Pathobiology of microRNA in health, disease and tumorigenesis

1. What is microRNA?

• They are transcribed from DNA but do not make proteins.
• Their function is to control how much protein is made from other genes.
• One miRNA can regulate many different mRNAs, so it can control an entire group of cellular functions.

MicroRNAs are small non-coding RNAs that regulate gene expression after transcription by inhibiting translation or causing degradation of target mRNA.

2. Normal formation and action

Steps

1. A miRNA gene is transcribed to form primary miRNA (pri-miRNA).
2. It is processed in the nucleus into a hairpin-shaped pre-miRNA.
3. Pre-miRNA moves to cytoplasm.
4. The enzyme Dicer cuts it to form mature miRNA.
5. One strand joins the RNA-induced silencing complex (RISC).
6. The miRNA-RISC complex binds to a complementary target mRNA.
7. It either:
   • destroys/cleaves the mRNA, or
   • blocks its translation into protein.

Flowchart to replicate

miRNA gene
    ↓ transcription
Primary miRNA (pri-miRNA)
    ↓ nuclear processing
Pre-miRNA hairpin
    ↓ export to cytoplasm
Dicer enzyme
    ↓
Mature miRNA
    ↓
RISC complex
    ↓ binds target mRNA
mRNA degradation OR inhibition of translation
    ↓
Decreased protein production

3. Role in health

• Embryonic development and cell differentiation
• Cell proliferation
• Apoptosis
• Stem-cell maintenance
• Immune responses
• Tissue repair
• Maintenance of normal cell identity

Easy analogy

• DNA gives the order.
• mRNA carries the order to the factory.
• miRNA is like a brake or volume-control button.
• It reduces protein production when the protein is not needed.

4. Role in disease

• Cancer
• Cardiovascular disease
• Inflammatory and autoimmune disorders
• Neurologic diseases
• Fibrosis
• Metabolic disorders

Abnormal miRNA → abnormal protein expression → disturbed cell function → disease

5. Role of microRNA in tumorigenesis

• Cell-cycle progression
• Apoptosis
• DNA repair
• Growth-factor signaling
• Angiogenesis
• Invasion and metastasis

1. an oncogene, called an oncomiR, or
2. a tumor suppressor.

A. miRNA acting as an oncogene: oncomiR

Mechanism

Overexpression of oncogenic miRNA
          ↓
Suppression of tumor-suppressor mRNA
          ↓
Reduced tumor-suppressor protein
          ↓
Increased cell survival and proliferation
          ↓
Tumor formation / progression

Example: miR-21

• reduced apoptosis
• increased proliferation
• increased invasion and metastasis

Overexpression of miR-21 acts as an oncomiR by suppressing tumor-suppressor genes, thereby promoting tumor growth, invasion and metastasis.

B. miRNA acting as a tumor suppressor

Mechanism

Loss or reduced expression of tumor-suppressor miRNA
          ↓
Oncogene mRNA is no longer inhibited
          ↓
Increased oncoprotein synthesis
          ↓
Uncontrolled proliferation and reduced apoptosis
          ↓
Tumorigenesis

Example: let-7

Loss of let-7
      ↓
Increased RAS protein
      ↓
Increased proliferative signaling
      ↓
Cancer development

Loss of let-7 permits increased RAS expression and promotes tumorigenesis.

6. Why miRNA abnormalities occur in cancer

• Deletion of miRNA genes
• Amplification of miRNA genes
• Chromosomal rearrangements
• Abnormal DNA methylation or other epigenetic changes
• Mutations affecting miRNA processing machinery, such as Dicer-related pathways
• Altered transcription of miRNA genes

7. Final comparison table

8. Short-answer format for MD pathology exam

MicroRNAs are small non-coding RNAs, approximately 21-30 nucleotides long, that regulate gene expression post-transcriptionally. They are processed from primary miRNA transcripts and, after Dicer-mediated maturation, become incorporated into the RNA-induced silencing complex (RISC). The miRNA-RISC complex binds target mRNA and causes mRNA degradation or inhibition of translation.

In normal tissues, miRNAs regulate development, differentiation, proliferation, apoptosis and cellular homeostasis. In tumors, abnormal miRNA expression contributes to tumorigenesis by altering expression of oncogenes and tumor-suppressor genes. Overexpressed miRNAs may act as oncogenes, or oncomiRs, by suppressing tumor-suppressor mRNAs. For example, miR-21 can promote tumor growth and invasion through suppression of tumor-suppressive targets. Conversely, loss of tumor-suppressor miRNAs permits increased expression of oncogenes; for example, loss of let-7 can increase RAS expression. Thus, miRNA dysregulation can promote cell proliferation, inhibit apoptosis, and facilitate invasion and metastasis.

Memory trick

• More oncomiR → less tumor suppressor → cancer
• Less tumor-suppressor miRNA → more oncogene → cancer