Nanog in Cancer and Stem Cells - Coursework Example

Name: Tutor: Title: Cancer and stem cells Institution: Date: NANOG in cancer and stem cells There are two key properties contained by the stem cells. One is the capacity to renew itself and the second is the capacity to produce daughter cells that posses dissimilar, more controlled characteristics (Sun et al. 2011). One of the grouping in which stem cells exist is pluripotent. This is the ability to create every cell family in the body, as well as germ cells like stem cells of the embryo. Nanog is a major inducer of pluripotency concerned in stem cells maintenance. Because Nanog is the major gene whose role is protection of pluripotency in stem cells, it is then considered that Nanog might be promoting a populace of stem cells in cancer. In various tumours, stem cells in cancer have been discovered. These include skin, brain, prostate, breast, leukemia, ovarian and pancreatic tumours among others. Stem cells in cancer have comparable characteristics of cell regeneration and differentiation like the normal stem cell, and generate every cell in tumour. Recent research has illustrated that NANOG supports the characteristics of stem cells in cancer and resistance of prostate cancer to androgen deficiency (Jeter 2011). Development of tumor has long been identified to resemble atypical embryogenesis. The embryonic stem cell (ESC) self regeneration gene NANOG is supposedly expressed by a number of epithelial cancer cells although a fundamental function in development of tumor has remained uncertain. Some studies have shown that cancer cells which are cultured, and also xenograft- and human chief cancer cells of prostate express a useful alternative of NANOG. NANOG mRNA in cells of cancer is derived chiefly from NANOGP8 which is a retrogene locus (Rajasekhar & Vemuri 2009). NANOG protein is visible in the cancer cells’ nucleus and is highly expressed in enduring prostate tumors compared to corresponding benign tissues. NANOGP8 mRNA and/or levels of NANOG protein are augmented in populations of progenitor cell/recognized cancer stem (Jeter 2009). Significantly, extensive analysis of loss-of-function shows that RNA intervention mediated NANOG knockdown inhibits development of tumor, ascertaining a practical significance for NANOG expression in cells of cancer (Jeter 2009). NANOG small hairpin RNA cancer cells which are transduced display reduced lasting clonogenic and clonal growth, decreased production and, in some situations, differentiation which is altered. Hence, this illustrates that NANOG, a cell destiny regulatory fragment known to be essential for ESC self regeneration, also has an original role in development of tumor. NANOG plays a role in the immunomodulatory effect of mesenchymal stem cells. It is well recognized that cells which are terminally differentiated and originate from mesenchymal stem cells (MSCs) will mislay the capacity of immunomodulation. NANOG is identified as the hub transcription feature in the protection of stem cell particular characteristics or stemness. Sources show that the inhibitory effect of MSCs on activation of lymphocytes and proliferation was considerably weakened after the knockdown of NANOG (Sun et al. 2011). Additionally, NANOG RNAi and experiments of chromatin immunoprecipitation revealed that NANOG hold back the DKK-1 expression and secretion, transforming growth factor (TGF) beta1, 2 and 3, all of which are significant elements mediating immunomodulation capacity of MSCs. NFkB: Role in normal development and inflammatory response and role in cancer Constituents of the nuclear factor-kB (NFkB) transcription factor lineage are expressed differentially in the B cell family. NFkB is a lineage of five factors of transcription. These are RelA, Rel B, c-Rel, Nfkb1/p50 and Nfkb2/p52 (Nishikori 2005). Individual disruption or two subunits of NFkB display different shortcomings in growth, activation, and survival of B lymphocytes. Although, the function played by every NFkB during the development of B cell has been unclear by molecular compensation. NFkB is a lineage of dimeric transcription features which are highly regulated and play essential functions in responses during inflammation and reactions of immunology (Nishikori 2005). Even though they are regularly activated concurrently, alternative and classical NFkB pathways of activation have different regulatory roles, generating secondary responses of inflammation and regulating development of lymphoid organ, correspondingly. Transcription factor of NFkB is quickly activated through various stimuli that signal a cell or organism to infectious or stressful conditions (Pomerantz, Denny & Baltimore 2005). These entail viral and bacterial products like dsRNA and lipopolysaccharide. NFkB controls various genes which are involved in the development and role of the immune reaction, inflammation, regulation of cell development and anti-apoptotic reactions. Various stimuli trigger NFkB by creating IkBs phosphorylation and destruction, molecules of inhibition that retain NFkB within the cytoplasm. NFkB is conveyed in the cytoplasm of nearly every type of cell, where its action is managed y a