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BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer

Authors: Lorna W Harries, John RB Perry, Paul McCullagh, Malcolm Crundwell

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

Genome wide association studies (GWAS) have identified several genetic variants that are associated with prostate cancer. Most of these variants, like other GWAS association signals, are located in non-coding regions of potential candidate genes, and thus could act at the level of the mRNA transcript.

Methods

We measured the expression and isoform usage of seven prostate cancer candidate genes in benign and malignant prostate by real-time PCR, and correlated these factors with cancer status and genotype at the GWAS risk variants.

Results

We determined that levels of LMTK2 transcripts in prostate adenocarcinomas were only 32% of those in benign tissues (p = 3.2 × 10-7), and that an independent effect of genotype at variant rs6465657 on LMTK2 expression in benign (n = 39) and malignant tissues (n = 21) was also evident (P = 0.002). We also identified that whilst HNF1B(C) and MSMB2 comprised the predominant isoforms in benign tissues (90% and 98% of total HNF1B or MSMB expression), HNF1B(B) and MSMB1 were predominant in malignant tissue (95% and 96% of total HNF1B or MSMB expression; P = 1.7 × 10-7 and 4 × 10-4 respectively), indicating major shifts in isoform usage.

Conclusions

Our results indicate that the amount or nature of mRNA transcripts expressed from the LMTK2, HNF1B and MSMB candidate genes is altered in prostate cancer, and provides further evidence for a role for these genes in this disorder. The alterations in isoform usage we detect highlights the potential importance of alternative mRNA processing and moderation of mRNA stability as potentially important disease mechanisms.
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Literature
1.
Sakr WA, Grignon DJ, Haas GP, Heilbrun LK, Pontes JE, Crissman JD: Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol. 1996, 30 (2): 138-144.PubMed
2.
Bratt O: Hereditary prostate cancer: clinical aspects. J Urol. 2002, 168 (3): 906-913. 10.1016/S0022-5347(05)64541-7.CrossRefPubMed
3.
Ben-Shlomo Y, Evans S, Ibrahim F, Patel B, Anson K, Chinegwundoh F, Corbishley C, Dorling D, Thomas B, Gillatt D, et al: The risk of prostate cancer amongst black men in the United Kingdom: the PROCESS cohort study. Eur Urol. 2008, 53 (1): 99-105. 10.1016/j.eururo.2007.02.047.CrossRefPubMed
4.
De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG: Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007, 7 (4): 256-269. 10.1038/nrc2090.CrossRefPubMedPubMedCentral
5.
Mitra A, Fisher C, Foster CS, Jameson C, Barbachanno Y, Bartlett J, Bancroft E, Doherty R, Kote-Jarai Z, Peock S, et al: Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer. 2008, 98 (2): 502-507. 10.1038/sj.bjc.6604132.CrossRefPubMedPubMedCentral
6.
Duggan D, Zheng SL, Knowlton M, Benitez D, Dimitrov L, Wiklund F, Robbins C, Isaacs SD, Cheng Y, Li G, et al: Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J Natl Cancer Inst. 2007, 99 (24): 1836-1844. 10.1093/jnci/djm250.CrossRefPubMed
7.
Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson JT, Thorleifsson G, Manolescu A, Rafnar T, Gudbjartsson D, Agnarsson BA, Baker A, et al: Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007, 39 (8): 977-983. 10.1038/ng2062.CrossRefPubMed
