PXD015120

PXD015120 is an original dataset announced via ProteomeXchange.

Title	Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis
Description	Here we utilized a mouse model of PDAC and human pancreatic cancer cell lines to investigate the role of HIF1alpha in pancreatic cancer. Contrary to the conventional notion that HIF1alpha plays a tumor promoting role in several cancers, our findings indicate a tumor suppressive role of HIF1alpha in PDAC. Ablation of Hif1alpha in mice resulted in drastically increased metastasis of the pancreatic cancer and substantially reduced survival. We traced HIF1alpha's metastasis-suppression to the regulation of Protein Phosphatase 1 Regulatory Inhibitor subunit 1B (PPP1R1B), a dual kinase/phosphatase inhibited by HIF1alpha. We show a mechanistic link between loss of HIF1alpha, increased expression of PPP1R1B and degradation of the p53 protein that promotes invasion and metastasis in both mouse and human PDACs. Increased expression of PPP1R1B correlates with higher metastasis and poor survival in human pancreatic cancer patients. Since the inhibition of PPP1R1B reduced the metastatic potential of pancreatic cancer cells, we propose PPP1R1B as a therapeutic target to improve the prognosis of pancreatic cancer patients. _____ LC-MS/MS methodology _____ Dried peptide samples were reconstituted with 2% ACN-0.1% FA and quantified by NanoDropTM spectrophometer (ThermoFisher) prior to LC-MS/MS analysis using a nanoACQUITY system (Waters) coupled to an Orbitrap Fusion Lumos mass spectrometer (Thermo Fisher Scientific). Peptides were separated using a 200 cm micro-chip pillar array C18 column (PharmaFluidics) at a flow rate of 500 nl/min using a 123-min gradient: 1% to 5% B in 1 min, 5% to 10% B in 22 min, 10% to 18% B in 53 min, 18% to 28% B in 39 min, and 28% to 38% B in 8 min (A= FA 0.1%; B=100% ACN: 0.1% FA). The mass spectrometer was operated in positive data-dependent acquisition mode. MS1 spectra were measured in the Orbitrap with a resolution of 60000 (AGC target: 4e5; maximum injection time:50 ms; mass range: from 375 to 1500 m/z). The instrument was set to run in top speed mode with 2 s cycles for the survey and the MS/MS scans. After a survey scan, the most abundant precursors (with charge state between +2 and +7) were isolated in the quadrupole (isolation window: 1.6 m/z) and fragmented in the Ion Routing Multipole HCD-Cell (collision energy: 30%). fragmented precursors were detected in the ion trap cell with a rapid scan (First mass: 110 m/z; AGC target for MS/MS: 1e4; maximum injection time: 35 ms). The dynamic exclusion was set to 60 s with a 10 ppm mass tolerance around the precursor.
HostingRepository	MassIVE
AnnounceDate	2021-02-04
AnnouncementXML	Submission_2021-02-04_14:07:04.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alexandre Rosa Campos
SpeciesList	scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090;
ModificationList	Oxidation; Acetyl
Instrument	Orbitrap Fusion ETD

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-21 22:49:01	ID requested
⏵ 1	2021-02-04 14:07:05	announced

Tiwari A, Tashiro K, Dixit A, Soni A, Vogel K, Hall B, Shafqat I, Slaughter J, Param N, Le A, Saunders E, Paithane U, Garcia G, Campos AR, Zettervall J, Carlson M, Starr TK, Marahrens Y, Deshpande AJ, Commisso C, Provenzano PP, Bagchi A, Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis. Gastroenterology, 159(5):1882-1897.e5(2020) [pubmed]

submitter keyword: Pancreatic Ductal Adenocarcinoma (PDAC), Protein Phosphatase 1 Regulatory Inhibitor subunit 1B (PPP1R1B), metastasis, HIF1 alpha

Anindya Bagchi
contact affiliation	Sanford Burnham Prebys Medical Discovery Institute
contact email	abagchi@sbpdiscovery.org
lab head
Alexandre Rosa Campos
contact affiliation	SBP Medical Discovery Institute
contact email	arosacampos@sbpdiscovery.org
dataset submitter

MassIVE dataset URI

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