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01-06-2019 | Ovarian Cancer | Original Article

Significant relationship between the LAT1 expression pattern and chemoresistance in ovarian clear cell carcinoma

Authors: Kimiya Sato, Morikazu Miyamoto, Masashi Takano, Kenichi Furuya, Hitoshi Tsuda

Published in: Virchows Archiv | Issue 6/2019

Abstract

L-type amino acid transporter 1 (LAT1) is a Na⁺-independent neutral amino acid transporter that plays a key role in cancer cell growth and survival. To determine the significance of LAT1 in prognosis and resistance to chemotherapy in ovarian carcinoma, we investigated the LAT1 expression in 245 ovarian carcinoma patients by immunohistochemistry using tissue microarray. High expression of LAT1 was detected in 85 (34.7%) patients. The ratio of high expression of LAT1 was significantly high in clear cell carcinoma and low in serous carcinoma compared to other histological types (P < 0.0001). High expression of LAT1 in ovarian carcinoma was associated with poorer prognosis as per log-rank test (P = 0.008). Cox’s univariate and multivariate analysis revealed that high expression of LAT1 is an independent marker indicating poor prognosis (hazard ratio = 2.810, P < 0.0001) as well as the FIGO stage III/IV (vs. I/II) and suboptimal surgery. High LAT1 expression was also found to be associated with resistance to chemotherapy (P = 0.016) notably in clear cell carcinoma. In conclusion, we demonstrate that LAT1 is not only associated with poor prognosis of ovarian carcinoma, but also associated with chemoresistance in ovarian carcinoma.

Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351:2519–2529CrossRef

Zhang XY, Zhang PY (2016) Recent perspectives of epithelial ovarian carcinoma. Oncol Lett 12:3055–3058CrossRefPubMedPubMedCentral

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 273:23629–23632CrossRefPubMed

Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima JI, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto KI, Takeda E, Goya T, Endou H (2001) Human L-type amino acid transporter 1 (LAT 1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 1514:291–302CrossRefPubMed

Nawashiro H, Otani N, Shinomiya N, Fukui S, Ooigawa H, Shima K, Matsuo H, Kanai Y, Endou H (2006) L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer 119:484–492CrossRefPubMed

Nakanishi K, Ogata S, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, Aida S, Kasamatsu H, Kawai T (2007) Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract. Virchows Arch 451:681–690CrossRefPubMed

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 (2008) Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer 98:742–748CrossRefPubMedPubMedCentral

Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, Ueno A, Kanai Y, Endou H, Okayasu I (2009) L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathol Int 59:7–18CrossRefPubMed

Liang Z, Cho HT, Williams L, Zhu A, Liang K, Huang K, Wu H, Jiang C, Hong S, Crowe R, Goodman MM, Shim H (2011) Potential biomarker of L-type amino acid transporter 1 in breast cancer progression. Nucl Med Mol Imaging 45:93–102CrossRefPubMed

10.

Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, Anzai N, Suzuki Y, Endou H, Okayasu I (2011) High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: comparison with non-cancerous lesions. Pathol Int 61:281–289CrossRefPubMed

11.

Uno K, Kuwabara H, Terado Y, Kojima K, Kawakami T, Kamma H, Sakurai H, Sakamoto A, Kurata A (2011) Divergent expression of L-type amino acid transporter 1 during uterine cervical carcinogenesis. Hum Pathol 42:1660–1666CrossRefPubMed

12.

Kaira K, Sunose Y, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Segawa A, Furuya M, Mori M, Oyama T, Takeyoshi I (2012) Prognostic significance of L-type amino-acid transporter 1 expression in surgically resected pancreatic cancer. Br J Cancer 107:632–638CrossRefPubMedPubMedCentral

13.

Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Yamaguchi A, Segawa A, Ide M, Mori M, Oyama T, Takeyoshi I (2013) Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer. BMC Cancer 13:482CrossRefPubMedPubMedCentral

14.

Toyoda M, Kaira K, Ohshima Y, Ishioka NS, Shino M, Sakakura K, Takayasu Y, Takahashi K, Tominaga H, Oriuchi N, Nagamori S, Kanai Y, Oyama T, Chikamatsu K (2014) Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. Br J Cancer 110:2506–2513CrossRefPubMedPubMedCentral

15.

