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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 1/2018

01-01-2018 | Original Article

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

Authors: 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 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.
Appendix
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Metadata
Title
Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma
Authors
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
Publication date
01-01-2018
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-017-3477-4

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