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Molecular Cancer
Published in: Molecular Cancer 1/2011

Open Access 01-12-2011 | Research

Minichromosome Maintenance Protein 7 is a potential therapeutic target in human cancer and a novel prognostic marker of non-small cell lung cancer

Authors: Gouji Toyokawa, Ken Masuda, Yataro Daigo, Hyun-Soo Cho, Masanori Yoshimatsu, Masashi Takawa, Shinya Hayami, Kazuhiro Maejima, Makoto Chino, Helen I Field, David E Neal, Eiju Tsuchiya, Bruce AJ Ponder, Yoshihiko Maehara, Yusuke Nakamura, Ryuji Hamamoto

Published in: Molecular Cancer | Issue 1/2011

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Abstract

Background

The research emphasis in anti-cancer drug discovery has always been to search for a drug with the greatest antitumor potential but fewest side effects. This can only be achieved if the drug used is against a specific target located in the tumor cells. In this study, we evaluated Minichromosome Maintenance Protein 7 (MCM7) as a novel therapeutic target in cancer.

Results

Immunohistochemical analysis showed that MCM7 was positively stained in 196 of 331 non-small cell lung cancer (NSCLC), 21 of 29 bladder tumor and 25 of 70 liver tumor cases whereas no significant staining was observed in various normal tissues. We also found an elevated expression of MCM7 to be associated with poor prognosis for patients with NSCLC (P = 0.0055). qRT-PCR revealed a higher expression of MCM7 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpressed MCM7 by cDNA microarray analysis. Suppression of MCM7 using specific siRNAs inhibited incorporation of BrdU in lung and bladder cancer cells overexpressing MCM7, and suppressed the growth of those cells more efficiently than that of normal cell strains expressing lower levels of MCM7.

