title: Increased NQO1 but not c-MET and survivin expression in non-small cell lung carcinoma with KRAS mutations.
abstract: Cigarette smoking is one of the most significant public health issues and the most common environmental cause of preventable cancer deaths worldwide. EGFR (Epidermal Growth Factor Receptor)-targeted therapy has been used in the treatment of LC (lung cancer), mainly caused by the carcinogens in cigarette smoke, with variable success. Presence of mutations in the KRAS (Kirsten rat sarcoma viral oncogene homolog) driver oncogene may confer worse prognosis and resistance to treatment for reasons not fully understood. NQO1 (NAD(P)H:quinone oxidoreductase), also known as DT-diaphorase, is a major regulator of oxidative stress and activator of mitomycins, compounds that have been targeted in over 600 pre-clinical trials for treatment of LC. We sequenced KRAS and investigated expression of NQO1 and five clinically relevant proteins (DNMT1, DNMT3a, ERK1/2, c-MET, and survivin) in 108 patients with non-small cell lung carcinoma (NSCLC). NQO1, ERK1/2, DNMT1, and DNMT3a but not c-MET and survivin expression was significantly more frequent in patients with KRAS mutations than those without, suggesting the following: (1) oxidative stress may play an important role in the pathogenesis, worse prognosis, and resistance to treatment reported in NSCLC patients with KRAS mutations, (2) selecting patients based on their KRAS mutational status for future clinical trials may increase success rate, and (3) since oxidation of nucleotides also specifically induces transversion mutations, the high rate of KRAS transversions in lung cancer patients may partly be due to the increased oxidative stress in addition to the known carcinogens in cigarette smoke.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Ahmet.Yilmaz2@osumc.edu.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Yilmaz
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Nehad.Mohamed@osumc.edu.
authors.forename: Nehad
authors.initials: N
authors.lastname: Mohamed
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Kara.Patterson@osumc.edu.
authors.forename: Kara A
authors.initials: KA
authors.lastname: Patterson
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Yan.Tang@osumc.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Konstantin.Shilo@osumc.edu.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.affiliation: Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA. Davis.28@osu.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Xiao-Ping.Zhou@osumc.edu.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Wendy.Frankel@osumc.edu.
authors.forename: Wendy
authors.initials: W
authors.lastname: Frankel
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. Greg.Otterson@osumc.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, The University of Montana, Missoula, MT 59812, USA. Howard.Beall@mso.umt.edu.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Beall
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA. Weiqiang.Zhao@osumc.edu.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012907:Smoking; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins