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Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation
Li,Licen1,2; Bao,Jiaolin1,2; Wang,Haitao1,2; Lei,Josh Haipeng1,2; Peng,Cheng1,2; Zeng,Jianming1,2; Hao,Wenhui1,2; Zhang,Xu1,2; Xu,Xiaoling1,2; Yu,Chundong4; Deng,Chu Xia1,2; Chen,Qiang1,2,3
2021
Source PublicationTheranostics
ISSN1838-7640
Volume11Issue:4Pages:1672-1689
Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. Methods: The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used in vivo metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. Results: We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, via upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. Conclusions: These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression via Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.

KeywordAib1 Ecm Hedgehog Mafb Pdac
DOI10.7150/thno.47390
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaResearch & Experimental Medicine
WOS SubjectMedicine, Research & Experimental
WOS IDWOS:000600553900011
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorChen,Qiang
Affiliation1.Cancer Centre,Faculty of Health Sciences,University of Macau,Macao
2.Centre for Precision Medicine Research and Training,Faculty of Health Sciences,University of Macau,Macao
3.Department of Laboratory Medicine,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou, Zhejiang,325000,China
4.State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen, Fujian,361012,China
First Author AffilicationCancer Centre;  Faculty of Health Sciences
Corresponding Author AffilicationCancer Centre;  Faculty of Health Sciences
Recommended Citation
GB/T 7714
Li,Licen,Bao,Jiaolin,Wang,Haitao,et al. Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation[J]. Theranostics,2021,11(4):1672-1689.
APA Li,Licen,Bao,Jiaolin,Wang,Haitao,Lei,Josh Haipeng,Peng,Cheng,Zeng,Jianming,Hao,Wenhui,Zhang,Xu,Xu,Xiaoling,Yu,Chundong,Deng,Chu Xia,&Chen,Qiang.(2021).Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation.Theranostics,11(4),1672-1689.
MLA Li,Licen,et al."Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation".Theranostics 11.4(2021):1672-1689.
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