Conclusions

Since MCM7 expression was generally low in a number of normal tissues we examined, MCM7 has the characteristics of an ideal candidate for molecular targeted cancer therapy in various tumors and also as a good prognostic biomarker for NSCLC patients.
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Literature
1.
Mansi L, Thiery-Vuillemin A, Nguyen T, Bazan F, Calcagno F, Rocquain J, Demarchi M, Villanueva C, Maurina T, Pivot X: Safety profile of new anticancer drugs. Expert Opin Drug Saf. 2010, 9: 301-317. 10.1517/14740330903530663CrossRefPubMed
2.
Guarneri V, Barbieri E, Dieci MV, Piacentini F, Conte P: Anti-HER2 neoadjuvant and adjuvant therapies in HER2 positive breast cancer. Cancer Treat Rev. 2010, 36 (Suppl 3): S62-66.CrossRefPubMed
3.
Ikeda N, Nagase S, Ohira T: Individualized adjuvant chemotherapy for surgically resected lung cancer and the roles of biomarkers. Ann Thorac Cardiovasc Surg. 2009, 15: 144-149.PubMed
4.
Sargent D, Grothey A: Adjuvant therapy for colon cancer: learning from the past to inform the future. Ann Surg Oncol. 2010, 17: 947-949. 10.1245/s10434-009-0880-zPubMedCentralCrossRefPubMed
5.
Undevia SD, Gomez-Abuin G, Ratain MJ: Pharmacokinetic variability of anticancer agents. Nat Rev Cancer. 2005, 5: 447-458. 10.1038/nrc1629CrossRefPubMed
6.
Branzei D, Foiani M: Maintaining genome stability at the replication fork. Nat Rev Mol Cell Biol. 2010, 11: 208-219. 10.1038/nrm2852CrossRefPubMed
7.
8.
Ilves I, Petojevic T, Pesavento JJ, Botchan MR: Activation of the MCM2-7 helicase by association with Cdc45 and GINS proteins. Mol Cell. 2010, 37: 247-258. 10.1016/j.molcel.2009.12.030CrossRefPubMed
9.
Tye BK: MCM proteins in DNA replication. Annu Rev Biochem. 1999, 68: 649-686. 10.1146/annurev.biochem.68.1.649CrossRefPubMed
10.
Chong JP, Mahbubani HM, Khoo CY, Blow JJ: Purification of an MCM-containing complex as a component of the DNA replication licensing system. Nature. 1995, 375: 418-421. 10.1038/375418a0CrossRefPubMed
11.
Blow JJ, Laskey RA: A role for the nuclear envelope in controlling DNA replication within the cell cycle. Nature. 1988, 332: 546-548. 10.1038/332546a0CrossRefPubMed
12.
13.
Costa A, Onesti S: The MCM complex: (just) a replicative helicase?. Biochem Soc Trans. 2008, 36: 136-140. 10.1042/BST0360136CrossRefPubMed
14.
Ishimi Y: A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J Biol Chem. 1997, 272: 24508-24513. 10.1074/jbc.272.39.24508CrossRefPubMed
15.
16.
Kelman Z, Lee JK, Hurwitz J: The single minichromosome maintenance protein of Methanobacterium thermoautotrophicum DeltaH contains DNA helicase activity. Proc Natl Acad Sci USA. 1999, 96: 14783-14788. 10.1073/pnas.96.26.14783PubMedCentralCrossRefPubMed
17.
Kato T, Daigo Y, Hayama S, Ishikawa N, Yamabuki T, Ito T, Miyamoto M, Kondo S, Nakamura Y: A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis. Cancer Res. 2005, 65: 5638-5646. 10.1158/0008-5472.CAN-05-0600CrossRefPubMed
18.
Kikuchi T, Daigo Y, Katagiri T, Tsunoda T, Okada K, Kakiuchi S, Zembutsu H, Furukawa Y, Kawamura M, Kobayashi K, Imai K, Nakamura Y: Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene. 2003, 22: 2192-2205. 10.1038/sj.onc.1206288CrossRefPubMed
19.
Taniwaki M, Daigo Y, Ishikawa N, Takano A, Tsunoda T, Yasui W, Inai K, Kohno N, Nakamura Y: Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer. Int J Oncol. 2006, 29: 567-575.PubMed
20.
Ishikawa N, Daigo Y, Yasui W, Inai K, Nishimura H, Tsuchiya E, Kohno N, Nakamura Y: ADAM8 as a novel serological and histochemical marker for lung cancer. Clin Cancer Res. 2004, 10: 8363-8370. 10.1158/1078-0432.CCR-04-1436CrossRefPubMed
21.
Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H, Miyagi Y, Nakayama H, Fujita M, Hosokawa M, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y: Cancer-testis antigen lymphocyte antigen 6 complex locus K is aserologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res. 2007, 67: 11601-11611. 10.1158/0008-5472.CAN-07-3243CrossRefPubMed
22.
Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, Field HI, Neal DE, Yamaue H, Ponder BA, Nakamura Y, Hamamoto R: Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer. 2010, 128: 574-586.CrossRef
23.
Hayami S, Yoshimatsu M, Veerakumarasivam A, Unoki M, Iwai Y, Tsunoda T, Field HI, Kelly JD, Neal DE, Yamaue H, Ponder BA, Nakamura Y, Hamamoto R: Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway. Mol Cancer. 2010, 9: 59- 10.1186/1476-4598-9-59PubMedCentralCrossRefPubMed
24.
Wallard MJ, Pennington CJ, Veerakumarasivam A, Burtt G, Mills IG, Warren A, Leung HY, Murphy G, Edwards DR, Neal DE, Kelly JD: Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma. Br J Cancer. 2006, 94: 569-577. 10.1038/sj.bjc.6602931PubMedCentralCrossRefPubMed
25.
Kitahara O, Furukawa Y, Tanaka T, Kihara C, Ono K, Yanagawa R, Nita ME, Takagi T, Nakamura Y, Tsunoda T: Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res. 2001, 61: 3544-3549.PubMed
26.
Nakamura T, Furukawa Y, Nakagawa H, Tsunoda T, Ohigashi H, Murata K, Ishikawa O, Ohgaki K, Kashimura N, Miyamoto M, Hirano S, Kondo S, Katoh H, Nakamura Y, Katagiri T: Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene. 2004, 23: 2385-2400. 10.1038/sj.onc.1207392CrossRefPubMed
27.
Yoshimatsu M, Toyokawa G, Hayami S, Unoki M, Tsunoda T, Field HI, Kelly JD, Neal DE, Maehara Y, Ponder BA, Nakamura Y, Hamamoto R: Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers. Int J Cancer. 2011, 128: 562-573. 10.1002/ijc.25366CrossRefPubMed
28.
Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y: SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol. 2004, 6: 731-740. 10.1038/ncb1151CrossRefPubMed
29.
Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, Field HI, Neal DE, Yamaue H, Ponder BA, Nakamura Y, Hamamoto R: Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer. 2011, 128: 574-586. 10.1002/ijc.25349CrossRefPubMed
30.
Sato N, Koinuma J, Fujita M, Hosokawa M, Ito T, Tsuchiya E, Kondo S, Nakamura Y, Daigo Y: Activation of WD repeat and high-mobility group box DNA binding protein 1 in pulmonary and esophageal carcinogenesis. Clin Cancer Res. 2010, 16: 226-239. 10.1158/1078-0432.CCR-09-1405CrossRefPubMed
31.
Callagy G, Cattaneo E, Daigo Y, Happerfield L, Bobrow LG, Pharoah PD, Caldas C: Molecular classification of breast carcinomas using tissue microarrays. Diagn Mol Pathol. 2003, 12: 27-34. 10.1097/00019606-200303000-00004CrossRefPubMed
32.
Callagy G, Pharoah P, Chin SF, Sangan T, Daigo Y, Jackson L, Caldas C: Identification and validation of prognostic markers in breast cancer with the complementary use of array-CGH and tissue microarrays. J Pathol. 2005, 205: 388-396. 10.1002/path.1694CrossRefPubMed
33.
Chin SF, Daigo Y, Huang HE, Iyer NG, Callagy G, Kranjac T, Gonzalez M, Sangan T, Earl H, Caldas C: A simple and reliable pretreatment protocol facilitates fluorescent in situ hybridisation on tissue microarrays of paraffin wax embedded tumour samples. Mol Pathol. 2003, 56: 275-279. 10.1136/mp.56.5.275PubMedCentralCrossRefPubMed
34.
Ishimi Y, Sugiyama T, Nakaya R, Kanamori M, Kohno T, Enomoto T, Chino M: Effect of heliquinomycin on the activity of human minichromosome maintenance 4/6/7 helicase. FEBS J. 2009, 276: 3382-3391. 10.1111/j.1742-4658.2009.07064.xCrossRefPubMed
35.
Lei M, Tye BK: Initiating DNA synthesis: from recruiting to activating the MCM complex. J Cell Sci. 2001, 114: 1447-1454.PubMed
36.
Koonin EV: A common set of conserved motifs in a vast variety of putative nucleic acid-dependent ATPases including MCM proteins involved in the initiation of eukaryotic DNA replication. Nucleic Acids Res. 1993, 21: 2541-2547. 10.1093/nar/21.11.2541PubMedCentralCrossRefPubMed
37.
Dimitrova DS, Prokhorova TA, Blow JJ, Todorov IT, Gilbert DM: Mammalian nuclei become licensed for DNA replication during late telophase. J Cell Sci. 2002, 115: 51-59.PubMedCentralCrossRefPubMed
38.
Fujioka S, Shomori K, Nishihara K, Yamaga K, Nosaka K, Araki K, Haruki T, Taniguchi Y, Nakamura H, Ito H: Expression of minichromosome maintenance 7 (MCM7) in small lung adenocarcinomas (pT1): Prognostic implication. Lung Cancer. 2009, 65: 223-229. 10.1016/j.lungcan.2008.11.007CrossRefPubMed
39.
Ramnath N, Hernandez FJ, Tan DF, Huberman JA, Natarajan N, Beck AF, Hyland A, Todorov IT, Brooks JS, Bepler G: MCM2 is an independent predictor of survival in patients with non-small-cell lung cancer. J Clin Oncol. 2001, 19: 4259-4266.PubMed
40.
Ishimi Y, Okayasu I, Kato C, Kwon HJ, Kimura H, Yamada K, Song SY: Enhanced expression of Mcm proteins in cancer cells derived from uterine cervix. Eur J Biochem. 2003, 270: 1089-1101. 10.1046/j.1432-1033.2003.03440.xCrossRefPubMed
41.
Honeycutt KA, Chen Z, Koster MI, Miers M, Nuchtern J, Hicks J, Roop DR, Shohet JM: Deregulated minichromosomal maintenance protein MCM7 contributes to oncogene driven tumorigenesis. Oncogene. 2006, 25: 4027-4032. 10.1038/sj.onc.1209435CrossRefPubMed
42.
Shohet JM, Hicks MJ, Plon SE, Burlingame SM, Stuart S, Chen SY, Brenner MK, Nuchtern JG: Minichromosome maintenance protein MCM7 is a direct target of the MYCN transcription factor in neuroblastoma. Cancer Res. 2002, 62: 1123-1128.PubMed
43.
Ren B, Yu G, Tseng GC, Cieply K, Gavel T, Nelson J, Michalopoulos G, Yu YP, Luo JH: MCM7 amplification and overexpression are associated with prostate cancer progression. Oncogene. 2006, 25: 1090-1098. 10.1038/sj.onc.1209134CrossRefPubMed
44.
Mukherjee P, Winter SL, Alexandrow MG: Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction. Mol Cell Biol. 30: 845-856.
45.
Tan DF, Huberman JA, Hyland A, Loewen GM, Brooks JS, Beck AF, Todorov IT, Bepler G: MCM2--a promising marker for premalignant lesions of the lung: a cohort study. BMC Cancer. 2001, 1: 6- 10.1186/1471-2407-1-6PubMedCentralCrossRefPubMed
46.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004, 350: 2335-2342. 10.1056/NEJMoa032691CrossRefPubMed
47.
Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009, 373: 1525-1531. 10.1016/S0140-6736(09)60569-9CrossRefPubMed
48.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006, 355: 2542-2550. 10.1056/NEJMoa061884CrossRefPubMed
49.
Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN, Gandara DR: Aurora kinases as anticancer drug targets. Clin Cancer Res. 2008, 14: 1639-1648. 10.1158/1078-0432.CCR-07-2179CrossRefPubMed
50.
Sharma S, Doherty KM, Brosh RM: DNA helicases as targets for anti-cancer drugs. Curr Med Chem Anticancer Agents. 2005, 5: 183-199. 10.2174/1568011053765985CrossRefPubMed
51.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010CrossRefPubMed
52.
Sawabata N, Asamura H, Goya T, Mori M, Nakanishi Y, Eguchi K, Koshiishi Y, Tsuchiya R, Okumura M, Miyaoka E, Fujii Y: [A Japanese lung cancer registry study at 2002]. Nihon Kokyuki Gakkai Zasshi. 48: 333-344.
Metadata
Title
Minichromosome Maintenance Protein 7 is a potential therapeutic target in human cancer and a novel prognostic marker of non-small cell lung cancer
Authors
Gouji Toyokawa
Ken Masuda
Yataro Daigo
Hyun-Soo Cho
Masanori Yoshimatsu
Masashi Takawa
Shinya Hayami
Kazuhiro Maejima
Makoto Chino
Helen I Field
David E Neal
Eiju Tsuchiya
Bruce AJ Ponder
Yoshihiko Maehara
Yusuke Nakamura
Ryuji Hamamoto
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2011
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-10-65

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