Reactive oxygen species (ROS) is a diverse group of small molecules with different reactivity, sources of production, and, ultimately, biological functions. Some of these molecules are important contributors to pathogenesis of major chronic diseases including cancer, diabetes, and atherosclerosis. Others play major roles in environmental, radiation and space biology. In normal state, specific ROS carry out homeostatic functions such as innate immunity and signaling. However, the word “ROS” is still often used in the literature as a generic term synonymous to oxidative stress. This review provides a brief description of ROS diversity, interrelations and main biological functions.

Reactive oxygen species

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool - Supporting Information

Oxidative stress, demonstrated by an accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), results in DNA damage, which is normally repaired by base excision repair enzymes including 8-OHdG DNA glycosylase (OGG1) and human MutY homolog (MUTYH), in addition to nucleotide pool sanitizing enzymes including MutT Homolog 1 (MTH1). Abnormalities of this repair system are present in various cancer types. The present study aimed to elucidate the clinicopathological significance of altered expression levels of inducible nitric oxide synthase (iNOS), 8-OHdG, OGG1, MTH1 and MUTYH in ulcerative colitis (UC) and UC-associated neoplasms. Immunohistochemical staining for these markers and p53 in 23 cases of UC-associated neoplasm (Group A, 14 carcinomas and nine dysplasias), 16 cases of UC without neoplasm (Group B) and 17 cases of normal colon specimens (Group C) was performed. Mutation analyses was conducted for KRAS proto-oncogene, GTPase (K-ras), tumor protein P53 (TP53) and isocitrate dehydrogenase (NADP (+)) 1, cytosolic (IDH1) genes. Immunohistochemically, the iNOS, 8-OHdG, OGG1 and MTH1 expression levels were increased in Groups A and B compared with Group C. The OGG1 and MTH1 expression levels in Group A were also increased compared with Group B. Group A and Group B exhibited increased cytoplasmic expression and decreased nuclear expression of MUTYH compared with Group C. Mutations of K-ras and TP53 were detected in 2/21 (9.5%) and 10/22 (45.5%) cases of Group A, respectively. IDH1 mutation was not detected in any cases. These findings suggest that, as a response to oxidative damage, OGG1 and MTH1 may be upregulated in UC through an inflammatory condition that progresses to cancer formation. Persisting oxidative damage stress may play a role in the pathogenesis of UC-associated tumors.

/pdf/overexpression-of-mth1-and-ogg1-proteins-in-ulcerative-2fogmf5r13.pdf

Overexpression of MTH1 and OGG1 proteins in ulcerative colitis‑associated carcinogenesis

// Jin Li 1 , Cheng-Cheng Yang 2 , Xin-Yuan Tian 1 , Yun-Xuan Li 2 , Ju Cui 3 , Zhe Chen 3 , Zhou-Lu Deng 4 , Fu-Jun Chen 5 , Hiroshi Hayakawa 6 , Mutsuo Sekiguchi 6 and Jian-Ping Cai 1 1 Peking University Fifth School of Clinical Medicine, Beijing Hospital, Beijing, P.R. China 2 School of Pharmacy, Wenzhou Medical University, Wenzhou, P.R. China 3 The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, P.R. China 4 Department of General Surgery, China-Japan Friendship Hospital, Beijing, P.R. China 5 Department of Anorectal Surgery, First Affiliated Hospital of Jiamusi University, Jiamusi, P.R. China 6 Frontier Research Center, Fukuoka Dental College, Fukuoka, Japan Correspondence to: Jian-Ping Cai, email: caijianping3200@bjhmoh.cn Keywords: MutT-related proteins; oxidized nucleotides; colorectal cancer; clinical relevance; prognosis Received: July 22, 2017      Accepted: August 17, 2017      Published: November 11, 2017 ABSTRACT Background: MutT-related proteins, including MTH1, MTH2, MTH3 and NUDT5, can effectively degrade 8-oxoGua-containing nucleotides. The MTH1 expression is elevated in many types of human tumors and MTH1 overexpression correlates with the tumor pathological stage and poor prognosis. However, the expression of other MutT-related proteins in human cancers remains unknown. The present study systematically investigated the expression of MTH1, MTH2, MTH3 and NUDT5 in human colorectal cancer to establish its clinical significance. Methods: Amounts of MutT- related mRNA and protein in CRC cell lines were assessed by qRT-PCR and Western blotting, respectively. Furthermore, the MutT-related protein expression was evaluated by immunohistochemical staining of tissue microarrays containing 87 paired CRC tissues and by Western blotting of 44 CRC tissue samples. Finally, the effect of knockdown of MutT-related proteins on CRC cell proliferation was investigated. Results: The expression of MTH1, MTH2, MTH3 and NUDT5 was significantly higher in CRC cells and CRC tissues than normal cells and tissues, and this phenomenon was significantly associated with AJCC stage and lymph node metastasis of CRC specimens. CRC patients with high expression of MTH1, MTH2 or NUDT5 had an extremely poor overall survival after surgical resection. Notably, NUDT5 was an independent prognostic factor of CRC patients. We found that knockdown of MutT-related proteins inhibited CRC cell proliferation. Conclusions: We showed for the first time that MutT-related proteins play an important role in CRC progression and prognosis. Further investigations are needed to elucidate the role of these proteins in CRC progression and their potential use for therapeutic targets.

/pdf/mutt-related-proteins-are-novel-progression-and-prognostic-3oavvgvpbb.pdf

MutT-related proteins are novel progression and prognostic markers for colorectal cancer.

Background/aims Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8-oxodG in hepatocytes. Methods The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. Results In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. Conclusion Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis.

/pdf/hepatitis-b-virus-x-protein-increases-8-oxo-7-8-dihydro-2-36gw629cx4.pdf

Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes

Background Cancers have dysfunctional redox regulation resulting in production of reactive oxygen species (ROS), damaging DNA, RNA and free NTPs, and causing the accumulation of oxidative nucleic acids in cytoplasm. The major types are 8-oxo-7,8-dihydroguanine(8-oxoGsn) in RNA and 8-oxo-7,8-dihydro-2' deoxyguanosine(8-oxodGsn) in Mt-DNA. The MTH1 protein sanitizes oxidized nucleotide pools from NTPs to monophosphates, preventing the occurrence of transversion mutations. This study concerned cytoplasmic 8-oxodGsn/Gsn and MTH1 expression in gastric cancer and para-cancer tissues and elucidated roles of nucleic-acid oxidation and anti-oxidation. Materials and methods A polymer HRP detection system was used to detect 8-oxo-Gsn/dGsn and MTH1 expression in 51 gastric cancer and para-cancer tissue samples. Analyses of patient clinical and pathological data were also performed. Results The expression of MTH1 and the 8-oxo-dGsn/Gsn ratio were significantly higher in cancer tissues than para-cancer tissues (P 0.05). Conclusions We found 8-oxo-dGsn/Gsn and MTH1 are both highly expressed in gastric cancer tissues, especially in well differentiated lesions. In addition, oxidated mtDNA is prevalently expressed in gastric cancers, while 8-oxo-Gsn expression in cytoplasmic RNA is a bit lower, but more selectively.

http://koreascience.or.kr:80/article/JAKO201534168452276.pdf

Expression of Cytoplasmic 8-oxo-Gsn and MTH1 Correlates with Pathological Grading in Human Gastric Cancer.

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Expression of Cytoplasmic 8-oxo-Gsn and MTH1 Correlates with Pathological Grading in Human Gastric Cancer.