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17.11.2017 | Original Article

Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma

verfasst von: Bolag Altan, Kyoichi Kaira, Akira Watanabe, Norio Kubo, Pinjie Bao, Gantumur Dolgormaa, Erkhem-Ochir Bilguun, Kenichiro Araki, Yoshikatsu Kanai, Takehiko Yokobori, Tetsunari Oyama, Masahiko Nishiyama, Hiroyuki Kuwano, Ken Shirabe

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2018

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Abstract

Purpose

L-type amino acid transporter 1 (LAT1) is linked to tumor cell proliferation, angiogenesis, and survival in various human cancers. Although the expression of LAT1 was identified as a significant prognostic predictor after surgery in patients with pancreatic ductal adenocarcinoma (PDAC), little is known about the clinical significance of LAT1 as a chemotherapeutic resistance factor in PDAC.

Methods

A total of 110 patients with surgically resected PDAC were retrospectively reviewed as the training set. Immunohistochemical staining of resected tumor specimens was assessed using anti-LAT1 antibodies. In vitro analysis of chemotherapy resistance and LAT1 function using PDAC cell lines was also performed.

Results

The rate of high expression of LAT1 was 64.1% (71/110). The high expression of LAT1 protein was significantly associated with tumor differentiation, tumor depth (T factor), lymph node metastasis, venous invasion, recurrence, and clinical response. By multivariate analysis, LAT1 was validated as an independent prognostic factor for predicting worse survival after surgery. We analyzed the TCGA data set and obtained similar results that the survival rates of SLC7A5 high expression group were poorer than that of low expression group. LAT1 could successfully predict the outcome of patients who received adjuvant chemotherapy after surgery (n = 88) and systemic chemotherapy after recurrence (n = 56). All patients with high LAT1 expression were non-responders, whereas approximately 30% of the patients with low LAT1 expression responders (p = 0.0002). By analyzing the TCGA online database, it was found that LAT1 closely correlated with hypoxia-induced genes, such as PTGES, PYGL, and KPNA2.

Conclusion

LAT1 as an independent prognostic marker is a potential molecular targeting gene to reduce chemoresistance and tumor growth in patients with PDAC, supported by our in vitro study.

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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96CrossRefPubMed

Cameron JL, Riall TS, Coleman J, Belcher KA (2006) One thousand consecutive pancreaticoduodenectomies. Ann Surg 244(1):10–15CrossRefPubMedPubMedCentral

Geer RJ, Brennan MF (1993) Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 165(1):68–72CrossRefPubMed

Balaban EP, Mangu PB, Khorana AA, Shah MA, Mukherjee S, Crane CH, Javle MM, Eads JR, Allen P, Ko AH, Engebretson A, Herman JM, Strickler JH, Benson AB 3rd, Urba S, Yee NS (2016) Locally advanced, unresectable pancreatic cancer: American society of clinical oncology clinical practice guideline. J Clin Oncol 34(22):2654–2668CrossRefPubMed

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(37):23629–23632CrossRefPubMed

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 (2001) Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 1514(2):291–302CrossRefPubMed

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 non-small cell lung cancer. Br J Cancer 98(4):742–748CrossRefPubMedPubMedCentral

Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T (2012) Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci 103(2):382–389CrossRefPubMed

Kaira K, Oriuchi N, Takahashi T, Nakagawa K, Ohde Y, Okumura T, Murakami H, Shukuya T, Kenmotsu H, Naito T, Kanai Y, Endo M, Kondo H, Nakajima T, Yamamoto N (2011) LAT1 expression is closely associated with hypoxic markers and mTOR in resected non-small cell lung cancer. Am J Transl Res 3(5):468–478PubMedPubMedCentral

10.

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(3):484–492CrossRefPubMed

11.

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(1):7–18CrossRefPubMed

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(4):632–638CrossRefPubMedPubMedCentral

13.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92(3):205–216CrossRefPubMed

14.

Yanagisawa N, Ichinoe M, Mikami T, Nakada N, Hana K, Koizumi W, Endou H, Okayasu I (2012) High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinoma. J Clin Pathol 65(11):109–123CrossRef

15.

