AGO2 promotes tumor progression in KRAS-driven mouse models of non-small cell lung cancer
| Autor: | Rui Wang, Fengyun Su, Alice Xu, Arul M. Chinnaiyan, Yunhui Cheng, Sunita Shankar, Jennifer Hon, Lisha Wang, Rahul Mannan, Jean Ching-Yi Tien, Andrew Goodrum, Vijaya L. Dommeti, Seema Chugh, Xuhong Cao, Xiaoming Wang, Carson Kenum, Yuping Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Lung Neoplasms
Medical Sciences AGO2 Proliferative index MAP Kinase Signaling System Biology Malignancy medicine.disease_cause Proto-Oncogene Proteins p21(ras) Mice Carcinoma Non-Small-Cell Lung medicine KRAS Gene silencing Animals Allele Lung cancer neoplasms Multidisciplinary Argonaute Biological Sciences medicine.disease digestive system diseases respiratory tract diseases Mice Inbred C57BL Disease Models Animal Tumor progression Argonaute Proteins Cancer research Disease Progression Signal Transduction nonsmall cell lung cancer |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance RAS proteins (HRAS, NRAS, and KRAS) integrate extracellular trophic signals to promote cell proliferation. Constitutively active KRAS drives tumor initiation and progression in nonsmall cell lung cancer (NSCLC). As RAS proteins are often refractory to direct pharmacological inhibition, RAS-interacting proteins are under investigation as potential drug targets. We previously found Argonaute 2 (AGO2) to bind RAS and positively regulate RAS-dependent signaling pathways. AGO2 knockdown blunted proliferation in NSCLC cells containing a KRAS-activating mutation. Here, we demonstrate that AGO2 promotes tumor progression in multiple mouse models of KRAS-driven NSCLC. In these animals, Ago2 knockout impairs tumor growth, lowers pathologic grade, and inhibits KRAS signaling. Targeting the AGO2-KRAS interaction may hold future therapeutic promise in NSCLC and other KRAS-driven malignancies. Lung cancer is the deadliest malignancy in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA-induced silencing complex (RISC)—physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-Kras G12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell–specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance. |
| Databáze: | OpenAIRE |
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