lineage of proteins of regulation, named inhibitors of NFkB (IkB) (Nishikori 2005). As NFkB has roles in the lymphocytes’ proliferation, segregation, and survival, augmented activation also takes part in the oncogenesis of various malignancies (Pomerantz, Denny & Baltimore 2005). Abnormal NFkB creation in these tumor cells originate from genetic modifications or the NFkB pathways activation by indirect systems. Current observations have recommended that NFkB offers a lot of the necessities for cellular alterations (Nishikori 2005). The association of tumorigenesis and NFkB is complex, although, as this transcription feature can as well repress growth of tumor in a number of cases. In the past, Coley’s toxin which was employed to treat cancer is essentially lipopolysaccharide (LPS), a powerful activator of NFkB. Presently used agents of chemotherapy like radiation and cytokines also trigger NFkB signaling. On the contrary, LPS has as well been revealed to augment the development of investigational metastases in a model of murine tumor (Pomerantz, Denny & Baltimore 2005). The incidence of inflammation subsequent to surgery can support the metastases growth in patients, possibly following a similar system. These contradictory actions of NFkB are not clearly understood, although may somewhat be explained by the dissimilarities amid chronic and acute inflammation; acute inflammation slows down, cancer development, while chronic inflammation supports tumor growth (Nishikori 2005). The dissimilar range of target genes improved and cell types activated in these two cases might establish the outcome of NFkB creation on tumor result. NFkB aims at various genes that promote tumor development, inflammation, immortality of cells, survival of cells, angiogenesis, propagation, promotion of tumor, and metastasis. There is activation of NFkB pathway in several cancers. NANOG, NFkB, Torres and Watt Duel function of NANOG in mouse embryonic stem (ES) cells as STAT3 activator and repressor of NFkB controlled transcription (Torre & Watt 2008). Proteins (Rel A) of NFkB revealed to intermingle directly with the region of c-terminal Nanog; Nanog slows down NFkB transcription that is regulated, thus pluripotency is maintained. ES cells are cells of pluripotency generated from the internal cell mass of blastocysts. In mouse ES cells, self renewal depends on Stat3 activation by leukemia inhibitory factor (LIF) in conjunction with signaling of bone morphogenic protein. Nanog which is the transcription factor is vital in pluripotency maintenance although the systems involved are poorly comprehended. An examination was done investigate the functional relations of Nanog with the pathways of Stat3 and NFkB. Nanog and Stat3 were discovered to bind to and trigger promoters of Stat3-dependent synergistically (Torre & Watt 2008). It was also discovered that Nanog attaches to proteins of NFkB; although, Nanog attaching reducing transcriptional action of NFkB proteins. Endogenous activity of NFkB and expression of target-gene augmented in the course of ES cells differentiation. Over appearance of NFkB proteins endorsed differentiation, whereas slowing down of NFkB signaling, by inherent ablation of the Ikbkg genetic material or over appearance of the IkappaBalpha super-repressor, augmented appearance of markers of pluripotency. For pluropotency maintenance of mouse ES cells, Nanog inhibits NFkB and work together with Stat3 (Torre & Watt 2008). The genetic material Nanog is conveyed in embryonic tissues ranging from 3.5-8.5 dpc and is comparatively powerfully expressed in the kidney, liver, testis, spleen, and ovary (Torre & Watt 2008). It is as well conveyed in ESCs, EC cells, embryonic germ cells and reduces in the course of ESC differentiation. It is needed for pluripotency maintenance. In vitro, deficiency of Nanog leads to segregation. Nanog over expression can sustain pluripotency of ESC without other associated factors of pluripotency (Rajasekhar & Vemuri 2009). Actually, over expression of Nanog alone has been discovered to decrease ESCs differentiation in differentiation-inducing circumstances. This consequence is also observed in the leukemia inhibitory factor (LIF) absence. Pluripotency of Nanog is through signal transducer activation and activator of transcription 3 (Stat3) and suppression of nuclear element of kappa light polypeptide genetic material enhancer in B-cells (NFkB) (Rajasekhar & Vemuri 2009). The NFkB expression is thought to be entailed in the neurodegeneration progress. Levels of Nanog expression in the mouse mesenchymal stem cells (mMSCs) were investigated using Western blotting. NFkB expression was investigated using Western blotting and RT-PCR, and also fluorescent microscope following immunocytochemical staining. Results showed that the Nanog protein levels of expression in Nanog-mMSCs were considerably increased and the amount of NFkB mRNA and expression of protein in Nanog-infected mMSCs were considerably lower compared to the control groups of Mock-mMSCs and the mMSCs (Torre & Watt 2008). Findings imply that mMSCs hereditarily adapted to over express Nanog can result to the inhibition of NFkB expression (Rajasekhar & Vemuri 