title: Glucose-regulated protein 94 deficiency induces squamous cell metaplasia and suppresses PTEN-null driven endometrial epithelial tumor development.
abstract: Endometrial carcinoma is the most prevalent gynecologic cancer in the United States. The tumor suppressor gene Pten (phosphatase and tensin homolog) is commonly mutated in the more common type 1 (endometrioid) subtype. The glucose-regulated protein 94 (GRP94) is emerging as a novel regulator for cancer development. Here we report that expression profiles from the Cancer Genome Atlas (TCGA) showed significantly increased Grp94 mRNA levels in endometrial tumor versus normal tissues, correlating with highly elevated GRP94 protein expression in patient samples and the requirement of GRP94 for maintaining viability of human endometrioid adenocarcinoma (EAC) cell lines. Through generation of uterus-specific knockout mouse models with deletion of Grp94 alone (c94f/f) or in combination with Pten (cPf/f94f/f), we discovered that c94f/f uteri induced squamous cell metaplasia (SCM) and reduced active nuclear β-catenin. The cPf/f94f/f uteri showed accelerated SCM and suppression of PTEN-null driven EAC, with reduced cellular proliferation, attenuated β-catenin signaling and decreased AKT/S6 activation in the SCM. In contrast to single PTEN knockout uteri (cPf/f), cPf/f94f/f uteri showed no decrease in E-cadherin level and no invasive lesion. Collectively, our study implies that GRP94 downregulation induces SCM in EAC and suppresses AKT/S6 signaling, providing a novel mechanism for suppressing EAC progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Jieli
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lijing
authors.initials: L
authors.lastname: Yao
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics-Gynecology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Department of Pathology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D051176:beta Catenin; C053387:endoplasmin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: PTEN; endometrial cancer; glucose-regulated protein 94 (GRP94); squamous cell metaplasia; β-catenin