An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development

Abstract

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRASG12C-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.

Argonaute Proteins Take Center Stage in Cancers

“…Mediates oncogenic activity of miR-10a [17] Recruites RNA Polymerase II to promoters of cancer related genes [18][19][20] Silencing inhibits hepatocellular carcinoma cells growth and migration [21] Silences interferon induced apoptosis via scattering of dsRNAs in breast cancer cells [22] Necessary for differentiation of leukaemia cells upon treatment with retinoic acid [23] Represses VEGF expression and vascularization under hypoxic stress [24] Mediates suppressive activity of miR-145-5p [25] Silencing inhibits growth of hypopharyngeal cancer cells [26] Stabilizes MYC mRNA stability [27] Enhances the activity of mutant KRAS protein [28,29] Overexpression results in decreased proliferation and motility of lung cancer cells [30] Interacts with ERβ receptor [31] Required for differentiation of leukaemia cells upon treatment with 1,25-dihydroxyvitamin D [32] Recruits Rad51, MMSET and KAT5 to DNA breaks [33,34] Enhances angiogenesis [35,36] Promotes telomerase activity [37]…”

“…The interaction markedly contributed to cytotoxicity of the drugs [ 60 ]. Furthermore, AGO2 was found to be an important binding partner of the protein product of KRAS , a well-characterized oncogene ( Figure 2 b) [ 28 , 29 ]. It was shown that high levels of AGO2 protein enhanced neoplastic transformation driven by KRAS mutants, whereas knockout of AGO2 resulted in the growth arrest of KRAS-dependent cancer cells [ 28 ].…”

“…It was shown that high levels of AGO2 protein enhanced neoplastic transformation driven by KRAS mutants, whereas knockout of AGO2 resulted in the growth arrest of KRAS-dependent cancer cells [ 28 ]. Moreover, AGO2-mutated KRAS interaction holds crucial importance in pancreatic ductal adenocarcinoma progression, where AGO2 expression is required for overcoming oncogene-induced senescence and cancer development [ 29 ].…”

“…( a ) The total number and ( b ) the number of cancer-related studies of AGO1–4 found in PubMed using keywords “AGO1/AGO2/AGO3/AGO4” and “cancer”, until 13 January 13 2021. ( c ) Highlighted studies that show the detailed molecular mechanisms of AGO1–4 in cancer-related processes, based on ref [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Created with BioRender.com (accessed date: 21 January 2021).…”

“… Graphical depiction of AGO-regulated tumor associated processes. ( a ) AGO4 enhances miRNA methylation, which inhibits miRNA activity [ 38 ]; ( b ) mutated KRAS protein negatively regulates AGO2 activity [ 28 , 29 ]; ( c ) AGO proteins mediate RNAi in cytoplasm [ 1 ] and ( d ) nucleus [ 47 ] in cancer cells; ( e ) AGO1 and AGO2 bind to promoters of oncogenes to activate transcription [ 18 , 19 , 20 ]; ( f ) AGO1 translational read-through variant, AGO1x, inhibits interferon-induced apoptosis via the depletion of nuclear dsRNA [ 22 ]; ( g ) AGO2 recruits RAD51, MMSET and KAT5 proteins to dsDNA breaks to facilitate DNA repair [ 33 , 34 ]; ( h ) AGO2 promotes telomerase activity [ 37 ]; ( i ) AGO2 tethers MYC mRNA and increases its stability [ 27 ]; ( j ) AGO2 activity is regulated via ERβ [ 31 ]. Created with BioRender.com (accessed date: 21 January 2021).…”