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Papers - KANAI Yae

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Liver atrophy after percutaneous transhepatic portal embolization occurs in two histological phases: Hepatocellular atrophy followed by apoptosis.

Iwao Y, Ojima H, Kobayashi T, Kishi Y, Nara S, Esaki M, Shimada K, Hiraoka N, Tanabe M, Kanai Y.

World J Hepatol (Baishideng Publishing Group Co) 9 ( 32 ) 1227 - 1238 2017

Accepted, ISSN 1948-5182

AIM To clarify the histological changes associated with liver atrophy after percutaneous transhepatic portal embolization (PTPE) in pigs and humans. METHODS As a preliminary study, we performed pathological examinations of liver specimens from five pigs that had undergone PTPE in a time-dependent model of liver atrophy. In specimens from embolized lobes (EMB) and nonembolized lobes (controls), we measured the portal vein to central vein distance (PV-CV), the area and number of hepatocytes per lobule, and apoptotic activity using the terminal deoxynucleotidyl transferase dUTP nickend labeling assay. Immunohistochemical reactivities were evaluated for light chain 3 (LC3) and lysosomal-associated membrane protein 2 (LAMP2) as autophagy markers and for glutamine synthetase and cytochrome P450 2E1 (CYP2E1) as metabolic zonation markers. Samples from ten human livers taken 20-36 d after PTPE were similarly examined. RESULTS PV-CVs and lobule areas did not differ between EMB and controls at day 0, but were lower in EMB than in controls at weeks 2, 4, and 6 (P ≤ 0.001). Hepatocyte numbers were not significantly reduced in EMB at day 0 and week 2 but were reduced at weeks 4 and 6 (P ≤ 0.05). Apoptotic activity was higher in EMB than in controls at day 0 and week 4. LC3 and LAMP2 staining peaked in EMB at week 2, with no significant difference between EMB and controls at weeks 4 and 6. Glutamine synthetase and CYP2E1 zonation in EMB at weeks 2, 4, and 6 were narrower than those in controls. Human results were consistent with those of porcine specimens. CONCLUSION The mechanism of liver atrophy after PTPE has two histological phases: Hepatocellular atrophy is likely caused by autophagy in the first 2 wk and apoptosis thereafter.

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Inhibition of PDGFR signaling prevents muscular fatty infiltration after rotator cuff tear in mice.

Shirasawa H, Matsumura N, Shimoda M, Oki S, Yoda M, Tohmonda T, Kanai Y, Matsumoto M, Nakamura M, Horiuchi K.

Sci Rep (NATURE PUBLISHING GROUP) 7 41552 2017

Accepted, ISSN 2045-2322

Fatty infiltration in muscle is often observed in patients with sizable rotator cuff tear (RCT) and is thought to be an irreversible event that significantly compromises muscle plasticity and contraction strength. These changes in the mechanical properties of the affected muscle render surgical repair of RCT highly formidable. Therefore, it is important to learn more about the pathology of fatty infiltration to prevent this undesired condition. In the present study, we aimed to generate a mouse model that can reliably recapitulate some of the important characteristics of muscular fatty infiltration after RCT in humans. We found that fatty infiltration can be efficiently induced by a combination of the following procedures: denervation of the suprascapular nerve, transection of the rotator cuff tendon, and resection of the humeral head. Using this model, we found that platelet-derived growth factor receptor-alpha (PDGFR alpha)-positive mesenchymal stem cells are induced after this intervention and that inhibition of PDGFR signaling by imatinib treatment can significantly suppress fatty infiltration. Taken together, the present study presents a reliable fatty infiltration mouse model and suggests a key role for PDGFR alpha-positive mesenchymal stem cells in the process of fatty infiltration after RCT in humans.

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The genomic and epigenomic landscape in thymic carcinoma.