8.
Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R, Hutchinson A, et al: Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet. 2008, 40 (3): 310-315. 10.1038/ng.91.CrossRefPubMed
9.
Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, Mulholland S, Leongamornlert DA, Edwards SM, Morrison J, et al: Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet. 2008, 40 (3): 316-321. 10.1038/ng.90.CrossRefPubMed
10.
Ord T, Ord D, Koivomagi M, Juhkam K, Ord T: Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5'-UTR. Gene. 2009, 444 (1-2): 24-32. 10.1016/j.gene.2009.06.001.CrossRefPubMed
11.
Ishii H, Kobayashi M, Sakuma Y: Alternative promoter usage and alternative splicing of the rat estrogen receptor alpha gene generate numerous mRNA variants with distinct 5'-ends. J Steroid Biochem Mol Biol. 2010, 118 (1-2): 59-69. 10.1016/j.jsbmb.2009.10.001.CrossRefPubMed
12.
Welham SJ, Clark AJ, Salter AM: A novel liver specific isoform of the rat LAR transcript is expressed as a truncated isoform encoded from a 5'UTR located within intron 11. BMC Mol Biol. 2009, 10: 30-10.1186/1471-2199-10-30.CrossRefPubMedPubMedCentral
13.
Cartegni L, Chew SL, Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002, 3 (4): 285-298. 10.1038/nrg775.CrossRefPubMed
14.
Fackenthal JD, Godley LA: Aberrant RNA splicing and its functional consequences in cancer cells. Dis Model Mech. 2008, 1 (1): 37-42. 10.1242/dmm.000331.CrossRefPubMedPubMedCentral
15.
Pajares MJ, Ezponda T, Catena R, Calvo A, Pio R, Montuenga LM: Alternative splicing: an emerging topic in molecular and clinical oncology. Lancet Oncol. 2007, 8 (4): 349-357. 10.1016/S1470-2045(07)70104-3.CrossRefPubMed
16.
Rajan P, Elliott DJ, Robson CN, Leung HY: Alternative splicing and biological heterogeneity in prostate cancer. Nat Rev Urol. 2009, 6 (8): 454-460. 10.1038/nrurol.2009.125.CrossRefPubMed
17.
Le Quesne JP, Spriggs KA, Bushell M, Willis AE: Dysregulation of protein synthesis and disease. J Pathol. 2010, 220 (2): 140-51.PubMed
18.
Chatterjee S, Pal JK: Role of 5'- and 3'-untranslated regions of mRNAs in human diseases. Biol Cell. 2009, 101 (5): 251-262. 10.1042/BC20080104.CrossRefPubMed
19.
Chen JM, Ferec C, Cooper DN: A systematic analysis of disease-associated variants in the 3' regulatory regions of human protein-coding genes I: general principles and overview. Hum Genet. 2006, 120 (1): 1-21. 10.1007/s00439-006-0180-7.CrossRefPubMed
20.
Applied-Biosystems: Relative quantitation of gene expression. User bulletin #2. 2001, 11-15.
21.
Harries LW, Bingham C, Bellanne-Chantelot C, Hattersley AT, Ellard S: The position of premature termination codons in the hepatocyte nuclear factor -1 beta gene determines susceptibility to nonsense-mediated decay. Hum Genet. 2005, 118 (2): 214-224. 10.1007/s00439-005-0023-y.CrossRefPubMed
22.
Harries LW, Wickham CL, Evans JC, Rule SA, Joyner MV, Ellard S: Analysis of haematopoietic chimaerism by quantitative real-time polymerase chain reaction. Bone Marrow Transplant. 2005, 35 (3): 283-290. 10.1038/sj.bmt.1704764.CrossRefPubMed
23.
Inoue T, Kon T, Ohkura R, Yamakawa H, Ohara O, Yokota J, Sutoh K: BREK/LMTK2 is a myosin VI-binding protein involved in endosomal membrane trafficking. Genes Cells. 2008, 13 (5): 483-495. 10.1111/j.1365-2443.2008.01184.x.CrossRefPubMed
24.
Kawa S, Fujimoto J, Tezuka T, Nakazawa T, Yamamoto T: Involvement of BREK, a serine/threonine kinase enriched in brain, in NGF signalling. Genes Cells. 2004, 9 (3): 219-232. 10.1111/j.1356-9597.2004.00714.x.CrossRefPubMed
