Role of MicroRNAs in cancer Therapeutics

Role of MicroRNAs in Cancer Therapeutics


Introduction To Cancer

  • Cancer is a consequence of disordered gene expression in which gene regulatory networks are broken down that maintain a balance between oncogenes and tumor suppressor genes.
  • Cancer is a major human health problem worldwide and the leading cause of death in many parts of the world. More than 60 percent of new cancer cases worldwide occur in Africa, Asia, and Central and South America, and about 70% of cancer deaths occur in these regions. There were 14 million new cases and 8.2 million cancer-related deaths worldwide in 2012.
  • The majority of cancer deaths occur in underdeveloped and developing countries. The world’s cancer deaths continue to rise, with around 9 million people dying from cancer in 2015 and around 11,4 million in 2030.
  • Cancer is associated with an abnormal increase in the number of cells and changes in mechanisms that regulate the birth and spread of new cells. Cancer is unique in comparison to other tumor-forming processes due to its ability to invade the surrounding fresh tissues.
  • Cancer development is a multi-step process during which normal cells gradually acquire abnormal proliferative and invasive properties.
  • Tumorigenesis is a unique form of the natural selection process that involves the accumulation of multiple somatic mutations in populations that are undergoing a neoplastic transformation.
  • Numerous exogenous chemical, physical or biological factors known as carcinogens are known to cause cancer.
  • Carcinogens affect human beings who vary in their ability to cope with them due to genetic, psychological, social, economic variations, as well as to endogenous processes in the human body that also contribute to the development of cancer.
  • Exogenous carcinogens are usually grouped as physical, chemical, and biological agents. Several forms of molecular alterations, such as gene amplification, insertions, deletions, rearrangements, and point mutations, have been documented in human cancers.
  • A number of positive and negative mediators of cell growth and differentiation have been identified and characterized that define the basic role of these genetic elements in neoplastic transformation and tumor development. Microarray-based gene expression studies have shown that cancer is a disorder involving abnormal gene expression.
  • Somatic mutations that occur during cancer development alter gene expression patterns that result in significant changes in cell physiology, including abnormally regulated cell proliferation, and invasive behavior.
  • However, the gene expression of a specific cancer signature can be used positively in the diagnosis and prediction of therapy responses.

Role of miRNAs

  • A family of small RNAs that control a broad variety of biological processes, including carcinogenesis, is microRNAs (miRNAs). miRNAs are highly dysregulated in cancer cells.
  • MiRNAs can act as either oncogenes or tumor suppressors under some conditions. The dysregulated miRNAs have been shown to influence the hallmarks of cancer, including maintaining proliferative signaling, evading growth suppressors, preventing cell death, initiating invasion and metastasis, and causing angiogenesis.
  • Around 30% of the human genes are regulated by miRNAs, half of which are aligned with or situated in delicate loci. The deregulation of miRNAs in tumor cells shows the modulation of tumor growth. Some miRNAs can simply function as tumor genes and others may act as tumor suppressors.
  • MicroRNAs have often been found in fragile chromosome regions that are susceptible to structural re-arrangement, deletion, and amplification and have therefore been implicated in malignancy.
  • All available evidence, in particular the expression profile data, points to almost ubiquitous deregulation of miRNA expression in human cancers.
  • The rationale for the role of miRNA as a tumor suppressor or oncogene is based on different types of evidence, provided as follows:
  1. Widespread dysregulation of miRNA expression in diverse cancers
  2. Loss or gain of miRNA function in tumor formation, owing to mutation, deletion, or amplification.
  3. Direct evidence of tumor-promoting or tumor-suppressing activity, using animal models
  4. Detailed information of cancer-relevant targets that throw light on how miRNA participates in oncogenesis
  • The first report on the involvement of miRNA in cancer development was published in 2002 in the Chromosome 13 deletion study, the most frequent chromosome abnormality in chronic lymphocytic leukemia ( CLL). Calin et al. ( 2002) found two miRNA genes, mir-15 and mir-16, located within this 30-kb deletion and whose miRNAs were absent or down-regulated in the majority (68%) of cases.
  • It was suggested that these two miRNAs were involved in the development of CLL in some way. It has now been generally recognized that the global loss of miRNA increases tumorigenesis.
  • Similarly, several later studies have shown that miR-34a was a direct transcriptional target of the p53 tumor suppressor protein, commonly known as a cellular gatekeeper, who is a critical regulator during cellular stress.
  • Considering their potential implications for tumor development, numerous efforts have focused on miRNA profile expression in various types of cancers such as lymphoma, lung cancer, colorectal cancer, myeloid and lymphoid leukemia, breast cancer, prostate cancer, ovarian cancer, and testicular germ cell cancer.
  • MicroRNA expression profiles in cancerous conditions provide important insights for a deeper understanding of tumor development or metastases, as well as cancer diagnosis and prognosis.
  • The expression profile of miRNA in cancerous conditions appears to be specific to a particular type of tissue since different types of tumors have distinctive patterns of miRNA expression.
  • For example, unique miRNA signatures that distinguish benign tumors from carcinoma tumors have been established for prostate cancer. A number of miRNAs are up-regulated, while several others are down-regulated during tumorigenesis.

Several mechanisms have been put forward for abnormal expression of miRNAs during cancer:

1. The discovery of miRNA loci at a chromosome breakpoint and specific genomic regions associated with cancer
2. The expression of miRNA may be influenced by the regulation of epigenetic silencing such as methylation and histone-modification losses.
3. Failure of the Drosha-processing step leads to widespread deregulation of the miRNAs
4. The processing of miRNA may be influenced by the point mutation of the precursor miRNA
5. Impairment of the miRNA function by introducing mutations in the target sequence

Role of MicroRNAs in cancer Therapeutics

microRNAs and the possible mechanisms.

  • let-7 and miR-34- Tumors in cancer cells have reduced expression of suppressive genes. The tumor suppressor miRNAs adversely induce cell division or apoptosis which stops the growth of the tumor. miRNAs are known to be tumor suppressors for families let-7 and miR-34.
  • miR-34a- Loss of miR-34a expression is linked with metastasis and recurrence of prostate cancer while restoring miR-34 expression is linked to the development and infiltration of clonogenic cells, chemotherapy apoptosis and cell activation, and pancreas radiation.
  • miR-34c- The family miR-34 can control expression and p53 mutation whilst the MYC target miR-34b and MYC target miR-34c. A loss of expression by miR-34 members of the family has attenuated DNA damage-induced oncogenesis due to the p53-dependent and p38-mitogen-activated protein kinases.
  • let-7, miR-200, and miR-30 – The family let-7, miR-200, and miR-30 are all thought important for the control of stem cells of breast cancer. In breast-cancer stem cells, the Let-7 family is unregulated.
  • miR-27a- Antisense miR-27a blocks the transversal cell cycle and triggers cell death.
  • miR-205- Inhibits downstream mediator Akt activation and improves reactivity to tyrosine kinase inhibitors.
  • miR-101- Promotes apoptosis and suppresses tumorigenicity.
  • miR-26a- Inhibits the proliferation of cancer cells, causes tumor-specific apoptosis and protects the progression of the disease without toxicity.

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More To Read…

 

  1. Micro-RNA (miRNA): Biogenesis & Function
  2. Regulation of miRNA