Saito M, Fujiwara Y, Asao T, Honda T, Shimada Y, Kanai Y, Tsuta K, Kono K, Watanabe S, Ohe Y, Kohno T. >

Carcinogenesis (OXFORD UNIV PRESS) 38 ( 11 ) 1084 - 1091 2017

Accepted, ISSN 01433334

Thymic carcinoma (TC) is a rare cancer whose genomic features have been examined in only a limited number of patients of European descent. Here, we characterized both genomic and epigenomic aberrations by whole exome sequencing, RNA sequencing, methylation array and copy number analyses in TCs from Asian patients and compared them with those in TCs from USA/European patients. Samples analyzed were 10 pairs of snap-frozen surgical specimens of cancerous and non-cancerous thymic tissue. All 10 cases were Japanese patients treated at the National Cancer Center Hospital, Japan, between 1994 and 2010. Mutational signature analysis indicated that the accumulation of age-related mutations drive TC development. We identified recurrent somatic mutations in TET2, CYLD, SETD2, TP53, FBXW7, HRAS and RB1, and no mutations in GTF2I, supporting the hypothesis that TC and thymoma are distinguishable by their genetic profiles. TCs with TET2 mutations had more hypermethylated genes than those without, and hyper-methylation was associated with downregulation of gene expression. Focal genome copy number gains, associated with elevated gene expression, were observed at the KIT (which is known to drive thymic carcinogenesis) and AHNAK2 gene loci. Taken together, the results suggest that the molecular processes leading to TC depend on the accumulation of genetic and epigenetic aberrations. In addition, epigenetic dysregulation as a result of the TET2 mutation was observed in a subset of TCs.

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Hyaluronan-binding protein involved in hyaluronan depolymerization controls endochondral ossification through hyaluronan metabolism.

Shimoda M, Yoshida H, Mizuno S, Hirozane T, Horiuchi K, Yoshino Y, Hara H, Kanai Y, Inoue S, Ishijima M, Okada Y.

Am J Pathol (ELSEVIER SCIENCE INC) 187 ( 5 ) 1162 - 1176 2017

Accepted, ISSN 00029440

Hyaluronan (HA) plays an important role in the development and maintenance of tissues, and its degradation is implicated in many pathologic conditions. We recently reported that HA-binding protein involved in HA depolymerization (CEMIP; alias HYBID/KIAA1199) is a key molecule in HA depolymerization, but its developmental and pathologic functions remain elusive. We generated Hybid-deficient mice using the Cre/Locus of crossover in P1 (LoxP) system and analyzed their phenotypes. Hybiddeficient mice were viable and fertile, but their adult long bones were shorter than those of wild-type animals. Hybid-deficient mice showed lengthening of hypertrophic zone in the growth plate until 4 weeks after birth. There were fewer capillaries and osteoclasts at the chondroosseous junction in the Hybid-deficient mice compared with the wild-type mice. In situ hybridization demonstrated that Hybid was expressed by hypertrophic chondrocytes at the chondroosseous junction. Cultured primary chondrocytes expressed higher levels of Hybid than did osteoblasts or osteoclasts, and the Hybid expression in the chondrocytes was up-regulated after maturation to hypertrophic chondrocytes.high-molecular-weight HA was accumulated in the lengthened hypertrophic zone in Hybid-deficient mice. In addition, high-molecular-weight HA significantly reduced cell growth and tube formation in vascular endothelial growth factor-stimulated or -nonstimulated endothelial cells. HA metabolism by HYBID is involved in endochondraL ossification during postnatal development by modulation of angiogenesis and osteoclast recruitment at the chondroosseous junction.

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Cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids.

Nakaoka T, Saito Y, Shimamoto Y, Muramatsu T, Kimura M, Kanai Y, Saito H.

