Bolag Altan1, Kyoichi Kaira2, Akira Watanabe3, Norio Kubo3, Pinjie Bao4, Gantumur Dolgormaa3, Erkhem-Ochir Bilguun5, Kenichiro Araki3, Yoshikatsu Kanai6, Takehiko Yokobori7, Tetsunari Oyama8, Masahiko Nishiyama5,7, Hiroyuki Kuwano4, Ken Shirabe3. 1. Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan. 2. Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan. kkaira1970@yahoo.co.jp. 3. Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan. 4. Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan. 5. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan. 6. Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan. 7. Division of Integrated Oncology Research, Research Program for Omics-Based Medical Science, Gunma University Initiative for Advanced Research, Maebashi, Gunma, Japan. 8. Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan.
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.
PURPOSE:L-type amino acid transporter 1 (LAT1) is linked to tumor cell proliferation, angiogenesis, and survival in various humancancers. 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.
Authors: Matthew B Nodwell; Hua Yang; Helen Merkens; Noeen Malik; Milena Čolović; Rainer E Martin; François Bénard; Paul Schaffer; Robert Britton Journal: J Nucl Med Date: 2019-01-25 Impact factor: 10.057
Authors: Zijian Wu; Jin Xu; Chen Liang; Qingcai Meng; Jie Hua; Wei Wang; Bo Zhang; Jiang Liu; Xianjun Yu; Si Shi Journal: Clin Transl Med Date: 2021-03