Obesity and altered angiogenic-related gene expression in endometrial cancer

Lauren Patterson Cobb; Sharareh Siamakpour-Reihani; Dadong Zhang; Xiaodi Qin; Kouros Owzar; Chunxiao Zhou; Thomas P Conrads; G Larry Maxwell; Kathleen M Darcy; Nicholas W Bateman; Tracy Litzi; Victoria Bae-Jump; Angeles Alvarez Secord

doi:10.1016/j.ygyno.2021.08.010

Obesity and altered angiogenic-related gene expression in endometrial cancer

Gynecol Oncol. 2021 Nov;163(2):320-326. doi: 10.1016/j.ygyno.2021.08.010. Epub 2021 Sep 15.

Affiliations

¹ Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA; Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA. Electronic address: lpcobb@mdanderson.org.
² Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, USA.
³ Bioinformatics Shared Resource, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
⁴ Bioinformatics Shared Resource, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; Duke Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
⁵ Division of Gynecologic Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, USA.
⁷ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, USA; Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA.
⁸ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA.
⁹ Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Abstract

Objectives: Evaluate association between obesity and angiogenic-related gene expression in endometrial cancer (EC). Evaluate interaction between diet and metformin on angiogenic-related gene expression.

Methods: We evaluated the association between 168 human angiogenic-related genes and body mass index (BMI) in the TCGA Uterine Corpus Endometrial Carcinoma cohort (endometrioid endometrial cancer (EEC) cohort n = 290, and copy number high cohort n = 55), an independent validation cohort from Gynecologic Cancer Center of Excellence (GYN-COE) (n = 62) and corresponding 185 homologous mouse genes in an LKB1^fl/flp53^fl/fl mouse model of EC (n = 20). Mice received 60% of calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% of calories from fat in a low-fat diet (LFD). After tumor growth, HFD (n = 5) and LFD (n = 5) mice were treated with metformin (200 mg/kg/day) or control. Whole transcriptome analysis of mouse tumors was performed using RNA-Seq.

Results: At a false-discovery rate of 10%, twenty-one angiogenic-related genes were differentially expressed with respect to BMI when adjusting for grade in the TCGA EEC cohort. Evaluation of these genes in the mouse model control group revealed association between increased Edil3 expression in HFD versus LFD mice (2.5-fold change (FC); unadjusted p = 0.03). An interaction was observed for expression of Edil3 between diet and metformin treatment (unadjusted p = 0.009). Association between BMI and increased expression of EDIL3 was validated in one of four EDIL3 probesets in the GYN-COE cohort (p = 0.0011, adjusted p = 0.0342).

Conclusions: Obesity may promote tumor progression via differential modulation of angiogenic pathways in EEC. Our exploratory findings demonstrated that EDIL3 may be a candidate gene of interest.

Keywords: Angiogenesis; Endometrial cancer; Gene expression; Metformin; Obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
Animals
Body Mass Index
Calcium-Binding Proteins / genetics*
Cell Adhesion Molecules / genetics*
Datasets as Topic
Diet, High-Fat / adverse effects
Disease Models, Animal
Disease Progression
Endometrial Neoplasms / genetics*
Endometrial Neoplasms / pathology
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Metformin / administration & dosage
Mice, Transgenic
Neovascularization, Physiologic / drug effects
Neovascularization, Physiologic / genetics*
Obesity / complications*
Obesity / genetics
RNA-Seq
Tumor Suppressor Protein p53 / genetics

Substances

Calcium-Binding Proteins
Cell Adhesion Molecules
EDIL3 protein, human
Edil3 protein, mouse
Trp53 protein, mouse
Tumor Suppressor Protein p53
Metformin
Stk11 protein, mouse
AMP-Activated Protein Kinases

Grants and funding

P30 CA014236/CA/NCI NIH HHS/United States