Cancer Sci (Blackwell Publishing Ltd) 108 ( 4 ) 678 - 684 2017

Accepted, ISSN 13479032

Tumor stem cells with self-renewal and multipotent capacity play critical roles in the initiation and progression of cancer. Recently, a new 3-D culture system known as organoid culture has been developed, allowing Lgr5-positive stem cells to form organoids that resemble the properties of original tissues. Here we established organoids derived from intestinal tumors of Apcmin/+ mice and normal intestinal epithelia of C57BL/6J mice and investigated the roles of microRNA (miRNA) in intestinal tumor organoids. The results of microarray analyses revealed that expression of the cluster miRNAs, miR-194 and miR-215 was markedly suppressed in intestinal tumor organoids in comparison with organoids derived from normal intestinal epithelia. Enforced expression of miR-194 resulted in inhibition of E2f3, a positive regulator of the cell cycle and growth suppression of intestinal tumor organoids. In addition, enforced expression of miR-215 suppressed the cancer stem cell signature through downregulation of intestinal stem cell markers including Lgr5. These findings indicate that the miRNA cluster including miR-194 and miR-215 plays important roles in suppressing the growth and attenuating the stemness of intestinal tumor organoids.

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Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy.

Yanagita T, Murata Y, Tanaka D, Motegi SI, Arai E, Daniwijaya EW, Hazama D, Washio K, Saito Y, Kotani T, Ohnishi H, Oldenborg PA, Garcia NV, Miyasaka M, Ishikawa O, Kanai Y, Komori T, Matozaki T.

JCI Insight (JCI Insight) 2 ( 1 ) e89140 2017

Accepted

© 2016 American Society for Clinical Investigation. All rights reserved. Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPα is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPα is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPα Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8+ T cells. In addition, the anti-SIRPα Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRPα-nonexpressing tumor cells. Anti-SIRPα Abs thus warrant further study as a potential new therapy for a broad range of cancers.

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Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis.

Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, Nozaki Y, Takahashi Y, Ito N, Shibuya A, Ojima H, Sukeda A, Seki Y, Kasama K, Yasuda K, Kanai Y.

Carcinogenesis (OXFORD UNIV PRESS) 38 ( 13 ) :261 - 270 2017

Accepted, ISSN 0008-5472

The aim of this study was to clarify the significance of DNA methylation alterations during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Single-CpG-resolution genome-wide DNA methylation analysis was performed on 264 liver tissue samples using the Illumina Infinium HumanMethylation450 BeadChip. After Bonferroni correction, 3331 probes showed significant DNA methylation alterations in 113 samples of non-cancerous liver tissue showing NASH (NASH-N) as compared with 55 samples of normal liver tissue (NLT). Principal component analysis using the 3331 probes revealed distinct DNA methylation profiles of NASH-N samples that were different from those of NLT samples and 37 samples of non-cancerous liver tissue showing chronic hepatitis or cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (viral-N). Receiver operating characteristic curve analysis identified 194 probes that were able to discriminate NASH-N samples from viral-N samples with area under the curve values of more than 0.95. JonckheereTerptsra trend test revealed that DNA methylation alterations in NASH-N samples from patients without hepatocellular carcinoma (HCC) were inherited by or strengthened in NASH-N samples from patients with HCC, and then inherited by or further strengthened in 22 samples of NASH-related HCC (NASH-T) themselves. NASH-and NASH-related HCC-specific DNA methylation alterations, which were not evident in viral-N samples and 37 samples of HCC associated with HBV or HCV infection, were observed in tumor-related genes, such as WHSC1, and were frequently associated with mRNA expression abnormalities. These data suggested that NASH-specific DNA methylation alterations may participate in NASH-related multistage hepatocarcinogenesis.

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DNA and Histone Methylation in Liver Cancer

Arai E., Yotani T., Kanai Y.

Cancer Drug Discovery and Development (Cancer Drug Discovery and Development) 0 ( 9783319597843 ) 437 - 460 2017

ISSN 21969906

© 2017, Springer International Publishing AG. Epigenetic alterations, such as alterations of histone modification and DNA methylation, occur in a genome-wide manner under precancerous conditions resulting from hepatitis B virus (HBV) or hepatitis C virus (HCV) infection followed by chronic hepatitis and cirrhosis, or aberrant lipogenesis and abnormal metabolism of reactive oxygen species that characterize the pathophysiology of non-alcoholic steatohepatitis (NASH). Once DNA methylation alterations occur at the precancerous stage, they are stably preserved on DNA double strands through methylation maintenance by DNA methyltransferase 1 (DNMT1). DNA methylation alterations associated with abnormalities of DNA methyltransferase, such as overexpression of DNMT1 and splicing alterations of DNMT3B, participate in multistage hepatocarcinogenesis from the precancerous stage to the malignant progression stage and are correlated with aggressiveness of hepatocellular carcinomas (HCCs) and poorer outcome of affected patients. A number of tumor-related genes, such as ATK3, APC, BMP4, CCL20, CDH1, CDKN2A, CDKN2B, CSPG2, DAB2IP, DCC, DLC1, DPT, DPYSL3, EMILIN2, FZD7, GRASP, GSTP1, HIST1H4F, IGFALS, MGMT, MZB1, NAT2, NEFH, NFATC1, PAX4, PDSS2, PER3, PROZ, PYCARD, RASSF1A, SPDY1, RUNX3, SCGB1D1, SFN, SMPD3, SOCS1, TIMP3, TLX3, TM6SF1, TRIM33, TRIM58, WFDC6, WNK2 and ZFP41, are known to be silenced by DNA hypermethylation in human HCCs. It is believed that DNA methylation alterations could be excellent biomarkers for carcinogenetic risk estimation and prognostication. To facilitate clinical application of DNA methylation diagnosis, a scaled-down device that allows quick and accurate analysis, even in small hospitals and clinics, is now being developed. One therapeutic strategy against HCC proliferation could involve a combination of epigenetic modifiers, such as a DNA methylation inhibitor, a histone deacetylase inhibitor and an S-adenosylhomocysteine hydrolase inhibitor, to sensitize cancer cells to conventional chemotherapies, in addition to eradication of hepatitis viruses for personalized and/or pre-emptive medical care.

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発育におけるHYBID(HYaluronan-Binding protein Involved in hyaluronan Depolymerization)の機能解析

下田将之, 吉田浩之, 水野早希子, 弘實透, 堀内圭輔, 吉野雄太, 原英彰, 石島旨章, 井上紳太郎, 金井弥栄, 岡田保典

日本創傷治癒学会プログラム・抄録集 ((一社)日本創傷治癒学会) 46回 161 - 161 2016.12

Accepted

早期肺腺癌におけるEGFR遺伝子変異と腫瘍間質構成細胞変化の検討

志満敏行, 重信敬夫, 下田将之, 大塚崇, 淺村尚生, 金井弥栄

肺癌 ((NPO)日本肺癌学会) 56 ( 6 ) 583 - 583 2016.11

ISSN 0386-9628

Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma

Hayashi, Takuma, Kawano, Miki, Ichimura, Tomoyuki, Ida, Koichi, Ando, Hirofumi, Zharhary, Dorit, Kanai, Yae, Aburatani, Hiroyuki, Tonegawa, Susumu, Shiozawa, Tanri, Yaegashi, Nobuo, Konishi, Ikuo

ANTICANCER RESEARCH (INT INST ANTICANCER RESEARCH) 36 ( 10 ) 4997 - 5007 2016.10

Research paper (scientific journal), ISSN 0250-7005

Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/beta 1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of similar to 37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/beta 1i expression, that is up-regulated by interferon-gamma (IFN gamma), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFN gamma signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/beta 1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/beta 1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

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【消化管II-下部消化管-】知っておきたい特殊な大腸腫瘍 UC関連dysplasia

下田, 将之, 岩男, 泰, 三上, 修治, 亀山, 香織, 金井, 弥栄

病理と臨床 34 ( 10 ) 1096 - 1101 2016.10

ISSN 0287-3745

Epigenome landscape of human normal purified hepatocytes: analysis by the International Human Epigenome Consortium (IHEC)