Isoda A, Kaira K, Iwashina M, Oriuchi N, Tominaga H, Nagamori S, Kanai Y, Oyama T, Asao T, Matsumoto M, Sawamura M (2014) Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. Cancer Sci 105:1496–1502CrossRefPubMedPubMedCentral

16.

Hayase S, Kumamoto K, Saito K, Kofunato Y, Sato Y, Okayama H, Miyamoto K, Ohki S, Takenoshita S (2017) L-type amino acid transporter 1 expression is upregulated and associated with cellular proliferation in colorectal cancer. Oncol Lett 14:7410–7416PubMedPubMedCentral

17.

Kaji M, Kabir-Salmani M, Anzai N, Jin CJ, Akimoto Y, Horita A, Sakamoto A, Kanai Y, Sakurai H, Iwashita M (2010) Properties of L-type amino acid transporter 1 in epidermal ovarian cancer. Int J Gynecol Cancer 20:329–336CrossRefPubMed

18.

Kaira K, Nakamura K, Hirakawa T, Imai H, Tominaga H, Oriuchi N, Nagamori S, Kanai Y, Tsukamoto N, Oyama T, Asao T, Minegishi T (2015) Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in patients with ovarian tumors. Am J Transl Res 7:1161–1171PubMedPubMedCentral

19.

Betsunoh H, Fukuda T, Anzai N, Nishihara D, Mizuno T, Yuki H, Masuda A, Yamaguchi Y, Abe H, Yashi M, Fukabori Y, Yoshida KI, Kamai T (2013) 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. BMC Cancer 13:509CrossRefPubMedPubMedCentral

20.

Fuchs BC, Bode BP (2005) Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol 15:254–266CrossRefPubMed

21.

Yamauchi K, Sakurai H, Kimura T, Wiriyasermkul P, Nagamori S, Kanai Y, Kohno N (2009) System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line. Cancer Lett 276:95–101CrossRefPubMed

22.

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 (2010) Inhibition of L-type amino acid transporter 1 has antitumor activity in non-small cell lung cancer. Anticancer Res 30:4819–4828PubMed

23.

Wang Q, Holst J (2015) L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am J Cancer Res 5:1281–1294PubMedPubMedCentral

24.

Fan X, Ross DD, Arakawa H, Ganapathy V, Tamai I, Nakanishi T (2010) Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors. Biochem Pharmacol 80:811–818CrossRefPubMed

25.

Huang Y, Anderle P, Bussey KJ, Barbacioru C, Shankavaram U, Dai Z, Reinhold WC, Papp A, Weinstein JN, Sadée W (2004) Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 64:4294–4301CrossRefPubMed

26.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRef

27.

Itamochi H, Kigawa J, Terakawa N (2008) Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci 99:653–658CrossRefPubMed

28.

Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, Suzuki M, Sato I, Taguchi K (2000) Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 88:2584–2589CrossRefPubMed

29.

Kaira K, Takahashi T, Murakami H, Shukuya T, Kenmotsu H, Naito T, Oriuchi N, Kanai Y, Endo M, Kondo H, Nakajima T, Yamamoto N (2011) Relationship between LAT1 expression and response to platinum-based chemotherapy in non-small cell lung cancer patients with postoperative recurrence. Anticancer Res 31:3775–3782PubMed

30.

Altan B, Kaira K, Watanabe A, Kubo N, Bao P, Dolgormaa G, Bilguun EO, Araki K, Kanai Y, Yokobori T, Oyama T, Nishiyama M, Kuwano H, Shirabe K (2018) Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma. Cancer Chemother Pharmacol 81:141–153CrossRefPubMed

Title: Significant relationship between the LAT1 expression pattern and chemoresistance in ovarian clear cell carcinoma
Authors: Kimiya Sato
Morikazu Miyamoto
Masashi Takano
Kenichi Furuya
Hitoshi Tsuda
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Keywords: Ovarian Cancer
Ovarian Cancer
Cytostatic Therapy
Published in: Virchows Archiv / Issue 6/2019
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-019-02520-0

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Significant relationship between the LAT1 expression pattern and chemoresistance in ovarian clear cell carcinoma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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