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01.09.2013 | Original Article

The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer

verfasst von: Beatrice Mohelnikova-Duchonova, Veronika Brynychova, Viktor Hlavac, Matej Kocik, Martin Oliverius, Jan Hlavsa, Eva Honsova, Jan Mazanec, Zdenek Kala, Bohuslav Melichar, Pavel Soucek

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2013

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Abstract

Objectives

The aim of this study was to investigate the prognostic significance of fourteen anticancer drug-relevant solute carrier transporters (SLCs) in pancreatic cancer in the context of clinical–pathological characteristics and the KRAS mutation status of tumors.

Methods

Tumors and non-neoplastic pancreatic tissues were obtained from 32 histologically verified patients with pancreatic ductal adenocarcinoma. The transcript profile of SLCs was assessed using quantitative real-time PCR. KRAS mutations in exon 2 were assessed by high-resolution melting analysis and confirmed by sequencing.

Results

SLC22A3 and SLC22A18 were upregulated and SLC22A1, SLC22A2, SLC22A11, SLC28A1, SLC28A3 and SLC29A1 were downregulated when compared with non-neoplastic pancreatic tissues. Moreover, significantly lower levels of SLC22A1, SLC22A11 and SLC29A1 were found in tumors with angioinvasion. There was also a significantly higher transcript level of SLC28A1 in tumors with regional lymph nodes affected by metastasis. The study found that a high expression of SLC28A1 was significantly associated with poor overall survival in unselected patients. In contrast, a high expression of SLC22A3 or SLC29A3 was significantly associated with longer overall survival in patients treated with nucleoside analogs. Protein expression of SLC22A1, SLC22A3 and SLC29A3 in tumor tissues of patients with pancreatic carcinoma was observed by immunoblotting for the first time. Finally, SLC levels were not found to be associated with KRAS mutation status in exon 2.

Conclusions

This study identified a number of associations of transcript levels of SLCs with prognosis of pancreatic cancer patients.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRef

Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554PubMedCrossRef

Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057PubMedCrossRef

Heinemann V, Haas M, Boeck S (2012) Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev 38:843–853PubMedCrossRef

Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H (2007) Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297:267–277PubMedCrossRef

Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825

Hlavata I, Mohelnikova-Duchonova B, Vaclavikova R, Liska V, Pitule P, Novak P, Bruha J, Vycital O, Holubec L, Treska V, Vodicka P, Soucek P (2012) The role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis 27:187–196PubMedCrossRef

Mohelnikova-Duchonova B, Brynychova V, Oliverius M, Honsova E, Soucek P (2013) Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and non-neoplastic tissues. Pancreas 42:707–716PubMedCrossRef

Huang Y (2007) Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy. Cancer Metastasis Rev 26:183–201PubMedCrossRef

10.

Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357PubMed

11.

Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD (2004) The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 447:735–743PubMedCrossRef

12.

Gray JH, Owen RP, Giacomini KM (2004) The concentrative nucleoside transporter family, SLC28. Pflugers Arch 447:728–734PubMedCrossRef

13.

Sprowl JA, Ness RA, Sparreboom A (2012) Polymorphic transporters and platinum pharmacodynamics. Drug Metab Pharmacokinet. doi:10.2133/dmpk.DMPK-12-RV-073

14.

Uwai Y, Taniguchi R, Motohashi H, Saito H, Okuda M, Inui K (2004) Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab Dispos 19:369–374CrossRef

15.

Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H (2002) Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther 302:666–671PubMedCrossRef

16.

Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama N, Yamamoto T (2005) Transport mechanism and substrate specificity of human organic anion transporter 2 (hOAT2[SLC22A7]). J Pharm Pharmacol 57:573–578PubMedCrossRef

17.

He H, Xu C, Zhao Z, Qin X, Xu H, Zhang H (2011) Low expression of SLC22A18 predicts poor survival outcome in patients with breast cancer after surgery. Cancer Epidemiol 35:279–285PubMedCrossRef

18.

