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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma

Authors: Hironori Betsunoh, Takehiko Fukuda, Naohiko Anzai, Daisaku Nishihara, Tomoya Mizuno, Hideo Yuki, Akinori Masuda, Yoshiyuki Yamaguchi, Hideyuki Abe, Masahiro Yashi, Yoshitatsu Fukabori, Ken-Ichiro Yoshida, Takao Kamai

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer.

Methods

To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting.

Results

Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors.

Conclusions

These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.
Appendix
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Literature
1.
Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med. 1996, 335: 865-875. 10.1056/NEJM199609193351207.CrossRefPubMed
2.
Athar U, Gentile TC: Treatment options for metastatic renal cell carcinoma: a review. Can J Urol. 2008, 15: 523-532.
3.
Chaffer CL, Weinberg RA: A perspective on cancer cell metastasis. Science. 2011, 331: 1559-1564. 10.1126/science.1203543.CrossRefPubMed
4.
De Berardinis RJ, Julian JL, Hatzivassiliou G, Thompson CB: The biology of cancer: metabolic reprogramming fuelscell growth and proliferation. Cell Metab. 2008, 7: 11-20. 10.1016/j.cmet.2007.10.002.CrossRef
5.
Barger JF, Plas DR: Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr Relat Cancer. 2010, 17: R287-R304. 10.1677/ERC-10-0106.CrossRefPubMed
6.
Christensen HN: Role of amino acid transport and countertransport in nurtrition and metabolism. Physiol Rev. 1990, 70: 43-77.PubMed
7.
8.
Ganapathy V, Thangaraju M, Prasad PD: Nutrient transporters in caner: relevance to Warburg hypothesis and beyond. Pharmacol THer. 2009, 121: 29-40. 10.1016/j.pharmthera.2008.09.005.CrossRefPubMed
9.
Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H: Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4 F2 antigen (CD98). J Biol Chem. 1998, 273: 23629-23632. 10.1074/jbc.273.37.23629.CrossRefPubMed
10.
Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H: Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta. 2001, 1514: 291-302. 10.1016/S0005-2736(01)00384-4.CrossRefPubMed
11.
Kobayashi H, Ishii Y, Takayama T: Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J Surg Oncol. 2005, 90: 233-238. 10.1002/jso.20257.CrossRefPubMed
12.
Nawashiro H, Otani N, Shinomiya N, Fukui S, Ooigawa H, Shima K, Matsuo H, Kanai Y, Endou H: L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer. 2006, 119: 484-492. 10.1002/ijc.21866.CrossRefPubMed
13.
Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T, Kanai Y, Endou H, Nakajima T, Mori M: Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer. 2008, 98: 742-748. 10.1038/sj.bjc.6604235.CrossRefPubMedPubMedCentral
14.
Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, Anzai N, Suzuki Y, Endou H, Okayasu I: High expression of L-type amino acid transporter 1 (LAT1) in gastric carcinomas: comparison with non-cancerous lesions. Pathol Int. 2011, 61: 281-289. 10.1111/j.1440-1827.2011.02650.x.CrossRefPubMed
15.
Nakanishi K, Ogata S, Matsui H, Kanai Y, Endou H, Hiroi S, Tominaga S, Aida S, Kasamatsu H, Kawai T: Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract. Virchows Arch. 2007, 451: 681-690. 10.1007/s00428-007-0457-9.CrossRefPubMed
16.
Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, Ueno A, Kanai Y, Endou H, Okayasu I: L-type amino acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathol Int. 2009, 59: 7-18. 10.1111/j.1440-1827.2008.02319.x.CrossRefPubMed
17.
Oda K, Hosoda N, Endo H, Saito K, Tsujihara K, Yamamura M, Sakata T, Anzai N, Wempe MF, Kanai Y, Endou H: L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci. 2010, 101: 173-179. 10.1111/j.1349-7006.2009.01386.x.CrossRefPubMed
