Virchows Archiv

, Volume 448, Issue 2, pp 142–150 | Cite as

LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung

  • Kuniaki Nakanishi
  • Hirotaka Matsuo
  • Yoshikatsu Kanai
  • Hitoshi Endou
  • Sadayuki Hiroi
  • Susumu Tominaga
  • Makio Mukai
  • Eiji Ikeda
  • Yuichi Ozeki
  • Shinsuke Aida
  • Toshiaki Kawai
Original Article


No previous study has investigated neutral large amino acid transporter type 1 (LAT1) in normal lung cells, or in atypical adenomatous hyperplasia(s) (AAH) and nonmucinous bronchioloalveolar carcinoma(s) (NMBAC) of the lung. The authors examined: (1) the levels of LAT1 mRNA/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 41 normal lung tissues and 34 NMBAC using semiquantitative reverse transcription–polymerase chain reaction; (2) LAT1 mRNA and protein expressions in 35 normal lung tissues, 34 AAH (11 lesions were interpreted as low-grade AAH and 23 as high-grade AAH), and 43 NMBAC using in situ hybridization and immunohistochemistry; and (2) the association of the incidences of LAT1 mRNA and protein expressions with cell proliferation in these lesions. The level of LAT1 mRNA/GAPDH mRNA (1) tended to be higher in NMBAC (12.0±8.1) than in normal lung tissues (1.0±0.2), and (2) covered a much wider range (from 0 to 276) in NMBAC than in normal lung tissues (from 0 to 5.8), with six NMBAC having values higher than 7.0, while 5.8 was the highest value detected in normal lung tissues. In peripheral normal lung tissues, LAT1 mRNA and protein were detected in bronchial surface epithelial cells and alveolar macrophages (but not in nonciliated bronchiolar epithelial cells, or in alveolar type I or type II cells). In bronchial surface epithelial cells, LAT1 protein appeared to be of a nodular type, which was considered to be a nonfunctional protein pattern. The incidences of positive expressions for LAT1 mRNA and protein were 54.5 and 27.3% in low-grade AAH, 65.2 and 52.2% in high-grade AAH, and 65.1 and 79.1% in NMBAC, respectively. In the case of LAT1 protein expression, significant differences could be shown between total (low-grade plus high-grade) AAH and NMBAC, and between low-grade AAH and NMBAC. Thus, in terms of the incidence of LAT1 protein expression, high-grade AAH appeared intermediate between low-grade AAH and NMBAC. The Ki-67 labeling index (a cell proliferation score) was significantly higher in those AAH and NMBAC that were LTA1-protein-positive than in their LAT1-protein-negative counterparts. In conclusion, LAT1 expression may increase with the upregulation of metabolic activity and cell proliferation in high-grade AAH and NMBAC.


Atypical adenomatous hyperplasia Pulmonary bronchioloalveolar carcinoma Amino acid transporter LAT1 


