Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

Prognostic value of LAT-1 status in solid cancer: A systematic review and meta-analysis

  • Jing-jing Lu ,

    Contributed equally to this work with: Jing-jing Lu, Ping Li, Yong Yang, Le Wang

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Ping Li ,

    Contributed equally to this work with: Jing-jing Lu, Ping Li, Yong Yang, Le Wang

    Roles Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Yong Yang ,

    Contributed equally to this work with: Jing-jing Lu, Ping Li, Yong Yang, Le Wang

    Roles Data curation, Investigation, Validation, Writing – review & editing

    Affiliation Department of Gastrointestinal Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Le Wang ,

    Contributed equally to this work with: Jing-jing Lu, Ping Li, Yong Yang, Le Wang

    Roles Investigation, Writing – review & editing

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Yan Zhang,

    Roles Writing – review & editing

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Jia-yao Zhu,

    Roles Writing – review & editing

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Xiao-ren Zhu,

    Roles Writing – review & editing

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯
  • Min-bin Chen

    Roles Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing

    cmb1981@outlook.com

    Affiliation Department of Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, China

    ⨯

Abstract

Background

The expression of the L-type amino acid transporter 1 (LAT1) plays a significant role in tumor progression. However, it remains unclear whether high LAT1 expression correlates with poor prognosis of solid tumor patients. Here, we conducted a meta-analysis to assess the potential of LAT1 in predicting the prognosis of tumor patients.

Methods and findings

A total of 4,579 cases were analyzed from 35 qualified studies. In patients with solid tumors, elevated expression of LAT1 is associated with poor prognosis (overall survival [OS]: pooled hazard ratio (HR) = 1.848, 95% confidence interval (CI) = 1.620–2.108, P < 0.001; disease free survival [DFS]: pooled HR = 1.923, 95% CI = 1.585–2.333, P < 0.001; progression free survival [PFS]: pooled HR = 1.345, 95% CI = 1.133–1.597, P = 0.001). Furthermore, in subgroup analysis, we found an association between high LAT1 expression and poor OS in non-small cell lung cancer (HR = 1.554, 95% CI = 1.345–1.794, P < 0.001), pancreatic cancer (HR = 2.052, 95% CI = 1.613–2.724, P < 0.001) and biliary tract cancer (HR = 2.253, 95% CI = 1.562–3.227, P < 0.001).

Conclusion

The results of this meta-analysis indicate the reliability and potential of using LAT1 expression as a predictive biomarker in solid cancers prior to treatment. However, further studies with larger sample sizes would be beneficial for fully evaluating the predictive value of LAT1 expression for clinical applications.

Citation: Lu J-j, Li P, Yang Y, Wang L, Zhang Y, Zhu J-y, et al. (2020) Prognostic value of LAT-1 status in solid cancer: A systematic review and meta-analysis. PLoS ONE 15(5): e0233629. https://doi.org/10.1371/journal.pone.0233629

Editor: Jason Chia-Hsun Hsieh, Chang Gung Memorial Hospital at Linkou, TAIWAN

Received: December 5, 2019; Accepted: May 10, 2020; Published: May 29, 2020

Copyright: © 2020 Lu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: Min-Bin Chen, Ping Li, Yan Zhang were supported by National Natural Science Foundation (Grant number: 81773192), Natural Science Foundation of Jiangsu Province (BK20171248), and The Foundation of tumor clinical and basic research team (KYC005). Min-Bin Chen was also supported by Jiangsu Province Youth Medical Talents Project (QNRC2016527) and Jiangsu Province“333 Project” Research Projects (2016-III-0367).

Competing interests: The authors have declared that no competing interests exist.

Introduction

The L-type amino acid transporter 1 (LAT1) is a membrane protein responsible for transporting neutral amino acids, including phenylalanine leucine, valine, etc., as a part of system L for cellular intake of nutrients [1]. LAT1, also known as 4F2 light chain, is connected through a disulfide bond to the membrane-spanning 4F2 heavy chain (CD98) for its functional expression as part of a heterodimeric complex in the plasma membrane [2, 3]. It has been previously reported that LAT1 is associated with the prognosis of tumors.