Eri Arai, Fumihito Miura, Yasushi Totoki, Satoshi Yamashita, Ying Tian, Masahiro Gotoh, Hidenori Ojima, Hiroyuki Nakagawa, Yoriko Takahashi, Hiromi Nakamura, Natsuko Hama, Mamoru Kato, Hiroshi Kimura, Yutaka Suzuki, Takashi Ito, Tatsuhiro Shibata, Yae Kanai

CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 76 2016.07

Accepted, ISSN 0008-5472

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ヒト正常肝細胞のエピゲノムプロファイル標準エピゲノムプロファイルと個体差

新井恵吏, 三浦史仁, 山下聡, 田迎, 後藤政広, 尾島英知, 鈴木穣, 伊藤隆司, 柴田龍弘, 金井弥栄

日本病理学会会誌 ((一社)日本病理学会) 105 ( 1 ) 361 - 361 2016.04

ISSN 0300-9181

Macroscopic features predict outcome in patients with pancreatic ductal adenocarcinoma.

Hori S, Shimada K, Ino Y, Oguro S, Esaki M, Nara S, Kishi Y, Kosuge T, Hattori Y, Sukeda A, Kitagawa Y, Kanai Y, Hiraoka N.

Virchows Arch (SPRINGER) 469 ( 6 ) 621 - 634 2016

Accepted, ISSN 09456317

As macroscopic appearance represents tumor microenvironment, it may also reflect the biological and clinicopathological characteristics of a cancer. The aim of the study was to evaluate the clinicopathological significance of the gross appearance of pancreatic ductal adenocarcinoma (PDA). We investigated fresh macroscopic features in 352 cases of PDA and their clinicopathological significance. Three unique gross features were found: a honeycomb-like appearance (diffusely distributed microcysts and interstitial fibrotic thickening), macroscopic necrosis, and a tube/branching structure (apparent small cylindrical or linear structure). A honeycomb-like appearance was present in 24 cases (6.8 %) and significantly associated with low serum CA19-9 level and well-differentiated adenocarcinoma. Macroscopic necrosis was present in 235 cases (66.8 %) and significantly correlated with tumor size, nodal metastasis, nerve plexus invasion, no adjuvant chemotherapy, and distant recurrence. The presence of macroscopic necrosis was significantly associated with shorter disease-specific survival (DSS) and disease-free survival (DFS). The presence of larger areas of necrosis (ae2 mm) was closely associated with shorter survival. A tube/branching structure was found in 179 cases (50.9 %), which was correlated with larger tumor size and no adjuvant chemotherapy and macroscopic necrosis. The presence of a tube/branching structure was significantly associated with shorter DSS and DFS. Multivariate survival analyses showed that the presence of tube/branching structures was an independent negative prognostic factor in patients having PDA. We suggest that the gross appearance of PDA reflects clinicopathological characteristics and may be useful in predicting prognosis.

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Lipidomic Signatures and Associated Transcriptomic Profiles of Clear Cell Renal Cell Carcinoma.

Saito K, Arai E, Maekawa K, Ishikawa M, Fujimoto H, Taguchi R, Matsumoto K, Kanai Y, Saito Y.

Sci Rep (NATURE PUBLISHING GROUP) 6 28932 2016

Accepted, ISSN 2045-2322

Renal cell carcinoma (RCC) is the most common histological type of adult kidney cancer. In this study, we obtained lipidomic profiles of clear cell RCC (ccRCC), a major RCC subtype, by performing a lipidomic analysis of specimens of cancerous tissue and the surrounding normal renal cortex obtained from the same patients (N = 49). We also compared the lipidomic profiles with the lipogenic transcriptome of specimens of cancerous tissue and the surrounding normal renal cortex for an additional set of patient samples (N = 95). Overall, we detected 326 lipids, including phospholipids, sphingolipids, neutral lipids, and eicosanoids. The levels of more than 70% of the detected lipids were significantly different (P < 0.01, corrected by the false discovery rate). The cancerous tissue was distinguished by higher levels of ether-type phospholipids, cholesterol esters, and triacylglycerols, as well as by lower levels of phospholipids (except for phosphatidylcholines) and polyunsaturated fatty acids. Characteristic changes in the levels of mRNAs and metabolites suggested that the phosphatidylethanolamine (PE) synthesis pathway is suppressed in ccRCC and associated with cell proliferation. The present study represents the lipidomic profiles of ccRCC, which provides novel information about the metabolic changes in renal cancerous tissue and RCC pathophysiology.

