Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

Barceló, Carles; Etchin, Julia; Mansour, Marc R.; Sanda, Takaomi; Ginestà, Mireia M.; Lobo, Víctor J. Sánchez-Arévalo; Real, Francisco X.; Capellà, Gabriel; Estanyol, Josep Marı́a; Jaumot, Montserrat; Look, A. Thomas; Agell, Neus

doi:10.1053/j.gastro.2014.06.041

Cited by 55 publications

(53 citation statements)

References 68 publications

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“…An association of mutant KRAS with the RNA machinery through binding to HNRNPA2B1 was also reported (Barcelo et al, 2014), supporting a likely interface of RAS with the RNA processing machinery, including the hub protein AGO2 as observed in our study. The EGFR kinase was also recently shown to phosphorylate AGO2 in response to hypoxia, leading to inhibition of AGO2-mediated microRNA processing (McCarthy, 2013; Shen et al, 2013).…”

Section: Discussionsupporting

confidence: 90%

KRAS Engages AGO2 to Enhance Cellular Transformation

et al. 2016

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SUMMARY Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between RAS and Argonaute 2 (AGO2). Endogenously, RAS and AGO2 co-sediment and co-localize in the endoplasmic reticulum. The AGO2 N-terminal domain directly binds the Switch II region of KRAS, agnostic of nucleotide (GDP/GTP) binding. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells, and AGO2 overexpression enhances KRASG12V-mediated transformation. Using AGO2−/− cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Mechanistically, oncogenic KRAS attenuates AGO2 mediated gene silencing. Overall, the functional interaction with AGO2 extends KRAS function beyond its canonical role in signaling.

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Section: Discussionsupporting

confidence: 90%

KRAS Engages AGO2 to Enhance Cellular Transformation

et al. 2016

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“…Encouraging results have been reported by recent studies showing that pancreatic carcinoma could be inhibited by controlling several biomarkers such as SMAD4, CXCR2, ABCG2 and Kras [28–34]. In addition, Barcelo et al showed that HNRNPA2B1 interacts with and regulates oncogenic Kras in pancreatic ductal adenocarcinoma cells, and Tauler et al indicated that HNRNPA2B1 modulates EMT in lung cancer cell lines [17, 35]. However, a clear relationship between HNRNPA2B1 and EMT in pancreatic cancer and the signalling pathway involved remain elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Other factors also directly or indirectly trigger EMT, including claudins, occludin, fibronectin, twist1, ZEB2 and snail [11–15]. Zhou et al [16] indicated that HNRNPAB induces EMT and promotes metastasis of hepatocellular carcinoma by transcriptionally activating snail [16], and Barcelo et al [17] showed that HNRNPA2B1 plays a key role in Kras-mutation associated pancreatic cancer [17]. Based on these findings, HNRNPA2B1 might play an important role in EMT during tumour development.…”

Section: Introductionmentioning

confidence: 99%

HNRNPA2B1 regulates the epithelial–mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway

et al. 2017

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BackgroundHeterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is closely related to tumour occurrence and development, oncogene expression, apoptosis inhibition and invasion and metastasis capacities. However, its function in the epithelial–mesenchymal transition (EMT) of pancreatic cancer is not fully understood.MethodsBy comparing various wild-type pancreatic cancer cell lines, we determined which have a higher expression level of HNRNPA2B1 accompanied by the higher expression of N-cadherin and vimentin and lower expression of E-cadherin. Therefore, to elucidate the role of HNRNPA2B1 in EMT, we generated models of HNRNPA2B1 knockdown and overexpression in different types of pancreatic cancer cell lines (MIA Paca-2, PANC-1 and Patu-8988) and examined changes in expression of EMT-related factors, including CDH1, CDH2, vimentin and snail.ResultsThe results show that HNRNPA2B1 promotes EMT development by down-regulating E-cadherin and up-regulating N-cadherin and vimentin, and also stimulates the invasion capacity and inhibits viability in human pancreatic cancer cell lines, the similar results in vivo experiments. Moreover, we found that HNRNPA2B1 likely regulates EMT progression in pancreatic carcinoma via the ERK/snail signalling pathway.ConclusionsThe results of this work suggest that HNRNPA2B1 inhibition has potential antitumour effects, which warrants in-depth investigation.

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“…Non-gastric cells HNRNPA2B1 knockdown blocked proliferation of human embryonic stem cells, prompted cell cycle arrest in G0/G1 phase (Choi, Lee, Jang, Kim, & Ryu, 2013) and increased apoptosis of pancreatic ductal adenocarcinoma cells (Barcelo et al, 2014).…”

Section: Gastric Cells and Other Cellsmentioning

confidence: 99%

Helicobacter pyloriouter inflammatory protein A (OipA) suppresses apoptosis of AGS gastric cells in vitro

Al-Maleki

Loke

Lui

et al. 2017

Cellular Microbiology

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Outer inflammatory protein A (OipA) is an important virulence factor associated with gastric cancer and ulcer development; however, the results have not been well established and turned out to be controversial. This study aims to elucidate the role of OipA in Helicobacter pylori infection using clinical strains harbouring oipA "on" and "off" motifs. Proteomics analysis was performed on AGS cell pre-infection and postinfection with H. pylori oipA "on" and "off" strains, using liquid chromatography/mass spectrometry. AGS apoptosis and cell cycle assays were performed. Moreover, expression of vacuolating cytotoxin A (VacA) was screened using Western blotting. AGS proteins that have been suggested previously to play a role or associated with gastric disease were down-regulated postinfection with oipA "off" strains comparing to oipA "on" strains. Furthermore, oipA "off" and ΔoipA cause higher level of AGS cells apoptosis and G0/G1 cell-cycle arrest than oipA "on" strains. Interestingly, deletion of oipA increased bacterial VacA production. The capability of H. pylori to induce apoptosis and suppress expression of proteins having roles in human disease in the absence of oipA suggests that strains not expressing OipA may be less virulent or may even be protective against carcinogenesis compared those expressing OipA. This potentially explains the higher incidence of gastric cancer in East Asia where oipA "on" strains predominates.

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Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

Cited by 55 publications

References 68 publications

KRAS Engages AGO2 to Enhance Cellular Transformation

KRAS Engages AGO2 to Enhance Cellular Transformation

HNRNPA2B1 regulates the epithelial–mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway

Helicobacter pyloriouter inflammatory protein A (OipA) suppresses apoptosis of AGS gastric cells in vitro

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