Amino acid transporters are essential for cell growth and proliferation [1, 4]. The upregulation of LAT1 facilitates the growth of tumor cells [4–9], while selective inhibition of LAT1 inhibits the growth and proliferation of tumor cells [10–16]. It has been reported that LAT1 expression levels positively correlate with cell proliferation (Ki-67 labeling index), p53 expression, VEGF levels as well as poor prognosis of patients in a variety of solid cancers [8, 9, 17–20]. LAT1 transports essential amino acids to provide nutrients for cancer cell growth. Moreover, LAT1 induces rapid dephosphorylation of mTORC1 effectors S6K1 and 4EBP1 through regulation of amino acids such as leucine to activate mTOR signaling pathway, promoting the occurrence of tumors [21, 22].

However, it remains unclear whether LAT1 expression is associated with a worse outcome across solid cancer patients. These conflicting results may be due to the small sample size among individual studies and limitations of current technology. Therefore, we conducted this meta-analysis to evaluate the prognostic value of LAT1 expression as a predictive biomarker with the goal of guiding clinicians and patients in determining the best course of treatment.

Materials and methods

Publication search

Primary literature was collected from electronic databases PubMed, EMBASE and Web of Science for the LAT1 studies until August 10, 2019, with the search terms: (LAT1 OR “L-type amino acid transporter 1” OR SLC7A5 OR 4F2lc OR CD98lc) AND (prognosis OR survival OR predict OR outcome) AND (neoplasms OR neoplasms OR cancer OR tumor OR carcinoma). All publications that met requirements were included as well as eligible studies identified within their references. References cited in the original studies were manually evaluated for inclusion/exclusion criteria. In the event that the study had ongoing investigation of the same patient pool, the largest sample size at the time was included for this meta-analysis.

Inclusion and exclusion criteria

The studies to be involved in this research were determined using the subsequent criteria: (a) evaluated the prognostic status of LAT1 in cancer, (b) provided HRs with 95% confidence intervals (CIs) or provided calculation or charts that displayed clear statistical analysis, (c) divided LAT1 status into ‘positive’ and ‘negative’ or ‘high’ and ‘low’, (d) articles issued in English.

Exclusion criteria: (a) reviews, summary of conference, editorials, letters, case reports, and abstracts, (b) the experiments were conducted in vivo or in vitro, but research design was not patient-based, (c) studies without HRs, 95% CI, or outcomes defined by OS, DFS, PFS, or the K-M survival curves. (d) the follow-up duration was less than 36 months.

Data extraction

Based on the above criteria, authors Lu and Li comprehensively collected relevant data from all qualified publications in a standardized manner. If a consensus could not be reached, the third author (Chen) independently assessed the data from the initial article to review the discrepancy and agreement was achieved through discussion. The study was based on three outcome endpoints: OS, DFS and PFS. We extracted the following information from the selected papers according to the criteria above, including the name of the first author, country of origin, year of publication, number of patients analyzed, antibody, cancer types, LAT1 detection method, cut-off value, endpoints and Newcastle-Ottawa Scale (NOS). The summary of the included studies can be found in Table 1. For articles plotting prognosis only with Kaplan-Meier curve, survival data was extracted with Engauge Digitiser V4.1, and then HRs and 95% CIs were estimated by Tierney's method [23]. NOS was used to assess the quality of all studies [24]. Studies with NOS scores ranging from 6 to 9 were used for quality control of methodology.

thumbnail
Download:
Table 1. Characteristics of studies included in the meta-analysis.

https://doi.org/10.1371/journal.pone.0233629.t001

Statistical analysis

The correlation between LAT1 expression and prognosis was assessed by meta-analysis using studies determined eligible by the inclusion criteria. The outcome endpoints (OS, DFS and PFS) were calculated for pooled HRs and 95% CIs. Subgroup analysis was conducted when each subgroup has or exceeds three studies. Higgins’s I2 statistic and Cochran’s Q test were used to evaluate statistical heterogeneity [25], and lack of heterogeneity among studies was indicated when P value >0.10 and I2<40%. In accordance with heterogeneity status, we used the random effects model or fixed effects model to merge HR.

This analysis uses Funnel plots and the Egger’s test to assess any potential publication bias [26]. In the event of publication bias, the Duval and Tweedie’s trim and fill method was used to evaluate their impact on the overall effect [27]. Sensitivity analysis also identified potential outliers by omitting each study or specific studies. Stata 14.0 (StataCorp, College Station, TX) was used to conduct statistical analyses. The P values were two-tailed and statistical significant when p<0.05, except for those with statistical heterogeneity.