  1. 1.
    Campbell WA, Thompson NL (2001) Overexpression of LAT1/CD98 light chain is sufficient to increase system L-amino acid transport activity in mouse hepatocytes but not fibroblasts. J Biol Chem 276:16877–16884CrossRefPubMedGoogle Scholar
  2. 2.
    Christensen HN (1990) Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 70:43–77PubMedGoogle Scholar
  3. 3.
    Chillaron J, Roca R, Valencia A, Zorzano A, Palacin M (2001) Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am J Physiol Renal Physiol 281:F995–F1018PubMedGoogle Scholar
  4. 4.
    Chomczyski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidium thiocyanate–phenol–chloroform extraction. Anal Biochem 162:156–159CrossRefPubMedGoogle Scholar
  5. 5.
    Kanai Y, Endou H (2003) Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity. J Toxicol Sci 28:1–17CrossRefPubMedGoogle Scholar
  6. 6.
    Kanai Y, Endou H (2001) Heterodimeric amino acid transporters: molecular biology and pathological and pharmacological relevance. Curr Drug Metab 2:339–354CrossRefPubMedGoogle Scholar
  7. 7.
    Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem 273:23629–23632CrossRefPubMedGoogle Scholar
  8. 8.
    Kim DK, Kanai Y, Choi HW, Tangtrongsup S, Chairoungdua A, Babu E, Tachampa K, Anzai N, Iribe Y, Endou H (2002) Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. Biochim Biophys Acta 1565:112–121PubMedCrossRefGoogle Scholar
  9. 9.
    Kitamura H, Kameda Y, Ito T, Hayashi H (1999) Atypical adenomatous hyperplasia of the lung. Am J Clin Pathol 111:610–622PubMedGoogle Scholar
  10. 10.
    Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F (1998) Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395:288–291CrossRefPubMedGoogle Scholar
  11. 11.
    Matsuo H, Tsukada S, Nakata T, Chairoungdua A, Kim DK, Cha SH, Inatomi J, Yorifuji H, Fukuda J, Endou H, Kanai Y (2000) Expression of a system L neutral amino acid transporter at the blood–brain barrier. NeuroReport 11:3507–3511PubMedCrossRefGoogle Scholar
  12. 12.
    Mori M, Rao SK, Popper HH, Cagle PT, Fraire AE (2001) Atypical adenomatous hyperplasia of the lung: a possible forerunner in the development of adenocarcinoma of the lung. Mod Pathol 14:72–84CrossRefPubMedGoogle Scholar
  13. 13.
    Nakanishi K (1990) Alveolar epithelial hyperplasia and adenocarcinoma of the lung. Arch Pathol Lab Med 114:363–368PubMedGoogle Scholar
  14. 14.
    Nakanishi K, Kawai T, Kumaki F, Hiroi S, Mukai M, Ikeda E (2002) Expression of human telomerase RNA component (hTERC) and telomerase reverse transcriptase (hTERT) mRNA in atypical adenomatous hyperplasia of the lung. Hum Pathol 33:697–702CrossRefPubMedGoogle Scholar
  15. 15.
    Nakanishi K, Kawai T, Kumaki F, Hiroi S, Mukai M, Ikeda E (2003) Survivin expression in atypical adenomatous hyperplasia of the lung. Am J Clin Pathol 120:712–719CrossRefPubMedGoogle Scholar
  16. 16.
    Nakanishi K, Kawai T, Kumaki F, Hiroi S, Mukai M, Ikeda E, Koering CE, Gilson E (2003) Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Clin Cancer Res 9:1105–1111PubMedGoogle Scholar
  17. 17.
    Nakanishi K, Hiroi S, Kawai T, Suzuki M, Torikata C (1998) Argyrophilic nucleolar-organizer region counts and DNA status in bronchioloalveolar epithelial hyperplasia and adenocarcinoma of the lung. Hum Pathol 29:235–239CrossRefPubMedGoogle Scholar
  18. 18.
    Nakanishi K, Uenoyama M, Tomita N, Morishita R, Kaneda Y, Ogihara T, Matsumoto K, Nakamura T, Maruta A, Matsuyama S, Kawai T, Aurues T, Hayashi T, Ikeda T (2002) Gene transfer of human hepatocyte growth factor into rat skin wounds mediated by liposomes coated with the sendai virus (hemagglutinating virus of Japan). Am J Pathol 161:1761–1772PubMedGoogle Scholar
  19. 19.
    Ohkame H, Masuda H, Ishii Y, Kanai Y (2001) Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in liver tumor lesions of rat models. J Surg Oncol 78:265–271CrossRefPubMedGoogle Scholar
  20. 20.
    Parmacek MS, Karpinski BA, Gottesdiener KM, Thompson CB, Leiden JM (1989) Structure, expression and regulation of the murine 4F2 heavy chain. Nucleic Acids Res 17:1915–1931PubMedCrossRefGoogle Scholar
  21. 21.
    Sang J, Lim YP, Panzica M, Finch P, Thompson NL (1995) TA1, a highly conserved oncofetal complementary DNA from rat hepatoma, encodes an integral membrane protein associated with liver development, carcinogenesis, and cell activation. Cancer Res 55:1152–1159PubMedGoogle Scholar
  22. 22.
    Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y (1999) Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 274:19745–19751CrossRefPubMedGoogle Scholar
  23. 23.
    Shennan DB, Thomson J, Barber MC, Travers MT (2003) Functional and molecular characteristics of system L in human breast cancer cells. Biochim Biophys Acta 1611:81–90PubMedCrossRefGoogle Scholar
  24. 24.
    Shimosato Y, Kodama T, Kameya T (1982) Morphogenesis of peripheral type adenocarcinoma of the lungs. In: Shimosato Y, Melamed MR, Nettesheim P (eds) Morphogenesis of lung cancer, vol 1. CRC Press, Boca Raton, FL, pp 65–89Google Scholar
  25. 25.
    Travis, WD, Colby TV, Corrin B, Shimosato T, Brambilla E (1999) World Health Organization international histologic classification of tumours. Histological typing of lung and pleural tumours, 3rd edn. Springer, Berlin Heidelberg New York, p 36Google Scholar
  26. 26.
    Wolf DA, Wang S, Panzica MA, Bassily NH, Thompson NL (1996) Expression of a highly conserved oncofetal gene, TA1/E16, in human colon carcinoma and other primary cancers: homology to Schistosoma mansoni amino acid permease and Caenorhabditis elegans gene products. Cancer Res 56:5012–5022PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Kuniaki Nakanishi
    • 1
  • Hirotaka Matsuo
    • 2
  • Yoshikatsu Kanai
    • 3
  • Hitoshi Endou
    • 3
  • Sadayuki Hiroi
    • 1
  • Susumu Tominaga
    • 1
  • Makio Mukai
    • 4
  • Eiji Ikeda
    • 5
  • Yuichi Ozeki
    • 6
  • Shinsuke Aida
    • 7
  • Toshiaki Kawai
    • 1
  1. 1.Department of PathologyNational Defense Medical CollegeTokorozawaJapan
  2. 2.Department of PhysiologyNational Defense Medical CollegeTokorozawaJapan
  3. 3.Department of Pharmacology and Toxicology, School of MedicineKyorin UniversityTokyoJapan
  4. 4.Division of Diagnostic Pathology, School of MedicineKeio UniversityTokyoJapan
  5. 5.Department of Pathology, School of MedicineKeio UniversityTokyoJapan
  6. 6.Department of SurgeryNational Defense Medical CollegeTokorozawaJapan
  7. 7.Department of Laboratory MedicineNational Defense Medical CollegeTokorozawaJapan

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