scholarly journals Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases

2021 ◽  
Author(s):  
Ian L. P. Beales ◽  
Olorunseun O. Ogunwobi
Keyword(s):  
Oesophageal Cancer ◽  
Small Gtpases ◽  
Dominant Negative ◽  
Kinase Assay ◽  
Barrett’S Oesophagus ◽  
Oesophageal Adenocarcinoma ◽  
Barrett's Oesophagus ◽  
Akt Activation ◽  
Adenocarcinoma Cells

AbstractObesity is a risk factor for Barrett’s oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett’s cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett’s oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users.

scholarly journals Cancer incidence and mortality risks in a large US Barrett's oesophagus cohort

Gut ◽  
2017 ◽  
Vol 67 (3) ◽  
pp. 418-529 ◽  
Author(s):  
Michael B Cook ◽  
Sally B Coburn ◽  
Jameson R Lam ◽  
Philip R Taylor ◽  
Jennifer L Schneider ◽  
...  
Keyword(s):  
Oesophageal Cancer ◽  
Absolute Risk ◽  
Barrett’S Oesophagus ◽  
Oesophageal Adenocarcinoma ◽  
Kaiser Permanente ◽  
Barrett's Oesophagus ◽  
Relative Risks ◽  
Incidence And Mortality ◽  
The Usa ◽  
Prostate Cancers

ObjectiveBarrett's oesophagus (BE) increases the risk of oesophageal adenocarcinoma by 10–55 times that of the general population, but no community-based cancer-specific incidence and cause-specific mortality risk estimates exist for large cohorts in the USA.DesignWithin Kaiser Permanente Northern California (KPNC), we identified patients with BE diagnosed during 1995–2012. KPNC cancer registry and mortality files were used to estimate standardised incidence ratios (SIR), standardised mortality ratios (SMR) and excess absolute risks.ResultsThere were 8929 patients with BE providing 50 147 person-years of follow-up. Compared with the greater KPNC population, patients with BE had increased risks of any cancer (SIR=1.40, 95% CI 1.31 to 1.49), which slightly decreased after excluding oesophageal cancer. Oesophageal adenocarcinoma risk was increased 24 times, which translated into an excess absolute risk of 24 cases per 10 000 person-years. Although oesophageal adenocarcinoma risk decreased with time since BE diagnosis, oesophageal cancer mortality did not, indicating that the true risk is stable and persistent with time. Relative risks of cardia and stomach cancers were increased, but excess absolute risks were modest. Risks of colorectal, lung and prostate cancers were unaltered. All-cause mortality was slightly increased after excluding oesophageal cancer (SMR=1.24, 95% CI 1.18 to 1.31), but time-stratified analyses indicated that this was likely attributable to diagnostic bias. Cause-specific SMRs were elevated for ischaemic heart disease (SMR=1.39, 95% CI 1.18 to 1.63), respiratory system diseases (SMR=1.51, 95% CI 1.29 to 1.75) and digestive system diseases (SMR=2.20 95% CI 1.75 to 2.75).ConclusionsPatients with BE had a persistent excess risk of oesophageal adenocarcinoma over time, although their absolute excess risks for this cancer, any cancer and overall mortality were modest.

scholarly journals Subtypes of Barrett’s oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis

Gut ◽  
2018 ◽  
Vol 68 (3) ◽  
pp. 389-399 ◽  
Author(s):  
Ming Yu ◽  
Sean K Maden ◽  
Matthew Stachler ◽  
Andrew M Kaz ◽  
Jessica Ayers ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Massively Parallel Sequencing ◽  
T Test ◽  
Barrett’S Oesophagus ◽  
Oesophageal Adenocarcinoma ◽  
Aberrant Methylation ◽  
Barrett's Oesophagus ◽  
Genome Wide

ObjectiveTo identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett’s oesophagus (BE).DesignWe performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.ResultsWe identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student’s t-test) and the highest global mutation load (p<0.05, Fisher’s exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch’s t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment.ConclusionsWe identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

scholarly journals Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323906
Author(s):  
Jue-Sheng Ong ◽  
Jiyuan An ◽  
Xikun Han ◽  
Matthew H Law ◽  
Priyanka Nandakumar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Testing ◽  
Association Studies ◽  
Barrett’S Oesophagus ◽  
Oesophageal Reflux ◽  
Oesophageal Adenocarcinoma ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Disease Heterogeneity ◽  
Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

scholarly journals Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Gut ◽  
2016 ◽  
Vol 66 (10) ◽  
pp. 1739-1747 ◽  
Author(s):  
Matthew F Buas ◽  
Qianchuan He ◽  
Lisa G Johnson ◽  
Lynn Onstad ◽  
David M Levine ◽  
...  
Keyword(s):  
Barrett’S Oesophagus ◽  
Oesophageal Adenocarcinoma ◽  
Barrett's Oesophagus ◽  
Germline Variation

scholarly journals MIC-1/GDF15 in Barrett’s oesophagus and oesophageal adenocarcinoma

2015 ◽  
Vol 112 (8) ◽  
pp. 1384-1391 ◽  
Author(s):  
O M Fisher ◽  
A J Levert-Mignon ◽  
S J Lord ◽  
K K M Lee-Ng ◽  
N K Botelho ◽  
...  
Keyword(s):  
Barrett’S Oesophagus ◽  
Oesophageal Adenocarcinoma ◽  
Barrett's Oesophagus
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