Results

Demographic characteristics

As shown in the search flowchart (Fig 1), we initially retrieved 107 records in document retrieval databases using a predefined search approach. After reviewing the retrieved titles and abstracts, we excluded 32 articles that described irrelevant endpoints of the 75 articles downloaded as full-text, we excluded 40 studies that were unrelated to prognosis (15 articles), had no prognosis data (11 articles), where the prognosis was related to CD98 (3 articles), LAT2 (1 article), LAT1 and ASCT2 co-expression (3 articles), status of LAT1 RNA in cancers(2 articles), or were a description about LAT1 detection technology(5 articles). The remaining 35 articles that reached our meta-analysis criteria were selected to evaluate LAT1 expression and solid cancer prognosis of patients. To assess the relevance between LAT1 and the prognosis of solid cancer, 4,579 eligible patients were selected for this analysis. Sample cases ranged from 21 to 321. Of the 35 prognostic studies, 35 were on OS, 5 on DFS, and 7 on PFS. Most studies were performed in Japan (n = 33), followed by China (n = 1) and Thailand (n = 1), respectively. As for the cancer type, 11 studies evaluated lung cancer, of which 10 were non-small cell lung cancer, pancreatic cancer and biliary tract cancer each have 3 studies, hepatocellular carcinoma, ovarian tumor, gastric cancer, prostatic cancer and colorectal cancer each have 2 studies, breast cancer, multiple myeloma, tongue cancer, laryngeal squamous cell carcinoma, cutaneous melanoma, cutaneous angiosarcoma, malignant pleural mesothelioma and adenoid cystic carcinoma each have 1 study.

thumbnail
Download:
Fig 1. The flow chart of the selection process in our meta-analysis.

https://doi.org/10.1371/journal.pone.0233629.g001

Evidence synthesis

This meta-analysis focused on the relationship between LAT1 status and the prognosis of cancer patients. In this study, the p value of heterogeneity test for OS was 0.004, and the I2 value was 43.0%. The random effect model was used. The results showed that there was a significant correlation between LAT1 high expression solid cancers and poor OS (pooled HR = 1.848, 95% CI = 1.620–2.108, P < 0.001) (Fig 2). Examining five DFS, the p value and I2 value of heterogeneity test report were 0.052 and 57.4%, respectively. The pooled HR and 95% confidence interval (CI) were calculated using the random effect model. The results suggested that LAT1 high expression was associated with poor DFS (pooled HR = 1.923, 95% CI = 1.585–2.333, P < 0.001) (Fig 3). Seven PFS databases were included in the meta-analysis, and the p value and I2 value of heterogeneity test report were 0.182 and 32.2%, respectively. The pooled HR and 95% confidence interval (CI) were calculated by using the fixed effect model. The results suggested that high LAT1 expression was associated with poor PFS (pooled HR = 1.345, 95% CI = 1.133–1.597, P = 0.001) (Fig 4).

thumbnail
Download:
Fig 2. The correlation between LAT1 high expression and overall survival (OS) of solid cancers.

https://doi.org/10.1371/journal.pone.0233629.g002

thumbnail
Download:
Fig 3. The correlation between LAT1 high expression and disease free survival (DFS).

https://doi.org/10.1371/journal.pone.0233629.g003

thumbnail
Download:
Fig 4. The correlation between LAT1 high expression and progression free survival (PFS).

https://doi.org/10.1371/journal.pone.0233629.g004

To explore the source of heterogeneity, subgroup analysis was performed when more than 3 articles participated in each type. The results of subgroup analysis are shown in Table 2. In the cancer subgroups, there was a significant relationship between high LAT1 expression and poor OS in solid tumors observed in patients with lung cancer (HR = 1.573, 95% CI = 1.309–1.890, P < 0.001), non-small cell lung cancer (HR = 1.554, 95% CI = 1.345–1.794, P < 0.001), pancreatic cancer (HR = 2.052, 95% CI = 1.613–2.724, P < 0.001) and biliary tract cancer (HR = 2.253, 95% CI = 1.562–3.227, P < 0.001). When analyzed by the statistical method of LAT1 prognosis, the relationship was still found in the multivariate analysis (OS: HR = 2.052, 95% CI = 1.770–2.378, P <0.001; PFS: HR = 1.547, 95% CI = 1.089–2.199, P = 0.015; DFS: HR = 1.884, 95% CI = 1.196–2.968, P = 0.006) and univariate analysis (OS: HR = 1.439, 95% CI = 1.153–1.797, P = 0.001). Furthermore, subgroup analysis from cut off found that >10% of tumor cells (OS: HR = 1.786, 95% CI = 1.503–2.122, P <0.001), scores of 3, 4 (OS: HR = 1.955, 95% CI = 1.493–2.558, P <0.001; PFS: HR = 1.349, 95% CI = 1.027–1.773, P = 0.032), scores of 6–9 (OS: HR = 1.792, 95% CI = 1.141–2.812, P = 0.011), other cut off value (OS: HR = 2.277, 95% CI = 1.557–3.331, P <0.001), all of the results showed a poorer prognosis. Moreover, in the ethnicity subgroup, most of studies were from Asian, the results shown high LAT1 expression were all associated with poorer prognosis (OS: HR = 1.848, 95% CI = 1.620–2.108, P <0.001; PFS: HR = 1.345, 95% CI = 1.133–1.597, P = 0.001; DFS: HR = 1.923, 95% CI = 1.585–2.333, P <0.001).

thumbnail
Download:
Table 2. Hazard ratio for the association between LAT1 expression and solid tumor prognosis.

https://doi.org/10.1371/journal.pone.0233629.t002

Publication bias and sensitivity analysis

Begg’s funnel plot and Egger’s test were used to detect publication bias of the above literature. There was no evidence of significant asymmetry on the funnel plot, and Egger's test found no publication bias (p<0.05) (Fig 5). Our sensitivity analysis confirmed the impact of these results. None of the individual studies had guided this meta-analysis and eliminating any single study had no significant effect on the final results (Fig 6).

thumbnail
Download:
Fig 5. Begg’s funnel plots for the studies involved in the meta-analysis.

A. overall survival B: progression free survival. C. disease free survival. Abbreviations: loghr, logarithm of HRs; s.e., standard error.

https://doi.org/10.1371/journal.pone.0233629.g005

thumbnail
Download:
Fig 6. Sensitivity analysis of the meta-analysis.

A. overall survival B: progression free survival. C disease free survival.

https://doi.org/10.1371/journal.pone.0233629.g006

Discussion

There is increasing evidence showing that LAT1 plays a significant role in promoting tumor cell growth and proliferation [2, 3, 28, 29]. By interfering with the expression of LAT1, Hayashi K et al. demonstrated that the proto-oncogene c-Myc binds to the LAT1 promoter sequence to accelerate its expression [30]. Furthermore, the heterodimeric complex formed by the binding of LAT1 and CD98 plays a significant role in integrin signaling of cancer cells, sequentially activating the phosphatidylinositide 3-kinase/AKT (PI3K/AKT), p130CAS and focal adhesion kinase (FAK) signaling pathway [31, 32]. The relationship of LAT1 expression levels and prognosis of solid cancer patients is difficult to determine from individual clinical reports, as they involve small sample sizes.

To our knowledge, this is the first complete study demonstrating the prognosis significance of LAT1 status in solid cancers. In this meta-analysis, we examined 16 cancer types, including lung cancer [16, 20, 33–41], pancreatic cancer [42–44], biliary tract cancer [45–47], hepatocellular carcinoma [48, 49], ovarian tumor [50, 51], breast cancer [8], gastric carcinomas [52, 53], prostatic cancer [7, 54], colorectal cancer [55, 56], adenoid cystic carcinoma [17], multiple myeloma [57], tongue cancer [58], laryngeal squamous cell carcinoma [59], cutaneous melanoma [60], cutaneous angiosarcoma [61] and malignant pleural mesothelioma [62]. We assessed the survival data of 4,579 cancer patients with regard to LAT1 status, and 35 different studies were systematically included. In summary, the results clearly indicate that LAT1 overexpression is an indicator for poor prognosis in solid cancer, with poor OS (pooled HR = 1.848, 95% CI = 1.620–2.108, P < 0.001), poor DFS (pooled HR = 1.923, 95% CI = 1.585–2.333, P < 0.001) and poor PFS (pooled HR = 1.345, 95% CI = 1.133–1.597, P = 0.001).

In our paper, we also used subgroup analysis to illustrate the relationship between high expression of LAT1 and prognosis. The subgroup analysis was conducted by at least 3 articles participated in each type including cancer type, HR estimation, cut off value and ethnicity. The significant relationship was still found in these subgroup.

