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Smad4-dependent suppressor pituitary homeobox 2 promotes PPP2R2A-mediated inhibition of Akt pathway in pancreatic cancer.

ABSTRACT: The importance of Pituitary homeobox 2 (Pitx2) in malignancy remains enigmatic, and Pitx2 has not been previously implicated in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed gene expression profiling of human PDAC tissues and identified Pitx2 as a promising candidate. Pitx2 expression was decreased from 2.6- to 19-fold in human PDAC tissues from microarray units. Immunochemistry staining showed that Pitx2 expression was moderate to intense in normal pancreatic and pancreatic intraepithelial neoplastic lesions, whereas low in human PDAC tissues. The Pitx2 levels correlated with overall patient survival post-operatively in PDAC. Induction of Pitx2 expression partly inhibited the malignant phenotype of PDAC cells. Interestingly, low Pitx2 expression was correlated with Smad4 mutant inactivation, but not with Pitx2 DNA-methylation. Furthermore, Smad4 protein bound to Pitx2 promoter and stimulated Pitx2 expression in PDAC. In addition, Pitx2 protein bound to the promoter of the protein phosphatase 2A regulatory subunit B55? (PPP2R2A) and upregulated PPP2R2A expression, which may activate dephosphorylation of Akt in PDAC. These findings provide new mechanistic insights into Pitx2 as a tumor suppressor in the downstream of Smad4. And Pitx2 protein promotes PPP2R2A expression which may inhibit Akt pathway. Therefore, we propose that the Smad4-Pitx2-PPP2R2A axis, a new signaling pathway, suppresses the pancreatic carcinogenesis.

SUBMITTER: Wang Q

PROVIDER: S-EPMC4905467 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Smad4-dependent suppressor pituitary homeobox 2 promotes PPP2R2A-mediated inhibition of Akt pathway in pancreatic cancer.

Wang Qi Q Li Juanjuan J Wu Wei W Shen Ruizhe R Jiang He H Qian Yuting Y Tang Yanping Y Bai Tingting T Wu Sheng S Wei Lumin L Zang Yi Y Zhang Ji J Wang Lifu L

Oncotarget 20160301 10

The importance of Pituitary homeobox 2 (Pitx2) in malignancy remains enigmatic, and Pitx2 has not been previously implicated in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed gene expression profiling of human PDAC tissues and identified Pitx2 as a promising candidate. Pitx2 expression was decreased from 2.6- to 19-fold in human PDAC tissues from microarray units. Immunochemistry staining showed that Pitx2 expression was moderate to intense in normal pancreatic and pancreat ...[more]

PMID: 26848620

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Project description:BackgroundPancreatic cancer (PC) is a highly lethal malignancy regarding digestive system, which is the fourth leading factor of cancer-related mortalities in the globe. Prognosis is poor due to diagnosis at advanced disease stage, low rates of surgical resection, and resistance to traditional radiotherapy and chemotherapy. In order to develop novel therapeutic strategies, further elucidation of the molecular mechanisms underlying PC chemoresistance is required. Ribosomal RNA biogenesis has been implicated in tumorigenesis. Small nucleolar RNAs (snoRNAs) is responsible for post-transcriptional modifications of ribosomal RNAs during biogenesis, which have been identified as potential markers of various cancers. Here, we investigate the U3 snoRNA-associated protein RRP9/U3-55 K along with its role in the development of PC and gemcitabine resistance.MethodsqRT-PCR, western blot and immunohistochemical staining assays were employed to detect RRP9 expression in human PC tissue samples and cell lines. RRP9-overexpression and siRNA-RRP9 plasmids were constructed to test the effects of RRP9 overexpression and knockdown on cell viability investigated by MTT assay, colony formation, and apoptosis measured by FACS and western blot assays. Immunoprecipitation and immunofluorescence staining were utilized to demonstrate a relationship between RRP9 and IGF2BP1. A subcutaneous xenograft tumor model was elucidated in BALB/c nude mice to examine the RRP9 role in PC in vivo.ResultsSignificantly elevated RRP9 expression was observed in PC tissues than normal tissues, which was negatively correlated with patient prognosis. We found that RRP9 promoted gemcitabine resistance in PC in vivo and in vitro. Mechanistically, RRP9 activated AKT signaling pathway through interacting with DNA binding region of IGF2BP1 in PC cells, thereby promoting PC progression, and inducing gemcitabine resistance through a reduction in DNA damage and inhibition of apoptosis. Treatment with a combination of the AKT inhibitor MK-2206 and gemcitabine significantly inhibited tumor proliferation induced by overexpression of RRP9 in vitro and in vivo.ConclusionsOur data reveal that RRP9 has a critical function to induce gemcitabine chemoresistance in PC through the IGF2BP1/AKT signaling pathway activation, which might be a candidate to sensitize PC cells to gemcitabine. Video abstract.

Project description:BackgroundAs a member of the ERM (ezrin-radixin-moesin) protein family, EZR has been recognized as a regulator of adhesion signal pathways by researchers. Moreover, EZR was thought to play irreplaceable roles in invasion and metastasis of versatile cancers. In this study, we managed to undermine the effect of EZR on proliferation and metastasis in pancreatic cancer (PC).MethodsTo analyze the impact of EZR expression on overall survival and free diseases survival of PC patients, we screened abnormally expressed EZR in PC using the Gene Expression Omnibus database (GEO database) and The Cancer Genome Atlas (TCGA) database. Following, Gene Ontology (GO)-based functional analysis and Gene set enrichment analysis (GSEA) was performed to predicate the possible biological processes in which EZR were involved. The clinicopathological characteristics and prognosis of PC patients were analyzed according to clinical data. Further, immunohistochemistry, western blotting and real time PCR analysis were conducted to analyze the expression level of EZR in PC and paired paracancerous tissues. The effect of EZR on proliferation of PC cell lines were detected by Cell Counting Kit-8 assay, and meanwhile, Transwell assay was performed to detect the effect of EZR on invasion and migration of PC cell.ResultEZR exhibited higher expression level in pancreatic cancer tissues and cell than paracancerous tissues and cell, and its expression level was positively correlated with poor overall survival and diseases-free survival in PC patients. CCK8 assay indicated that EZR facilitated the proliferation of PC cells, meanwhile, Transwell assay showed that EZR promoted the migration and invasion of PC cells. The GO analysis predicated that EZR was involved in biological processes including cell adhesion, ameboidal-type cell migration, cell junction assembly. Through GSEA analysis, pancreatic cancer pathway, and the adhesion junction pathway were screened as the mostly enriched pathways in EZR-regulated pathological process. The inhibition of EZR suppressed proliferation and migration of PC cells. Western blot experiment revealed a positive correlation between EZR and FAK, the proliferation invasion and migration ability of PC cells were significantly decreased after knockdown of EZR.ConclusionOur finding revealed EZR accelerated the progression of PC via FAK/AKT signaling pathway.

Dataset Information

Smad4-dependent suppressor pituitary homeobox 2 promotes PPP2R2A-mediated inhibition of Akt pathway in pancreatic cancer.

Publications

Smad4-dependent suppressor pituitary homeobox 2 promotes PPP2R2A-mediated inhibition of Akt pathway in pancreatic cancer.

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