25.
Eto M, Elliott E, Prickett TD, Brautigan DL: Inhibitor-2 regulates protein phosphatase-1 complexed with NimA-related kinase to induce centrosome separation. J Biol Chem. 2002, 277 (46): 44013-44020. 10.1074/jbc.M208035200.CrossRefPubMed
26.
Kesavapany S, Lau KF, Ackerley S, Banner SJ, Shemilt SJ, Cooper JD, Leigh PN, Shaw CE, McLoughlin DM, Miller CC: Identification of a novel, membrane-associated neuronal kinase, cyclin-dependent kinase 5/p35-regulated kinase. J Neurosci. 2003, 23 (12): 4975-4983.PubMed
27.
Puri C, Chibalina MV, Arden SD, Kruppa AJ, Kendrick-Jones J, Buss F: Overexpression of myosin VI in prostate cancer cells enhances PSA and VEGF secretion, but has no effect on endocytosis. Oncogene. 29 (2): 188-200. 10.1038/onc.2009.328.
28.
Beke L, Nuytten M, Van Eynde A, Beullens M, Bollen M: The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. Oncogene. 2007, 26 (31): 4590-4595. 10.1038/sj.onc.1210248.CrossRefPubMed
29.
Hyakutake H, Sakai H, Yogi Y, Tsuda R, Minami Y, Yushita Y, Kanetake H, Nakazono I, Saito Y: Beta-microseminoprotein immunoreactivity as a new prognostic indicator of prostatic carcinoma. Prostate. 1993, 22 (4): 347-355. 10.1002/pros.2990220409.CrossRefPubMed
30.
Ohnuma S, Miura K, Horii A, Fujibuchi W, Kaneko N, Gotoh O, Nagasaki H, Mizoi T, Tsukamoto N, Kobayashi T, et al: Cancer-associated splicing variants of the CDCA1 and MSMB genes expressed in cancer cell lines and surgically resected gastric cancer tissues. Surgery. 2009, 145 (1): 57-68. 10.1016/j.surg.2008.08.010.CrossRefPubMed
31.
Harries L, Brown J, Gloyn AL: Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes. PLoS One. 2009, 4 (11): e7855-10.1371/journal.pone.0007855.CrossRefPubMedPubMedCentral
32.
Terasawa K, Toyota M, Sagae S, Ogi K, Suzuki H, Sonoda T, Akino K, Maruyama R, Nishiwara N, Imai K, et al: Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines. Br J cancer. 2006, 94 (6): 914-921. 10.1038/sj.bjc.6602984.CrossRefPubMedPubMedCentral
33.
Rebouissou S, Vasiliu V, Thomas C, Bellane-Chantelot C, Bui H, Chretien Y, Timsit J, Rosty C, Laurent-Puig P, Chauveau D, et al: Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Human Molecular Genetics. 2005, 14 (5): 603-614. 10.1093/hmg/ddi057.CrossRefPubMed
34.
Sun J, Zheng SL, Wiklund F, Isaacs SD, Purcell LD, Gao Z, Hsu FC, Kim ST, Liu W, Zhu Y, et al: Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat Genet. 2008, 40 (10): 1153-1155. 10.1038/ng.214.CrossRefPubMedPubMedCentral
35.
Bach I, Yaniv M: More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA preocessing. The EMBO Journal. 1993, 12 (11): 4229-4242.PubMedPubMedCentral
36.
Romero L, Ng L, Kirby G: Chemical Inducers of Rodent Glutathione S-Transferases Down-Regulate Human GSTA1 Transcription through a Mechanism Involving Variant Hepatic Nuclear Factor 1-C. Mol Pharmacol. 2006, 70 (1): 277-286.PubMed
37.
Eiberg H, Troelsen J, Nielsen M, Mikkelsen A, Mengel-From J, Kjaer KW, Hansen L: Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Hum Genet. 2008, 123 (2): 177-187. 10.1007/s00439-007-0460-x.CrossRefPubMed
Metadata
Title
Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer
Authors
Lorna W Harries
John RB Perry
Paul McCullagh
Malcolm Crundwell
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-315

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