The results of our current analysis may be affected by a number of limitations. First, the meta-analysis may be influenced by the exclusion of articles that are not published in English as well as articles that are proceedings or books. Despite our rigorous search and attempts to obtain unpublished information, some data loss was inevitable. Second, most of the studies involved were retrospective, with positive results more likely to be published than negative. Third, although the expression of LAT1 was detected by immunohistochemistry in all studies, the antibody concentration and cut-off value were different for each study, which could lead to some deviation in the combined analysis. Lastly, LAT1 is typically co-expressed with CD98, which may play a synergistic role in the development and progression of tumors.

Despite these limitations, this meta-analysis has several advantages. This is the first comprehensive statistical study of LAT1 that evaluates the prognostic significance of LAT1 status in solid cancers before treatment. We collected 4,579 patients from the limited subsets, which represented a large number of cases and significantly improved the statistical value in this analysis. Additionally, no publication biases were detected, suggesting that the results of the analysis are impartial.

The results suggest that before tumor treatment, the expression of LAT1 can be used to predict tumor patient outcome. Nevertheless, to verify our finding more accurately, more comprehensive studies will be required to evaluate the predictive value of high LAT1 expression for future clinical practice.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

https://doi.org/10.1371/journal.pone.0233629.s001

(DOC)

Acknowledgments

We would like to acknowledge the participants for the preliminary survey, data collection and analysis. We would also like to thank those for checking and reviewing this paper.