Sheng-Hua Chu S-H, Ma Y-B, Feng D-F, Li Z-Q, Jiang P-C (2013) Predictive value of the SLC22A18 protein expression in glioblastoma patients receiving temozolomide therapy. J Transl Med 11:69PubMedCrossRef

19.

Greene FL, Trotti A III, Fritz AG, et al (2010) In: Edge SB (ed) AJCC cancer staging handbook, 7th edn. American Joint Committee on Cancer, 2009, Chicago

20.

Soucek P, Anzenbacher P, Skoumalova I, Dvorak M (2005) Expression of cytochrome P450 genes in CD34 + hematopoietic stem and progenitor cells. Stem Cells 23:1417–1422PubMedCrossRef

21.

Topic E, Gluhak J (1991) Isolation of restrictable DNA. Eur J Clin Chem Clin Biochem 29:327–330PubMed

22.

Mohelnikova-Duchonova B, Oliverius M, Honsova E, Soucek P (2012) Evaluation of reference genes and normalization strategy for quantitative real-time PCR in human pancreatic carcinoma. Dis Markers 32:203–210PubMedCrossRef

23.

Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines, minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55:611–622PubMedCrossRef

24.

Vobořilová J, Němcová-Fürstová V, Neubauerová J, Ojima I, Zanardi I, Gut I, Kovář J (2011) Cell death induced by novel fluorinated taxanes in drug-sensitive and drug-resistant cancer cells. Invest New Drugs 29:411–423PubMedCrossRef

25.

Hlaváč V, Brynychová V, Václavíková R, Ehrlichová M, Vrána D, Pecha V, Koževnikovová R, Trnková M, Gatěk J, Kopperová D, Gut I, Souček P (2013) The expression profile of ABC transporter genes in breast carcinoma. Pharmacogenomics 14:515–529PubMedCrossRef

26.

Mohelnikova-Duchonova B, Soucek P (2012) The role of membrane transporters in cellular resistance of pancreatic carcinoma to gemcitabine and erlotinib. In: Watanabe HS (ed) Horizons in cancer research, vol 46. NOVA Science Publishers Inc, NY, pp 183–196

27.

García-Manteiga J, Molina-Arcas M, Casado FJ, Mazo A, Pastor-Anglada M (2003) Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2′,2′-difluorodeoxycytidine- induced cytotoxicity. Clin Cancer Res 9:5000–5008PubMed

28.

Tsujie M, Nakamori S, Nakahira S, Takahashi Y, Hayashi N, Okami J, Nagano H, Dono K, Umeshita K, Sakon M, Monden M (2007) Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer. Anticancer Res 27:2241–2249PubMed

29.

Mori R, Ishikawa T, Ichikawa Y, Taniguchi K, Matsuyama R, Ueda M, Fujii Y, Endo I, Togo S, Danenberg PV, Shimada H (2007) Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. Oncol Rep 17:1201–1205PubMed

30.

Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura K, Minoguchi M, Izawa T, Mizukami Y, Okumura T, Kohgo Y (2007) Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br J Cancer 96:457–463PubMedCrossRef

31.

Maréchal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K, Couvelard A, Svrcek M, Bardier-Dupas A, Hammel P, Sauvanet A, Louvet C, Paye F, Rougier P, Penna C, André T, Dumontet C, Cass CE, Jordheim LP, Matera EL, Closset J, Salmon I, Devière J, Emile JF, Van Laethem JL (2012) Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology 143:664–674PubMedCrossRef

32.

Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, Dicker AP, Mackey JR (2009) Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 136:187–195PubMedCrossRef

33.

Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR (2004) The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 10:6956–6961PubMedCrossRef

34.

Morinaga S, Nakamura Y, Watanabe T, Mikayama H, Tamagawa H, Yamamoto N, Shiozawa M, Akaike M, Ohkawa S, Kameda Y, Miyagi Y (2012) Immunohistochemical analysis of human equilibrative nucleoside transporter-1 (hENT1) predicts survival in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy. Ann Surg Oncol 19(Suppl 3):S558–S564PubMedCrossRef

35.

Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, Iannopollo M, Bevilacqua G, Mosca F, Danesi R (2006) Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 66:3928–3935PubMedCrossRef

36.

Kim R, Tan A, Lai KK, Jiang J, Wang Y, Rybicki LA, Liu X (2011) Prognostic roles of human equilibrative transporter 1 (hENT1) and ribonucleoside reductase subunit M1 (RRM1) in resected pancreatic cancer. Cancer 117:3126–3134PubMedCrossRef

37.

Murata Y, Hamada T, Kishiwada M, Ohsawa I, Mizuno S, Usui M, Sakurai H, Tabata M, Ii N, Inoue H, Shiraishi T, Isaji S (2012) Human equilibrative nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3-T4 pancreatic cancer patients treated with preoperative gemcitabine-based chemoradiotherapy. J Hepatobiliary Pancreat Sci 19:413–425PubMedCrossRef

38.

Kawada N, Uehara H, Katayama K, Nakamura S, Takahashi H, Ohigashi H, Ishikawa O, Nagata S, Tomita Y (2012) Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine. J Hepatobiliary Pancreat Sci 19:717–722PubMedCrossRef

39.

Baldwin SA, Yao SY, Hyde RJ, Ng AM, Foppolo S, Barnes K, Ritzel MW, Cass CE, Young JD (2005) Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J Biol Chem 280:15880–15887PubMedCrossRef

40.

Govindarajan R, Leung GP, Zhou M, Tse CM, Wang J, Unadkat JD (2009) Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol 296:G910–G922PubMedCrossRef

41.

Endo Y, Obata T, Murata D, Ito M, Sakamoto K, Fukushima M, Yamasaki Y, Yamada Y, Natsume N, Sasaki T (2007) Cellular localization and functional characterization of the equilibrative nucleoside transporters of antitumor nucleosides. Cancer Sci 98:1633–1637PubMedCrossRef

42.

Bhutia YD, Hung SW, Patel B, Lovin D, Govindarajan R (2011) CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells. Cancer Res 71:1825–1835PubMedCrossRef

43.

Gloeckner-Hofmann K, Guillén-Gómez E, Schmidtgen C, Porstmann R, Ziegler R, Stoss O, Casado FJ, Rüschoff J, Pastor-Anglada M (2006) Expression of the high-affinity fluoropyrimidine-preferring nucleoside transporter hCNT1 correlates with decreased disease-free survival in breast cancer. Oncology 70:238–244PubMedCrossRef

44.

Cano-Soldado P, Pastor-Anglada M (2012) Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition. Med Res Rev 32:428–457PubMedCrossRef

45.

Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, Chen Y, Komori T, Gray JW, Chen X, Lippard SJ, Giacomini KM (2006) Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res 66:8847–8857PubMedCrossRef

46.

Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui K (2006) Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther 319:879–886PubMedCrossRef

47.

Ciarimboli G, Ludwig T, Lang D, Pavenstädt H, Koepsell H, Piechota HJ, Haier J, Jaehde U, Zisowsky J, Schlatter E (2005) Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 167:1477–1484PubMedCrossRef

48.

Rudloff U, Bhanot U, Gerald W, Klimstra DS, Jarnagin WR, Brennan MF, Allen PJ (2010) Biobanking of human pancreas cancer tissue: impact of ex vivo procurement times on RNA quality. Ann Surg Oncol 17:2229–2236PubMedCrossRef

Titel: The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer
verfasst von: Beatrice Mohelnikova-Duchonova
Veronika Brynychova
Viktor Hlavac
Matej Kocik
Martin Oliverius
Jan Hlavsa
Eva Honsova
Jan Mazanec
Zdenek Kala
Bohuslav Melichar
Pavel Soucek
Publikationsdatum: 01.09.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2013
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2246-2

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The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer