title: Inhibition of mesothelin as a novel strategy for targeting cancer cells.
abstract: Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro-oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of β-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies.
authors.affiliation: Molecular Medicine Laboratory, Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Vidya
authors.initials: V
authors.lastname: Bodempudi
authors.forename: Zhengian
authors.initials: Z
authors.lastname: Liu
authors.forename: Emma
authors.initials: E
authors.lastname: Borrego-Diaz
authors.forename: Farnaz
authors.initials: F
authors.lastname: Yamoutpoor
authors.forename: Anna
authors.initials: A
authors.lastname: Meyer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Woo
authors.forename: Weihong
authors.initials: W
authors.lastname: Pan
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: Mojtaba S
authors.initials: MS
authors.lastname: Olyaee
authors.forename: Tuba
authors.initials: T
authors.lastname: Esfandyari
authors.forename: Faris
authors.initials: F
authors.lastname: Farassati
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D058851:GPI-Linked Proteins / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D000090204:Mesothelin; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D058851:GPI-Linked Proteins; D035683:MicroRNAs; C000715528:Msln protein, mouse; D034741:RNA, Small Interfering; D000090204:Mesothelin