CCAAT/enhancer binding protein delta (C/EBPδ) demonstrates a dichotomous role in tumour initiation and promotion of epithelial carcinoma

Ramlogan Sowamber; Rania Chehade; Mahmoud Bitar; Leah V Dodds; Anca Milea; Brian Slomovitz; Patricia A Shaw; Sophia H L George

doi:10.1016/j.ebiom.2019.05.002

CCAAT/enhancer binding protein delta (C/EBPδ) demonstrates a dichotomous role in tumour initiation and promotion of epithelial carcinoma

EBioMedicine. 2019 Jun:44:261-274. doi: 10.1016/j.ebiom.2019.05.002. Epub 2019 May 9.

Authors

Ramlogan Sowamber¹, Rania Chehade¹, Mahmoud Bitar¹, Leah V Dodds², Anca Milea¹, Brian Slomovitz³, Patricia A Shaw⁴, Sophia H L George⁵

Affiliations

¹ Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
² Sylvester Comprehensive Cancer Center, Miami, Florida, United States; University of Miami, Leonard Miller School of Medicine, Miami, Florida, United States.
³ Sylvester Comprehensive Cancer Center, Miami, Florida, United States; Department of Obstetrics and Gynecology and Reproductive Sciences, Division of Gynecology Oncology, Miami, Florida, United States; University of Miami, Leonard Miller School of Medicine, Miami, Florida, United States.
⁴ Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
⁵ Sylvester Comprehensive Cancer Center, Miami, Florida, United States; Department of Obstetrics and Gynecology and Reproductive Sciences, Division of Gynecology Oncology, Miami, Florida, United States; University of Miami, Leonard Miller School of Medicine, Miami, Florida, United States. Electronic address: sophia.george@med.miami.edu.

Abstract

Background: CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBPδ in different tumours, such as glioblastoma and breast cancer either promotes tumour progression or inhibits growth and has low expression in normal tissue until activated by cytotoxic stressors.

Methods: Higher overall expression of C/EBPδ in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBPδ in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBPδ in proliferation, migration, and the epithelial to mesenchymal transition.

Findings: Expression of C/EBPδ induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBPδ in epithelial cancer cell lines did not have significant effects on proliferation, yet overexpression demonstrated downregulation of growth, similar to normal fallopian tube cells. C/EBPδ promoted a partial mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating Vimentin and N-cadherin in FTE cells and increased migratory activity, which suggests a regulatory role in the epithelial-mesenchymal plasticity of these cells.

Interpretation: Our findings suggest that C/EBPδ regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis. FUND: This study was funded by the CDMRP Ovarian Cancer program (W81WH-0701-0371, W81XWH-18-1-0072), the Princess Margaret Cancer Centre Foundation, Foundation for Women's Cancer - The Belinda-Sue/Mary-Jane Walker Fund, Colleen's Dream Foundation and Sylvester Comprehensive Cancer Center.

Keywords: C/EBPδ; Epithelial to mesenchymal transition; Fallopian tube epithelia; High-grade serous ovarian cancer.

MeSH terms

Biomarkers, Tumor
CCAAT-Enhancer-Binding Protein-delta / metabolism*
Carcinoma / etiology*
Carcinoma / metabolism*
Carcinoma / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism*
Epithelial-Mesenchymal Transition / genetics
Female
Gene Expression
Humans
Immunohistochemistry
Models, Biological
Mucous Membrane / metabolism
Mucous Membrane / pathology
Neoplasm Grading
Phenotype
RNA Interference

Substances

Biomarkers, Tumor
CCAAT-Enhancer-Binding Protein-delta