Review Article

Molecular Mechanisms Underlying the Role of MicroRNAs in the Chemoresistance of Pancreatic Cancer

Figure 1

MicroRNA and their involvement in oncologenic signaling cascades in pancreatic cancer. EGFR pathway. Activation of the EGF receptor results in autophosphorylation of key tyrosine residues which subsequent activation of downstream signalling cascades including the RAS/extracellular signal regulated kinase (ERK) pathway, the phosphatidylinositol 3-kinase (PI3) pathway and the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway. All of them result in cell survival promotion. Notch pathway. A ligand on one cell induces a series of proteolytic cleavage events in a Notch receptor on a contacting cell. These cleavage events release the Notch intracellular domain (NICD), which translocates to the nucleus to activate the transcription of Notch target genes together with CSL (CBF1/Suppressor of Hairless/LAG-1). The notch signaling pathway is important for cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes. Hedgehog pathway. Hedgehog is a secreted ligand that binds to its receptor, Patched (PTCA1). When PTCA1 is activated, it leads to inhibition of the Smoothened (Smo) receptor. Smo is then able to inhibit the phosphorylation and cleavage of Gli, which prevents the formation of repressive Gli (GliR) and promotes the formation of activated Gli (GliA). GliA then translocates into the nucleus and initiates transcription of target genes, which play a role in stem cell regulation. TGF-β pathway. TGF receptors are activated after binding with their ligand, which leads to further phosphorylation of receptor-regulated SMADs (mainly SMAD2 and SMAD3). Phosphorylated SMAD2/3 form heteromeric complexes with SMAD4, which accumulate in the nucleus and activate transcription of different genes, including those responsible for cell cycle arrest. Wnt pathway. In the absence of signal, action of the destruction complex (CKIα, GSK3β, APC, and Axin) creates a hyperphosphorylated β-catenin, which is a target for ubiqitination and degradation by the proteosome. Binding of Wnt ligand to a Frizzled/LRP-5/6 receptor complex leads to stabilization of hypophosphorylated β-catenin, which interacts with TCF/LEF proteins in the nucleus to activate transcription.
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