The Role of microRNAs in the Regulation of Apoptosis

miRNA in cancer: apoptosis which is also known as programmed cell death is very important in animal’s development and disease. However, any dysregulation in apoptosis can lead to various neoplastic processes (NEOPLASIA is the abnormal growth and proliferation of abnormal cells or abnormal amount of cells due to a benign or malignant process). ApoptomiRs is the miRNA that regulates the apoptosis and this can be proapoptotic (that leads to apoptosis) or antiapoptotic.

Drosophila gene banatam are the first miRNA that regulates the apoptosis by suppressing the proapoptotic factor hid, thus facilitating proliferation.

In 2002 , the first evidence came into light that miRNAs also play role in cancer ( termed oncomiRs) development. In this study they found that tumor suppressor genes at chromosome 13q14,which is frequently deleted in chronic lymphocytic leukemia(CLL).In CLL there is increased number of nondividing malignant B cells which overexpresses the Bcl2( which is antiapoptotic B-cell lymphoma 2 protien. Instead for coding for tumor suppressor protein in CLL this region contained 2 mirna genes ,miR-15a and miR-16-1, which when overexpressed were found to negatively regulate antiapoptotic Bcl2 gene at the posttranscriptional level.

MiR-34 family is one of the example of tumor suppressor. Due to upregulation of p53( a potent tumor suppressor/ cell cycle regulator) miR-34 expression gets increased which leads to G1 arrest in a complementary and parallel fashion to mrnas that are directly activated by p53. Due to inhibition of silent mating information regulator 1 (SIRT1) by miR-34 upregulation of p53,p21and PUMA (p53- upregulated modulator of apoptosis ) takes place which in turn helps in regulating cell cycle and apoptosis and functioning as a tumor suppressor by modulating the SIRT1-p53 pathway.

MiR-34 also mediated growth arrest by direct regulation of cell cycle regulatory factors , such as cyclin E2(CCNE2) , cyclin dependent kinase 4 (CDK4) , E2F3, and hepatocyte growth factor receptor( c-Met) , ulitamtely leading to increased caspase- dependent cell death. MiR-34 also helps in inhibiting the proliferation and growth of tumor initiating cells in human pancrease and its overexpression in p53 deficient human pancreatic cancer cell partially restored the tumor suppressing function of p53. For cancer therapy MCL-1 expression is reduced by miR-29b which lead to tumor cell apoptosis . let-7a act as a tumor suppressor by directly targeting the expression of RAS and HMGA2, 2 widely recognized oncogenes.

MiRNA can also promote tumor development (oncogenes) depending on the functioning of target proteins they regulate. Examples include miR-155 and miR-17-92 cluster . these mirnas helps in tumor development in the B cell lymphomas. Ectopic expression in miR-155 in transgenic mice resulted in pre-B cell expansion, splenomegaly, and lymphopenia that preceded the development of lymphoblastic leukemia and lymphoma.
Other examples are miR-17-92 cluster are overexpressed in several neoplasms , including lymphoma ,multiple myeloma, medulloblastoma, and cancers of the lung, colon, breast, and prostate. Also miR-21 are overexpressed in neoplasms which includes glioblastoma, lymphomas,and cancers of the breast,ovary, colon, rectum, pancreas, lung, liver, gallbladder, prostate, stomach , thyroid , and cervix. miR-26 act as oncogene in glioma and glioblastoma by regulating PTEN, the molecular antagonist of the Akt pathway, resulting in the inhibition of RB1 and MAP3K2/MEKK2 expression and JNK – dependent apoptosis.