Mihaela Chivu-Economescu1, Denisa L Dragu2, Laura G Necula2,3,4, Lilia Matei2, Ana Maria Enciu4,5, Coralia Bleotu2, Carmen C Diaconu2. 1. Cellular and Molecular Department, Stefan S. Nicolau Institute of Virology, Mihai Bravu 285 Ave, 030304, Bucharest, Romania. mihaela.chivu@gmail.com. 2. Cellular and Molecular Department, Stefan S. Nicolau Institute of Virology, Mihai Bravu 285 Ave, 030304, Bucharest, Romania. 3. Nicolae Cajal Institute, Titu Maiorescu University, Bucharest, Romania. 4. Biochemistry-Proteomics Department, Victor Babes National Institute of Pathology, Bucharest, Romania. 5. Cell Biology and Histology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
Abstract
BACKGROUND: Keratin 17 (KRT17) was shown to be an important molecular marker for predicting the carcinogenesis, progression, and prognosis of various cancer types. Our previous studies identified KRT17 as a possible biomarker for gastric cancer by gene microarray, with an elevated expression that occurred early during tumorigenesis and increased during tumor progression. Based on these findings, we aimed to investigate KRT17 biological functions in gastric adenocarcinoma and its possible use as a rational molecular target for anticancer therapy. METHODS: We used RNA interference-mediated knockdown of KRT17 expression and analyzed the effects on cell proliferation, cell migration, and signal transduction in two gastric cell lines (AGS and NCI-N87) in vitro and on xenograft growth in vivo. RESULTS: The functional analysis of KRT17 knockdown cell lines showed a decreased cell proliferation (with 42.36% ± 3.2%) and migration ability (with 37.2% ± 6.2%) relative to scrambled siRNA control. The in vivo tumorigenicity on nude mice exhibited a significant decrease in tumor weight with 69.14% in xenografts obtained from AGS cells and 84.43% in xeno-NCI-N87 tumors. The analysis on KRT17 knockdown outcome on intracellular signaling identifies AKT/mTOR as the main affected pathway that sustains proliferation and survival, and also the AMPKα1/CREB pathway that was recently shown to induce organ protection and antiinflammatory response. CONCLUSIONS: Our results highlight KRT17 as a possible biomarker in gastric cancer promoting tumor growth, motility, and invasion, and suggest that KRT17 can be a valuable molecular target for development of anti-gastric cancer-specific therapies.
BACKGROUND:Keratin 17 (KRT17) was shown to be an important molecular marker for predicting the carcinogenesis, progression, and prognosis of various cancer types. Our previous studies identified KRT17 as a possible biomarker for gastric cancer by gene microarray, with an elevated expression that occurred early during tumorigenesis and increased during tumor progression. Based on these findings, we aimed to investigate KRT17 biological functions in gastric adenocarcinoma and its possible use as a rational molecular target for anticancer therapy. METHODS: We used RNA interference-mediated knockdown of KRT17 expression and analyzed the effects on cell proliferation, cell migration, and signal transduction in two gastric cell lines (AGS and NCI-N87) in vitro and on xenograft growth in vivo. RESULTS: The functional analysis of KRT17 knockdown cell lines showed a decreased cell proliferation (with 42.36% ± 3.2%) and migration ability (with 37.2% ± 6.2%) relative to scrambled siRNA control. The in vivo tumorigenicity on nude mice exhibited a significant decrease in tumor weight with 69.14% in xenografts obtained from AGS cells and 84.43% in xeno-NCI-N87 tumors. The analysis on KRT17 knockdown outcome on intracellular signaling identifies AKT/mTOR as the main affected pathway that sustains proliferation and survival, and also the AMPKα1/CREB pathway that was recently shown to induce organ protection and antiinflammatory response. CONCLUSIONS: Our results highlight KRT17 as a possible biomarker in gastric cancer promoting tumor growth, motility, and invasion, and suggest that KRT17 can be a valuable molecular target for development of anti-gastric cancer-specific therapies.
Authors: Daniel A Escobar; Ana M Botero-Quintero; Benjamin C Kautza; Jason Luciano; Patricia Loughran; Sophie Darwiche; Matthew R Rosengart; Brian S Zuckerbraun; Hernando Gomez Journal: J Surg Res Date: 2014-10-08 Impact factor: 2.192
Authors: Mihaela Chivu Economescu; Laura G Necula; Denisa Dragu; Liviu Badea; Simona O Dima; Stefan Tudor; Anca Nastase; Irinel Popescu; Carmen C Diaconu Journal: Hepatogastroenterology Date: 2010 Nov-Dec
Authors: Alexa B Turke; Youngchul Song; Carlotta Costa; Rebecca Cook; Carlos L Arteaga; John M Asara; Jeffrey A Engelman Journal: Cancer Res Date: 2012-05-02 Impact factor: 12.701
Authors: Jacques Ferlay; Isabelle Soerjomataram; Rajesh Dikshit; Sultan Eser; Colin Mathers; Marise Rebelo; Donald Maxwell Parkin; David Forman; Freddie Bray Journal: Int J Cancer Date: 2014-10-09 Impact factor: 7.396
Authors: Seçil Demirkol Canlı; Ege Dedeoğlu; Muhammad Waqas Akbar; Barış Küçükkaraduman; Murat İşbilen; Özge Şükrüoğlu Erdoğan; Seda Kılıç Erciyas; Hülya Yazıcı; Burçak Vural; Ali Osmay Güre Journal: PLoS One Date: 2020-04-20 Impact factor: 3.240
Authors: Mihaela Chivu-Economescu; Lilia Matei; Laura G Necula; Denisa L Dragu; Coralia Bleotu; Carmen C Diaconu Journal: World J Gastroenterol Date: 2018-05-14 Impact factor: 5.742