title: ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer.
abstract: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are highly activated in cancer and involved in tumorigenesis and resistance to anti-cancer therapy. UPR is becoming a promising target of anti-cancer therapies. Thus, the identification of UPR components that are highly expressed in cancer could offer new therapeutic opportunity.In this study, we demonstrate that Endoplasmic Reticulum Metallo Protease 1 (ERMP1) is broadly expressed in a high percentage of breast, colo-rectal, lung, and ovary cancers, regardless of their stage and grade. Moreover, we show that loss of ERMP1 expression significantly hampers proliferation, migration and invasiveness of cancer cells. Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. Loss of ERMP1 also prevents the expression of GRP78/BiP, a UPR stress marker involved in the activation of the survival pathway. Finally, ERMP1 silencing in cells exposed to hypoxia leads to inhibition of the Nrf2-mediated anti-oxidant response and to reduction of accumulation of HIF-1, the master transcription factor instructing cells to respond to hypoxic stress. Our results suggest that ERMP1 could act as a molecular starter to the survival response induced by extracellular stresses. Moreover, they provide the rationale for the design of ERMP1-targeting drugs that could act by inhibiting the UPR initial adaptive response of cancer cells and impair cell survival.
authors: Externautics SpA, Siena, Italy.
authors: Alberto
authors: A
authors: Grandi
authors: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors: Alice
authors: A
authors: Santi
authors: Externautics SpA, Siena, Italy.
authors: Susanna
authors: S
authors: Campagnoli
authors: Externautics SpA, Siena, Italy.
authors: Matteo
authors: M
authors: Parri
authors: Department of Pathology, European Institute of Oncology, Milan, Italy.
authors: Elisa
authors: E
authors: De Camilli
authors: Department of Immunology, The Fourth Military Medical University, Xi'an, China.
authors: Chaojun
authors: C
authors: Song
authors: Department of Immunology, The Fourth Military Medical University, Xi'an, China.
authors: Boquan
authors: B
authors: Jin
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Aurelien
authors: A
authors: Lacombe
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Serenella
authors: S
authors: Castori-Eppenberger
authors: Externautics SpA, Siena, Italy.
authors: Paolo
authors: P
authors: Sarmientos
authors: Externautics SpA, Siena, Italy.|Centre for Integrative Biology - CIBIO, University of Trento, Trento, Italy.
authors: Guido
authors: G
authors: Grandi
authors: Department of Pathology, European Institute of Oncology, Milan, Italy.|Department of Oncology and hemato-oncology, University of Milan, Italy.
authors: Giuseppe
authors: G
authors: Viale
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Luigi
authors: L
authors: Terracciano
authors: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors: Paola
authors: P
authors: Chiarugi
authors: Externautics SpA, Siena, Italy.
authors: Piero
authors: P
authors: Pileri
authors: Externautics SpA, Siena, Italy.|INGM Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milano, Italia.
authors: Renata
authors: R
authors: Grifantini
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response
chemical_list: D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C570900:ERMP1 protein, human; D010447:Peptide Hydrolases
keywords: ERMP1; UPR; immunohistochemistry; monoclonal antibody; oxidative stress