Altan B, Yokobori T, Mochiki E, Ohno T, Ogata K, Ogawa A, Yanai M, Kobayashi T, Luvsandagva B, Asao T, Kuwano H (2013) Nuclear karyopherin-α2 expression in primary lesions and metastatic lymph nodes was associated with poor prognosis and progression in gastric cancer. Carcinogenesis 34(10):2314–2321CrossRefPubMed

16.

Ohshima Y, Kaira K, Yamaguchi A, Oriuchi N, Tominaga H, Nagamori S, Kanai Y, Yokobori T, Miyazaki T, Asao T, Tsushima Y, Kuwano H, Ishioka NS (2016) Efficacy of systemic L amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma. Cancer Sci 107(10):1499–1505CrossRefPubMedPubMedCentral

17.

Bakkevold KE, Arnesjø B, Dahl O, Kambestad B (1993) Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of vater–results of a controlled, prospective, randomised multicentre study. Eur J Cancer 29A(5):698–703CrossRefPubMed

18.

Tsao JI, Rossi RL, Lowell JA (1994) Pylorus-preserving pancreatoduodenectomy. Is it an adequate cancer operation. Arch Surg 129(4):405–12CrossRefPubMed

19.

Yeo CJ, Cameron JL, Maher MM, Sauter PK, Zahurak ML, Talamini MA, Lillemoe KD, Pitt HA (1995) A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. Ann Surg 222(4):580–588CrossRefPubMedPubMedCentral

20.

Trede M, Schwall G, Saeger HD (1990) Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 211(4):447–458CrossRefPubMedPubMedCentral

21.

Kang MJ, Jang JY, Lee KB, Chang YR, Kwon W, Kim SW (2014) Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance. Ann Surg 260(2):356–363CrossRefPubMed

22.

Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW, European Study Group for Pancreatic Cancer (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350(12):1200–1210CrossRefPubMed

23.

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(3):267–277CrossRefPubMed

24.

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(11):3775–3782PubMed

25.

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(12):4819–4828PubMed

26.

Lee JJ¹, Natsuizaka M, Ohashi S, Wong GS, Takaoka M, Michaylira CZ, Budo D, Tobias JW, Kanai M, Shirakawa Y, Naomoto Y, Klein-Szanto AJ, Haase VH, Nakagawa H (2010) Hypxia activates the cyclooxygenase-2-prostaglandin E synthase axis. Carcinogenesis 31:427–434CrossRefPubMed

27.

Blanco FF, Jimbo M, Wulkuhle J, Gallagher I, Deng J, Enyenihi L, Meisner-Kober N, Londin E, Rigoutsos I, Sawicki JA, Risbud MV, Witkiewicz AK, McCue PA, Jiang W, Rui H, Yeo CJ, Petricoin E, Winter JM, Brody JR (2016) The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells. Oncogene 35(19):2529–2521CrossRefPubMed

28.

He YW, Zhao ML, Yang XY, Zeng J, Deng QH, He JX (2015) Prognostic value of ERCC1, RRM1, and TS proteins in patients with resected non-small cell lung cancer. Cancer Chemother Pharmacol 75(4):861–867CrossRefPubMed

29.

Jordheim LP, Sève P, Trédan O, Dumontet C (2011) The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol 12(7):693–702CrossRefPubMed

30.

Takeuchi K, Ogata S, Nakanishi K, Ozeki Y, Hiroi S, Tominaga S, Aida S, Matsuo H, Sakata T, Kawai T (2010) LAT1 expression in non-small-cell lung carcinomas: analyses by semiquantitative reverse transcription-PCR (237 cases) and immunohistochemistry (295 cases). Lung Cancer 68(1):58–65CrossRefPubMed

Titel: Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma
verfasst von: Bolag Altan
Kyoichi Kaira
Akira Watanabe
Norio Kubo
Pinjie Bao
Gantumur Dolgormaa
Erkhem-Ochir Bilguun
Kenichiro Araki
Yoshikatsu Kanai
Takehiko Yokobori
Tetsunari Oyama
Masahiko Nishiyama
Hiroyuki Kuwano
Ken Shirabe
Publikationsdatum: 17.11.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2018
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3477-4

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Springer Medizin

Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma

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Purpose

Methods

Results

Conclusion

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Springer Medizin

Abstract

Purpose

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Conclusion

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