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Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass.

Hirozane T, Tohmonda T, Yoda M, Shimoda M, Kanai Y, Matsumoto M, Morioka H, Nakamura M, Horiuchi K.

Sci Rep (NATURE PUBLISHING GROUP) 6 34426 2016

Accepted, ISSN 2045-2322

Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-kappa B signaling and an increase in the expression of NF-kappa B-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.

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SMYD2 overexpression is associated with tumor cell proliferation and a worse outcome in human papillomavirus-unrelated nonmultiple head and neck carcinomas.

Ohtomo-Oda R, Komatsu S, Mori T, Sekine S, Hirajima S, Yoshimoto S, Kanai Y, Otsuji E, Ikeda E, Tsuda H.

Hum Pathol (W B SAUNDERS CO-ELSEVIER INC) 49 145 - 155 2016

Accepted, ISSN 00468177

Human papillomavirus (HPV) unrelated head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease, and there are no suitable prognostic or predictive markers. The SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase for histone H31(36 and p53K370, that regulates transcription was previously found to be a cancer-promoting gene in esophageal squamous cell carcinoma. In this study, we investigated whether SMYD2 is a possible oncogene and a prognostic indicator in HPV-unrelated, multiple and nonmultiple HNSCC. Among 197 HPV-unrelated HNSCC cases, over expression of SMYD2 protein was detected in 75 (60%) of 126 nonmultiple cases and 51 (70%) of 71 multiple cases. In nonmultiple cases, patients with SMYD2-overexpressing tumors had a worse overall survival rate than did those with nonexpressing tumors (P = .017, log-rank test), and SMYD2 positivity was independently associated with overall survival in the multivariate analysis (P = .003). In both nonmultiple and multiple groups, the combination of SMYD2 and p53 immunopositivity was a significant prognostic indicator (P = .027 and.015). In 5 HNSCC cell lines, overexpression of SMYD2 messenger RNA and protein was observed, but there was no notable amplification at 1q32-41.1. The proliferation of UM-SCC-17B HPV-unrelated HNSCC cell line was inhibited by knockdown of SMYD2 gene expression. These findings suggest that SMYD2 plays a role in tumor progression and might be a useful prognosticator in HPV-unrelated, nonmultiple HNSCC. (C) 2015 Elsevier Inc. All rights reserved.

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Genomic landscape of experimental bladder cancer in rodents and its application to human bladder cancer: Gene amplification and potential overexpression of Cyp2a5/CYP2A6 are associated with the invasive phenotype.

Kanemoto K, Fukuta K, Kawai N, Tozawa K, Ochiai M, Okamoto K, Ohnami S, Sakamoto H, Yoshida T, Kanai Y, Katoh M, Yasui T, Kohri K, Kakizoe T, Nakagama H.

PLoS One (PUBLIC LIBRARY SCIENCE) 11 ( 11 ) e0167374 2016

Accepted, ISSN 1932-6203

Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with increased malignancy and that CYP2A6 can be a candidate prognostic biomarker in this type of cancer.

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Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer.

Kamino H, Nakamura Y, Tsuneki M, Sano H, Miyamoto Y, Kitamura N, Futamura M, Kanai Y, Taniguchi H, Shida D, Kanemitsu Y, Moriya Y, Yoshida K, Arakawa H.

Oncogenesis (NATURE PUBLISHING GROUP) 4 e181 2016

Accepted, ISSN 2157-9024

Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.

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