33 In this study, we suggest that Ser is a more predominant phosphorylation site on YBX1 than Ser However, details are still unknown regarding the exact order of these phosphorylation events.

Roles of NF-κB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches

Furthermore, the IF data Fig. The concept of protein modulators of RelA, i. In their report, the authors provided a repertoire of near modulators for experimental validation. Remarkably, one of their predicted novel modulators was YBX1. Therefore, this study is of great novelty and significance. In a broader scope, a fascinating aspect regarding the novel phosphorylation of Ser and Ser of YBX1 could be its potential influence on the overall YBX1 functions.

For instance, YBX1 is well known for playing an important role in translation control. In the future, it would be of immense interest to explore whether phosphorylation of Ser and Ser on YBX1 may play any role in translational control of EMT genes as well as other important functions of YBX1.

NF-kappaB and cancer: how intimate is this relationship.

Finally, this research may provide a potential therapeutic approach in colon cancer treatment. In the future, it would be very interesting to explore whether phosphorylation of Ser and Ser of YBX1 could be generalized to some other types of cancer beyond colon cancer, therefore providing novel therapeutic approaches to other types of cancer as well.

Experimental Procedures Cell Lines and Antibodies The cell line has been described previously The following antibodies were obtained from commercial sources: The mutated site was then confirmed by sequencing. Expression of the respective constructs was confirmed using Western blotting with specific antibodies. To experimentally identify the target genes of miRa-3p, we performed reporter-based screens as described below. As shown in Fig. To identify the regulatory sequence in the 3' UTR of NIK, we constructed additional reporters with mutated sequences in the seed region Fig.

The reporter containing the mutated miRa-3p seed sequence prevented the effects of anti-miRa-3p treatment Fig.

nf kb and cancer how intimate is this relationship right

B Reporter-based miRa-3p target gene screening. The red box represents the mutated target region. To assess the biological function of miRa-3p in apoptotic signals, we transfected miRa-3p mimics into the LoVo cells, and found that trans-fection with miRa-3p mimics promoted the apoptosis of the LoVo cells Fig. In addition, miRa-3p overexpression led to the activation of caspase-3 Fig. Collectively, these findings indicate that miRa-3p mediates apoptosis through the suppression of NIK in colonic cell lines.

To demonstrate the role of miRa-3p in cancer cell survival, we examined whether the transfection of miRa-3p mimics resulted in a killing effect against the cancer cells, and the number of apoptotic cells was determined by Hoechst staining.

The results revealed that the expression of miRa-3p facilitated tumor cell death Fig. Taken together, these lines of experimental evidence definitively support two notions: B Transfection with miRa-3p mimics promoted the apoptosis of the LoVo cells.

C Overexpression of miRa-3p led to the activation of caspase Increasing evidence has suggested the important role of miRNAs in cancer progression 22 For instance, miR, miR and miR have been shown to increase the resistance of CRC cells to 5-fluorouracil 5-FU 24 — 26and a polymorphism in pre-miRa has been shown to significantly correlate with the risk of developing CRC Furthermore, miR is increased in colorectal carcinoma, suggesting that it is a potential prognostic factor for CRC 28 — However, the role of miRa-3p in CRC remaines to be elucidated.

In this study, we mainly focused on the functional significance of miRa-3p in abnormal CRC cell proliferation. Our results revealed a profound downregulation of miRa-3p in all CRC cases, suggesting that the loss of miRa-3p is a prerequisite for the development of CRC.

nf kb and cancer how intimate is this relationship right

These results indicate that the downregulation of miRa-3p may be a common occurrence in CRC and that miRa-3p may be used as a biomarker to predict clinical outcome and metastasis in patients with CRC. In the present study, we identified NIK as a target of miRa-3p. By combining a specific inhibitor and mutations in the miRa-3p-binding site, we demonstrated that miRa-3p recognizes and negatively regulates the 3' UTR of NIK Fig.

Second, by introducing an miRa-3p precursor or inhibitor, we demonstrated that the amount of miRa-3p inversely correlates with the levels of expression and downstream signaling of NIK. Collectively, we provide definitive evidence demonstrating that miRa-3p negatively regulates NIK expression and activity. These findings suggest that an aberrant gene expression pattern correlates with the malignant phenotype, which provides important clues as to the clinical manifestations and may help identify therapeutic targets in CRC cells.

Roles of NF-κB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches

Moreover, our results provide evidence indicating that miRa-3p is an important tumor suppressor. Acknowledgments This study was funded by the Science and Technology Program.

We appreciate the work from all researchers in this article. CA Cancer J Clin. Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells. How intimate is this relationship. A key regulator in the immune system and in cancer. Cytokine Growth Factor Rev. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Role of microRNAa in normal and malignant hematopoietic stem cell function.