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

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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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Acknowledgements

We thank Ms. Yuka Matsui for her technical assistance during the manuscript preparation, and Ms. Yukie Saito, Ms. Tomoko Yano and Ms. Ayaka Ishida, and Ms. Ayaka Ishikubo for their excellent assistance.

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Authors and Affiliations

  1. Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Bolag Altan & Kyoichi Kaira

  2. Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan

    Akira Watanabe, Norio Kubo, Gantumur Dolgormaa, Kenichiro Araki & Ken Shirabe

  3. Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan

    Pinjie Bao & Hiroyuki Kuwano

  4. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan

    Erkhem-Ochir Bilguun & Masahiko Nishiyama

  5. Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan

    Yoshikatsu Kanai

  6. Division of Integrated Oncology Research, Research Program for Omics-Based Medical Science, Gunma University Initiative for Advanced Research, Maebashi, Gunma, Japan

    Takehiko Yokobori & Masahiko Nishiyama

  7. Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan

    Tetsunari Oyama

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  1. Bolag Altan
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  2. Kyoichi Kaira
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Correspondence to Kyoichi Kaira.

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Altan, B., Kaira, K., Watanabe, A. et al. Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma. Cancer Chemother Pharmacol 81, 141–153 (2018). https://doi.org/10.1007/s00280-017-3477-4

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  • DOI: https://doi.org/10.1007/s00280-017-3477-4

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