References

  1. 1. Christensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiological Reviews. 1990;70(1):43–77. pmid:2404290
  2. 2. Kanai Y, Segawa H, Miyamoto KI, Uchino H, Takeda E, Endou H, Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). Journal of Biological Chemistry. 1998;273(37):23629–32. pmid:9726963
  3. 3. Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. BBA—Biomembranes. 2001;1514(2):291–302. pmid:11557028
  4. 4. Mcgivan JD, Pastor-Anglada M. Regulatory and molecular aspects of mammalian amino acid transport. Biochemical Journal. 1994;299 (Pt 2)(299 (Pt 2)):321–34. pmid:8172590
  5. 5. Kobayashi H, Ishii Y, Takayama T. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. Journal of surgical oncology. 2005;90(4):233–8. pmid:15906366
  6. 6. Sakata T, Ferdous G, T, Satoh T, Baba S, Muto T, Ueno A, et al. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathology international. 2010;59(1):7–18. pmid:19121087
  7. 7. Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, et al. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathology international. 2009;59(1):7–18. pmid:19121087
  8. 8. Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer science. 2012;103(2):382–9. pmid:22077314
  9. 9. Kyoichi K, Noboru O, Toshiaki T, Kazuo N, Yasuhisa O, Takehiro O, et al. LAT1 expression is closely associated with hypoxic markers and mTOR in resected non-small cell lung cancer. American journal of translational research. 2011;3(5):468–78. pmid:22046488
  10. 10. Huttunen KM, Gynther M, Huttunen J, Puris E, Spicer JA, Denny WA. A Selective and Slowly Reversible Inhibitor of L-Type Amino Acid Transporter 1 (LAT1) Potentiates Anti-Proliferative Drug Efficacy in Cancer Cells. Journal of medicinal chemistry. 2016;59(12):acs.jmedchem.6b00190. pmid:27253989
  11. 11. Koji O, Noriko H, Hiroshi E, Kunio S, Kenji T, Michio Y, et al. L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer science. 2010;101(1):173–9. pmid:19900191
  12. 12. Shennan DB, Jean T. Inhibition of system L (LAT1/CD98hc) reduces the growth of cultured human breast cancer cells. Oncology reports. 2008;20(4):885–9. pmid:18813831
  13. 13. Park NS, Kim SG, Kim HK, Moon SY, Kim CS, Cho SH, et al. Characterization of amino acid transport system L in HTB-41 human salivary gland epidermoid carcinoma cells. Anticancer research. 2008;28(5A):2649–55. pmid:19035290
  14. 14. Kim C, Park KJ, Park JR, Kanai Y, Endou H, Park J, et al. The RNA Interference of Amino Acid Transporter LAT1 Inhibits the Growth of KB Human Oral Cancer Cells. Anticancer research. 2006;26(4B):2943. pmid:16886618
  15. 15. Chun Sung K, Seon-Ho C, Sung CH, Sook-Young L, Hitoshi E, Yoshikatsu K, et al. BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells. Biological & pharmaceutical bulletin. 2008;31(6):1096–100. pmid:18520037
  16. 16. Imai H, Kaira K, Oriuchi N, Shimizu K, Tominaga H, Yanagitani N, et al. Inhibition of L-type amino acid transporter 1 has antitumor activity in non-small cell lung cancer. Anticancer research. 2010;30(12):4819–28. pmid:21187458
  17. 17. Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, Tominaga H, et al. Clinicopathological significance of L-type amino acid transporter 1 (LAT1) expression in patients with adenoid cystic carcinoma. Pathology oncology research: POR. 2013;19(4):649–56. pmid:23516127
  18. 18. Kyoichi K, Noboru O, Toshiaki T, Kazuo N, Yasuhisa O, Takehiro O, et al. L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma. Anticancer research. 2011;31(12):4075–82. pmid:22199264
  19. 19. Kyoichi K, Toshiaki T, Masato A, Hiroaki A, Kazuo N, Yasuhisa O, et al. CD98 expression is associated with the grade of malignancy in thymic epithelial tumors. Oncology reports. 2010;24(4):861. pmid:20811665
  20. 20. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. British journal of cancer. 2008;98(4):742–8. pmid:18253116
  21. 21. Nissim H, Nahum S. Upstream and downstream of mTOR. Genes & Development. 2004;18(16):1926. pmid:15314020
  22. 22. Bond P. Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance. Journal of the International Society of Sports Nutrition. 2016;13(1):8. pmid:26937223
  23. 23. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8(1):16.
  24. 24. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25(9):603–5. pmid:20652370
  25. 25. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal. 2003;327(7414):557–60. pmid:12958120
  26. 26. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109). pmid:9492690
  27. 27. Duval S, Tweedie R. Trim and Fill: A Simple Funnel-Plot–Based Method of Testing and Adjusting for Publication Bias in Meta-Analysis. Biometrics. 2000;56(2):455–63(9). pmid:10877304
  28. 28. Sang J, Lim YP, Panzica M, Finch P, Thompson NL. TA1, a highly conserved oncofetal complementary DNA from rat hepatoma, encodes an integral membrane protein associated with liver development, carcinogenesis, and cell activation. Cancer research. 1995;55(5):1152. pmid:7532544
  29. 29. Wolf DA, Wang S, Panzica MA, Bassily NH, Thompson NL. Expression of a highly conserved oncofetal gene, TA1/E16, in human colon carcinoma and other primary cancers: homology to Schistosoma mansoni amino acid permease and Caenorhabditis elegans gene products. Cancer research. 1996;56(21):5012. pmid:8895758
  30. 30. Hayashi K, Jutabha P, Endou H, Anzai N. c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells[J]. Oncology Reports, 2012, 28(3):862–866. pmid:22736142
