Oncogenic microRNA: miR21 Signal Pathway unvealed

1. Background: miR-21

• miR-21 is one of the best-studied oncogenic microRNAs (“oncomiRs”).

• Like other miRNAs, it regulates gene expression post-transcriptionally.

• Mechanism: It binds to complementary sequences in the 3′-UTR of target mRNAs → leads to either mRNA degradation or translation inhibition.

• Its targets are mostly tumor suppressor genes, phosphatases, and pro-apoptotic proteins.

2. DUSP8 (Dual Specificity Phosphatase 8)

• DUSP8 is a MAPK phosphatase.

• It dephosphorylates and inactivates MAP kinases, especially:

  • JNK (c-Jun N-terminal kinase)

  • p38 MAPK

• By doing this, DUSP8 acts as a negative regulator of MAPK signaling, which is central to stress response, proliferation, and apoptosis.

3. Molecular Interaction: miR-21 → DUSP8

• miR-21 directly binds to the 3′-UTR of DUSP8 mRNA.

• This results in:

  • Suppression of DUSP8 expression (reduced protein levels).

  • Loss of phosphatase activity against JNK/p38 MAPKs.

4. Pathway Consequences

• With less DUSP8, the JNK and p38 MAPK pathways remain phosphorylated (active).

• Outcomes:

  • Enhanced cell proliferation (due to sustained MAPK signaling).

  • Reduced apoptosis (as JNK/p38 balance is shifted).

  • Tumor progression, invasion, and chemoresistance in many cancers (glioblastoma, breast, gastric, etc.).

5. Simplified Flow

miR-21 ↑ → binds DUSP8 mRNA 3′-UTR → DUSP8 ↓ 
→ JNK/p38 MAPK dephosphorylation blocked → JNK/p38 stay active 
→ proliferation ↑, apoptosis ↓ → oncogenesis

✅ So, miR-21 acts like a brake-remover: by silencing DUSP8, it prevents the “off-switch” for stress-activated MAPKs, leading to unchecked cancer cell signaling.