18.
Wagner CA, Lang F, Broer S: Function and structure of heterodimeric acid transporters. Am J Physio Cell Physiol. 2001, 281: c1077-c1093.
19.
Babu E, Kanai Y, Chairoungdua A, Kim DK, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H: Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem. 2003, 278: 43838-43845. 10.1074/jbc.M305221200.CrossRefPubMed
20.
Bodoy S, Martín L, Zorzano A, Palacín M, Estévez R, Bertran J: Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem. 2005, 280: 12002-12022. 10.1074/jbc.M408638200.CrossRefPubMed
21.
Kurayama R, Ito N, Nishibori Y, Fukuhara D, Akimoto Y, Higashihara E, Ishigaki Y, Sai Y, Miyamoto K, Endou H, Kanai Y, Yan K: Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis. Lab Invest. 2011, 91: 992-1006. 10.1038/labinvest.2011.43.CrossRefPubMed
22.
Sekine Y, Nishibori Y, Akimoto Y, Kudo A, Ito N, Fukuhara D, Kurayama R, Higashihara E, Babu E, Kanai Y, Asanuma K, Nagata M, Majumdar A, Tryggvason K, Yan K: Amino acid transporter LAT3 is required for podocyte development and function. J Am Soc Nephrol. 2009, 20: 1586-1596. 10.1681/ASN.2008070809.CrossRefPubMedPubMedCentral
23.
Suwa H, Ohshio G, Imamura T, Watanabe G, Arii S, Imamura M, Narumiya S, Hiai H, Fukumoto M: Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br J Cancer. 1998, 77: 147-152. 10.1038/bjc.1998.23.CrossRefPubMedPubMedCentral
24.
Kamai T, Yanai Y, Arai K, Abe H, Yamanishi T, Kurimoto M, Yoshida K-I: Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis. BMC Cancer. 2007, 7: 1471-2407. 7-159CrossRef
25.
Fuhrman SA, Lasky LC, Lmas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982, 6: 655-663. 10.1097/00000478-198210000-00007.CrossRefPubMed
26.
Sobin LH, Gospodarowicz MK, Wittekind CH: International union against cancer. UICC. TNM classification of malignant tumors. 2009, New York: Wiley-Liss, 255-257. 7
27.
Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H, Yoshida K-I: Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res. 2003, 9: 2632-2641.PubMed
28.
Furuya N, Kamai T, Shirataki H, Yanai Y, Fukuda T, Mizuno T, Kambara T, Nakanishi K, Abe H, Yoshida K-I: Serum interferon alpha receptor 2 mRNA may predict efficacy of interferon alpha with/without low-dose sorafenib for metastatic clear cell renal cell carcinoma. Cancer Immunol Immunother. 2011, 60: 793-808. 10.1007/s00262-011-0989-3.CrossRefPubMedPubMedCentral
29.
Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126/science.1160809.CrossRefPubMedPubMedCentral
30.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011, 144: 646-674. 10.1016/j.cell.2011.02.013.CrossRefPubMed
31.
Oxender DL, Christensen HN: Evidence for two types of mediation of neutral amino acid transport in Ehrlich cells. Nature. 1963, 197: 765-767. 10.1038/197765a0.CrossRefPubMed
32.
Novick AC: Open surgery of the kidney. Campbell-Walsh Urology. Edited by: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. 2007, Philadelphia: Saunders Elsevier, 1686-1758. 9
33.
Fuchs BC, Bode BP: Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime?. Semin Cancer Biol. 2005, 15: 254-266. 10.1016/j.semcancer.2005.04.005.CrossRefPubMed
34.
Yamauchi K, Sakurai H, Kimura T, Wiriyasermkul P, Nagamori S, Kanai Y, Kohno N: System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line. Cancer Lett. 2009, 276: 95-101. 10.1016/j.canlet.2008.10.035.CrossRefPubMed
35.
Imai H, Kaira K, Oriuchi N, Shimizu K, Tominaga H, Yanagitani N, Sunaga N, Ishizuka T, Nagamori S, Promchan K, Nakajima T, Yamamoto N, Mori M, Kanai Y: Inhibition of L-type amino acid transporter 1 has antitumor activity in non-small cell lung cancer. Anticancer Res. 2010, 30: 4819-4828.PubMed
36.
Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, Minhas V, Lehman ML, Hendy SC, Buchanan G, Nelson CC, Rasko JE, Holst J: Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res. 2011, 71: 7525-7536. 10.1158/0008-5472.CAN-11-1821.CrossRefPubMed
37.
Abe H, Kamai T: Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol. 2013, 10.1111 In publication
38.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ: Global ARCC trial : temsirolimus, interferon Alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007, 356: 2271-2281. 10.1056/NEJMoa066838.CrossRefPubMed
39.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A: RECORD-1 study group: efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008, 372: 449-456. 10.1016/S0140-6736(08)61039-9.CrossRefPubMed
40.
Hayashi K, Jutabha P, Endou H, Anzai N: c-Myc is crucial for the expression of LAT1 in MIA paca-2 human pancreatic cancer cells. Oncol Rep. 2012, 28: 862-866.PubMed
41.
Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV: Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol. 2004, 24: 5923-5936. 10.1128/MCB.24.13.5923-5936.2004.CrossRefPubMedPubMedCentral
42.
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, LA LA, Dang CV: Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000, 275: 21797-21800. 10.1074/jbc.C000023200.CrossRefPubMed
43.
Dang CV, Le A, Gao P: MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009, 15: 6479-6483. 10.1158/1078-0432.CCR-09-0889.CrossRefPubMedPubMedCentral
44.
45.
Tang SW, Chang WH, Su YC, Chen YC, Lai YH, Wu PT, Hsu CI, Lin WC, Lai MK, Lin JY: MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma. Cancer Lett. 2009, 273: 35-43. 10.1016/j.canlet.2008.07.038.CrossRefPubMed
46.
Liu Y, Yin B, Zhang C, Zhou L, Fan J: Has-let-7a functions as a tumor suppressor in renal cell carcinoma cell lines by targeting c-myc. Biochem Biophys Res Commun. 2012, 417: 371-375. 10.1016/j.bbrc.2011.11.119.CrossRefPubMed
47.
Luo X, Yin P, Reierstad S, Ishikawa H, Lin Z, Pavone ME, Zhao H, Marsh EE, Bulun SE: Progesterone and Mifepristone regulate L-type amino acid transporter 2 and 4 F2 heavy chain expression in uterine leiomyoma cells. J Clin Endocrinol Metab. 2009, 94: 4533-4539. 10.1210/jc.2009-1286.CrossRefPubMedPubMedCentral
48.
Kaira K, Ohde Y, Endo M, Nakagawa K, Okumura T, Takahashi T, Murakami H, Tsuya A, Nakamura Y, Naito T, Kondo H, Nakajima T, Yamamoto N: Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors. Oncol Rep. 2011, 26: 931-937.PubMed
49.
Takeuchi H, Kubota T, Kitai R, Nakagawa T, Hashimoto N: CD98 immunoreactivity in multinucleated giant cells of glioblastomas: an immunohistochemical double labeling study. Neuropathology. 2008, 28: 127-131. 10.1111/j.1440-1789.2007.00859.x.CrossRefPubMed
50.
Kaira K, Oriuchi N, Shimizu K, Ishikita T, Higuchi T, Imai H, Yanagitani N, Sunaga N, Hisada T, Ishizuka T, Kanai Y, Endou H, Nakajima T, Endo K, Mori M: Correlation of angiogenesis with 18 F-FMT and 18 F-FDG uptake in non-small cell lung cancer. Cancer Sci. 2009, 100: 753-758. 10.1111/j.1349-7006.2008.01077.x.CrossRefPubMed
51.
Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Kawashima O, Kamide Y, Ishizuka T, Kanai Y, Nakajima T, Mori M: CD98 expression is associated with poor prognosis in resected non-small cell lung cancer with lymph node metastasis. Ann Surg Oncol. 2009, 16: 3437-3481.CrossRef
Metadata
Title
Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma
Authors
Hironori Betsunoh
Takehiko Fukuda
Naohiko Anzai
Daisaku Nishihara
Tomoya Mizuno
Hideo Yuki
Akinori Masuda
Yoshiyuki Yamaguchi
Hideyuki Abe
Masahiro Yashi
Yoshitatsu Fukabori
Ken-Ichiro Yoshida
Takao Kamai
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-509

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