Causes And Effects Of Micrornas

An effective breast cancer treatment in some women can be traced to the root of the disease. Some of the most aggressive form of breast cancers are caused by a transmembrane receptor protein known as Human Epidermal Growth Factor Receptor 2 (HER2) which is a member of the HER family of receptor tyrosine kinase. Approximately 20,000 HER2 receptor are normally expressed on surface of healthy breast cell however, in about 25% of breast cancer cells the HER2 protein is overexpressed resulting in tumour cells with as many as over 2 million receptors present on their surface. This cancer is known as HER2 positive (HER2+). The effect of HER2 overexpression is an increase in receptor mediated intracellular signalling causing the cell

As the cells change, it begins to divide rapidly causing a tumor to form. The term “breast cancer” refers to a malignant tumor that has developed from cells in the breast. Breast cancer can begin in different areas of the breast, or in some cases, the tissues in between. There are many different types of breast cancer, including non-invasive, invasive, recurrent, metastatic breast cancer, as well as the intrinsic or molecular subtypes of breast cancer. Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20-30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality.

MicroRNAs (miRNA) are small noncoding RNA, usually 17-25 nucleotides long that are able to bind complementary sequences of target messenger RNA (mRNA) and to induce both their degradation and translational repression (Fortunato, et al 2014). They are one of the most significant classes of non-coding RNA molecules (eg. small interfering RNA (siRNA) and ribozymes) that act within the cell. MiRNAs are also evolutionary conserved in different species from plants to humans and are encoded by their respective genes (Bader, 2012).

Breast cancer exists today as a vicious disease which has multiple facets for killing its host. The largest indicator of survival rate is length of time alive after diagnosis with the disease, and then whether or not the disease has metastasized to a new location in the body. For breast cancer patients, the 5-year survival rate of patients below Stage 4 is 90%. The stages below the 4 stage represent the stages where the breast cancer has not metastasized into other regions of the body. When breast cancer metastasizes into another region of the body, the 5-year survival rate of these individuals drops to 22%. The most common places of metastasis include the brain, liver, and lungs. The goal of studying cell line 231BR is that of

approximately 80 - 90% of pancreatic cancers, 50% of colorectal cancers, 30% of thyroid cancers, 30% of NSCLC and 5% of breast and prostate cancers 13,14 [13,14]. RAS proteins are a family of GTPases activated by cell surface receptors by displacing guanosine diphosphate (GDP) molecules with guanosine triphosphate (GTP) molecules. Active GTP-RAS is then able to recruit and activate several intracellular signaling pathways, such as RAS-REF-MEK-ERK (also known as MAPK/ERK Pathway) and phosphoinositide-3 kinase (PI3K) pathway. In the RAS-RAF-MEK-ERK pathway, the RAS regulates the activity of downstream RAF proteins which are then able to phosphorylate and activate MEK. Activation of MEK, in turn, phosphorylates and activates ERK which is responsible for activating a range of transcription factors within the nucleus that are involved in cell proliferation 15 [15]. The other RAS dependent pathway is the complex PI3K pathway where the catalytic p110 subunit of the PI3K is activated that phosphorylates PIP2 to PIP3 or Phosphatidylinositol (3,4,5) Triphosphate which in turn phosphorylates and activates AKT, AKT plays a critical role in regulating cellular growth and apoptosis. Conversely, the tumor suppressor protein Phosphatidylinositol 3 Kinase Phosphatase with Tensin homolog (PTEN)

Internationally, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer related death amongst women. (CITE) Each year an estimated 1.7 million new cases are diagnosed worldwide, and more than 500,000 women will die of the disease. (CITE) According to (CITE), somewhere in the world one woman is diagnosed with breast cancer every 19 seconds and more than three women die of breast cancer every five minutes worldwide. (CITE) Breast cancer is a heterogeneous condition that contains more than 20 different subtypes. (ALC) These various subtypes are grouped based upon the genes in which they express. This includes the genes for the estrogen receptor (ER), progesterone receptor (PR), and HER-2 receptor, all of which influence cell growth rate and the metastatic potential of cancer cells. (CITE)[8, 9 ALC] The purpose of this paper is to explore XYZ of the HER-2 positive breast cancer subtype.

The purpose of this experiment is to express cell signalling by finding the value of unknown samples of pERK (phosphorylated extracellular signal regulated kinases) using healthy (HMEC) and cancer (SKBR3) mammary cells. The observed cell receptor is known as CXCR4 which is stimulated by its agonist CXCL12 (protein). A negative control (antagonist AMD3100) was also used to ensure that the response is specific to CXCR4. The experiment is performed by finding the phosphorylated ERK (extracellular- signal- regulated kinases) using enzyme- linked- immunosorbent assay

There are many evidences that demonstrates role played by miRNA in various cardio vascular diseases. In a study Dicer was deleted that led a phenotype in myocardial and vascular lineage. In cardiac myocytes miR-1 is the most populated. Expression levels of several miRNA like miR-10a, miR-145, miR-143 and miR-126100−102 In a study it showed that hypoxia had potential to induce the expression of miR-210 in endothelial cells. It was concluded that overexpression of miR-210 leads to increase in capillary like structure formation, when miR-210 was inhibited the tube formation and migration was decreased (15).

Aim1. To define the role of miR-125a and miR-223 in modulating Aicda and Prdm1 expression, CSR and plasma cell differentiation, by overexpression of miR-125a and miR-223 or inhibiting these microRNA, white mRNA “sponge” that competitively inhibit miR-125a or miR-223 using retrovirus construct.

Western blot showed that miR-138-5p could also inhibit the expression of PCNA, which was thought to be a proliferation biological marker13 .These results showed that miR-138-5p inhibited the proliferation of breast cancer cells.

We have therefore further characterized the functional roles of IL-6 in the metastasis of breast cancer and demonstrated that IL-6 is a promising molecular target for the development of molecularly-targeted therapeutic strategies against IL-6. In this study, to characterize the extent to which IL-6 is capable of inducing a metastatic phenotype, we established IL-6 over-expression cell lines MCF-7IL-6 2# and MCF-7IL-6 14# and IL-6 knockdown cell lines MDA-MB-231/IL-6-/+. We employed the breast cancer model in conjunction with gene expression profiling with RNA-seq data as an efficient tool for high-throughput analysis and to screen for differentially expressed genes. Our aim was to identify the gene candidates essential for IL-6-promoted tumor metastasis and invasion by comparing IL-6 over-expression cell lines MCF-7IL-6 2# and MCF-7IL-6 14# with MCF-7, IL-6 knockdown cell lines MDA-MB-231/IL-6-/+ with MDA-MB-231. We found that IL-6 significantly promoted breast cancer metastasis in vivo and in vitro. Furthermore, we also suggested a novel role for the CDKN1A and EPAS1 as a crucial factor in the IL-6-induced migration and invasion of breast

The general characteristics of tumor include the increased proliferation rate and migration ability, the loss of cellular identity and the failure of controlling the cellular death. How is miRNA involved in the development of cancer? Kolokythas et al. considered it was possible that the involvement of miRNA in cancer merely reflected the loss of normal cellular characteristics during malignant transformation [21]. Furthermore, microRNAs have also been documented to have roles in all of the cancer hallmarks defined by Hanahan and Weinberg in 2011[18-13].

DICER expression was evaluated by immunohistochemistry in a large tissue microarray containing 87 serous and 39 non-serous ovarian tumors. DICER expression negatively correlated with node status and tumor grade. Low DICER expression in serous tumors was associated with poor overall survival. A similar trend was found for all tumors in the dataset but the analysis was not performed for specific histotypes. MicroRNA profiling in tumors with low DICER showed significant downregulation of many microRNA molecules compared to tumors with high DICER expression. Additionally, tumors with low DICER expression also had low estrogen receptor expression (19). On the other hand, Zhang et al (20) did not find any significant difference in DICER or DROSHA expression by QPCR or immunohistochemistry

There are three kinases involved in the MAPK phosphorelay system which act in series: MAPK kinase kinase (MKKK), MAP kinase (MKK) and MAPK (JNK), which respond to external stimuli, shown in Figure 1 (Johnson et al, 2005). There are a wide range of stimuli that can activate regulation of JNK including ultraviolet irradiation, growth factors (tumour necrosis factor-), cytokines and even protein synthesis inhibitors (anisomycin) activates MKKK and using phosphorylation to activate the next kinase in the process, MKK, which in turn phosphorylates MAPK (Dérijard et al, 1994; Kallunki et al, 1994; Lange-Carter et al, 1993). There are 13 different MKKK including MEKK1-4, MLK2/3 and DLK that can act in the JNK pathway which provides the ability to responds these different external signals (Brown and Sacks, 2009; Dérijard et al, 1994; Johnson and Lapadat, 2002; Kallunki et al, 1994). In the sequence of MEKK there are specific motifs

As it has been suggested functional miRNA are present above 0.1% of the total reads. A 0.1 % cut-off in was applied in all cell lines, for selection of functionally relevant miRNAs in our analysis [91, 101]. In comparison to U2932 and U2932-EBV, our data show that 52 out of 68 miRNA in total cellular miRNA profile, and 49 out of 57 miRNA in Ago2 miRNAs profile, even though at different ratios but were present in both U2932 and U2932-EBV cells(appendix x). In comparison of SUDHL5 and SUDHL5-EBV cells, we found that 55 out of 84 miRNA, in total cellular miRNA profile, and 46 out of 73 miRNA, in Ago2 miRNAs profile, even though at different ratios but were present in both SUDHL5 and SUDHL5-EBV cells .