2009). This inhibition of NFkB may possibly have significant implications for the neurodegeneration treatment, and thus further scientific examinations of these relations will have important impact on potential clinical efforts to ease disease progression. Brachyury regulates Nanog to repress differentiation genes controlled by NFkB in colorectal cancer cells Brachyury is a human protein encoded by the T genetic material (Huang 2010). It is also a transcription factor in the T-box compound of genetic material. The primary identification of Brachyury was for its role in notochord differentiation in mouse and mesoderm specification (Kilic 2011). In cells of cancer, it is known that Brachyury stimulates EMT, Nanog upstream, resistance of radiotherapy, CSC markers and self-renewal CSCs (Kilic 2011). Cells that generate Brachyury and Nanog also generate stem cell marker of CRS. One of the major key changes in expression of genes after reduction in Brachyury was in a genetic material called Nanog. Nanog is a major stimulator of pluripotency associated in the stem cells maintenance (Jeter 2009). Very infrequent brachyury and nanog positive cell would stay in the epithelial form. Colorectal tissues go through uninterrupted renewal to sustain normal operation (Huang 2010). The process of renewal is produced by multipotent, stem cells that are tissue specific that bring about specific cell types of this tissue (Huang 2010). Such stem cells that are tissue specific are important for controlling self-regeneration and differentiation with the intention that proliferation of cell is stabilized with turnover. Signaling via constituents of the beta-catenin pathway is important in sustaining stem cells in several epithelial tissues, as well intestine (Huang 2010). Additional to its function in sustaining mature stem cells, beta-catenin is vital in the pluripotency maintenance in mouse and ES cells (Kilic 2011). The cells which initiate colorectal cancer (CRC) are the cancer stem cells (CSCs) (Kilic 2011). Colorectal tumors go through epithelial to mesenchymal evolution (EMT)-like procedure at the enveloping front, facilitating invasion and metastasis, and present research has connected this procedure to the attainment of stem cell-like characteristics (Kilic 2011). It is of essential significance to comprehend the molecular occurrences resulting to the founding of cells that initiate cancer and how these systems relate to cellular switch in the course of tumourigenesis (Huang 2010). An in vitro mechanism is used to review alterations in CRC cells at the enveloping front (mesenchymal-like cells) and inner mass (epithelial-like cells) of cancer. Results indicate that the stimulator of the mesoderm Brachyury is conveyed in CRC cells subpopulations that look like enveloping front mesenchymal-like cells, where it operates to inflict properties of CSCs in an entire reversible way, implying reversible formation and variation of such cells (Huang 2010). Brachyury itself controlled by the oncogene beta-catenin, controls Nanog and the other stemness indicators including a section of indicators defining CRC-CSC whose occurrence has been connected with poor prognosis of patients (Sarkar 2012). Related regulation of Nanog via Brachyury was noted in other lines of cells, implying this may be a pathway general to cells of cancer going through mesenchymal alteration. It is suggested that Brachyury might control Nanog in CRC cells that resemble the mesenchyme to inflict a plastic-state, facilitating fitness of cells to react to signals prompting attack or metastasis (Kilic 2011). Thus, Brachyury controls Nanog to inhibit differentiation genes managed by NFkB in colorectal cancer cells (Sarkar 2012). Bibliography Huang Z et al. 2010, Overepression of Nanog gene in mouse mesenchymal stem cells and its influence on NFkB expression, Chinese Journal of Biotechnology Vol. 26 Issue 5 pp 671-678. Jeter CR et al. 2009, Functional evidence that the self-renewal gene NANOG regulates tumor development, Stem Cells, Vol. 27 Issue 5 pp 993-1005. Jeter CR et al. 2011, NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation, Oncogene, Vol. 30 Issue 36 pp 3833-45. Kilic N et al. 2011, Brachyury expression predicts poor prognosis at early stages of colorectal cancer. European Journal of Cancer. 47, 1080-1085. Nishikori M 2005, Classical and Alternative NFkB activation Pathways and Their Roles in Lymphoid malignancies, J. Clin. Exp. Hematopathol, Vol. 45 Issue 1 pp 15-21. Pomerantz J., Denny E & Baltimore D 2005, CARD11 mediates factor-specific activation of NFkB by the T cell receptor complex, The EMBO Journal, Vol. 21 Issue 19 pp 5184-5194. Rajasekhar K & Vemuri M 2009, Regulatory networks in stem cells. New York, Humana Press. Sarkar D et al. 2012, BRACHYURY confers cancer stem cell characteristics on colorectal cancer cells, International Journal of Cancer Vol. 130 Issue 2 pp 328-37. Sun Z et al. 2011, NANOG has a role in mesenchymal stem cells’ immunomodulatory effect, Stem Cells Dev., Vol. 20 Issue 9 pp1521-8. Torre J & Watt FM (2008), Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkB and cooperating with Stat3, Nat Cell Biol Vol 10 Issue 2 pp 194-201. Read More