  31. 31. Rintoul RC, Buttery RC, Mackinnon AC, Weng SW, Mosher D, Haslett C, et al. Cross-Linking CD98 Promotes Integrin-like Signaling and Anchorage-independent Growth. Molecular biology of the cell. 2002;13(8):2841. pmid:12181350
  32. 32. Feral C C, Nishiya N, Fenczik C A, Stuhlmann H, Slepak M, Ginsberg M H. CD98hc (SLC3A2) mediates integrin signaling[J]. Proceedings of the National Academy of Sciences, 2005, 102(2):355–360. http://dx.doi.org/10.1073/pnas.0404852102
  33. 33. Imai H, Kaira K, Oriuchi N, Yanagitani N, Sunaga N, Ishizuka T, et al. L-type amino acid transporter 1 expression is a prognostic marker in patients with surgically resected stage I non-small cell lung cancer. Histopathology. 2009;54(7):804–13. pmid:19635099
  34. 34. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in stage I pulmonary adenocarcinoma. Lung cancer. 2009;66(1):120–6. pmid:19171406
  35. 35. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. CD98 expression is associated with poor prognosis in resected non-small-cell lung cancer with lymph node metastases. Annals of surgical oncology. 2009;16(12):3473–81. pmid:19777189
  36. 36. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in surgically resectable stage III non-small cell lung cancer. Experimental and therapeutic medicine. 2010;1(5):799–808. pmid:22993604
  37. 37. Kaira K, Oriuchi N, Shimizu K, Imai H, Tominaga H, Yanagitani N, et al. Comparison of L-type amino acid transporter 1 expression and L-[3-18F]-alpha-methyl tyrosine uptake in outcome of non-small cell lung cancer. Nuclear medicine and biology. 2010;37(8):911–6. pmid:21055621
  38. 38. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in early stage squamous cell carcinoma of the lung. Cancer science. 2009;100(2):248–54. pmid:19068093
  39. 39. Takeuchi K, Ogata S, Nakanishi K, Ozeki Y, Hiroi S, Tominaga S, et al. LAT1 expression in non-small-cell lung carcinomas: analyses by semiquantitative reverse transcription-PCR (237 cases) and immunohistochemistry (295 cases). Lung cancer. 2010;68(1):58–65. pmid:19559497
  40. 40. Yazawa T, Shimizu K, Kaira K, Nagashima T, Ohtaki Y, Atsumi J, et al. Clinical significance of coexpression of L-type amino acid transporter 1 (LAT1) and ASC amino acid transporter 2 (ASCT2) in lung adenocarcinoma. American journal of translational research. 2015;7(6):1126–39. pmid:26279756
  41. 41. Kaira K, Kawashima O, Endoh H, Imaizumi K, Goto Y, Kamiyoshihara M, et al. Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma. Human pathology. 2019;84:142–9. pmid:30300664
  42. 42. Kaira K, Sunose Y, Arakawa K, Ogawa T, Sunaga N, Shimizu K, et al. Prognostic significance of L-type amino-acid transporter 1 expression in surgically resected pancreatic cancer. British journal of cancer. 2012;107(4):632–8. pmid:22805328
  43. 43. Yanagisawa N, Ichinoe M, Mikami T, Nakada N, Hana K, Koizumi W, et al. High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas. Journal of clinical pathology. 2012;65(11):1019–23. pmid:22813728
  44. 44. Altan B, Kaira K, Watanabe A, Kubo N, Bao P, Dolgormaa G, et al. Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma. Cancer chemotherapy and pharmacology. 2018;81(1):141–53. pmid:29149426
  45. 45. Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, et al. 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. 2013;13:482. pmid:24131658
  46. 46. Yanagisawa N, Hana K, Nakada N, Ichinoe M, Koizumi W, Endou H, et al. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas. Cancer medicine. 2014;3(5):1246–55. pmid:24890221
  47. 47. Yothaisong S, Namwat N, Yongvanit P, Khuntikeo N, Puapairoj A, Jutabha P, et al. Increase in L-type amino acid transporter 1 expression during cholangiocarcinogenesis caused by liver fluke infection and its prognostic significance. Parasitology international. 2017;66(4):471–8. pmid:26657242
  48. 48. Namikawa M, Kakizaki S, Kaira K, Tojima H, Yamazaki Y, Horiguchi N, et al. Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma. Hepatology research: the official journal of the Japan Society of Hepatology. 2015;45(9):1014–22. pmid:25297701
  49. 49. Li J, Qiang J, Chen SF, Wang X, Fu J, Chen Y. The impact of L-type amino acid transporter 1 (LAT1) in human hepatocellular carcinoma. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2013;34(5):2977–81. pmid:23696029
  50. 50. Kaira K, Nakamura K, Hirakawa T, Imai H, Tominaga H, Oriuchi N, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in patients with ovarian tumors. American journal of translational research. 2015;7(6):1161–71. pmid:26279759
  51. 51. Sato K, Miyamoto M, Takano M, Furuya K, Tsuda H. Significant relationship between the LAT1 expression pattern and chemoresistance in ovarian clear cell carcinoma. Virchows Archiv: an international journal of pathology. 2019;474(6):701–10. pmid:30637450
  52. 52. Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, et al. High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: comparison with non-cancerous lesions. Pathology international. 2011;61(5):281–9. pmid:21501294
  53. 53. Ichinoe M, Yanagisawa N, Mikami T, Hana K, Nakada N, Endou H, et al. L-Type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: Its correlation with size of metastatic lesion and Ki-67 labeling. Pathology, research and practice. 2015;211(7):533–8. pmid:25908107
  54. 54. Yanagisawa N, Satoh T, Hana K, Ichinoe M, Nakada N, Endou H, et al. L-amino acid transporter 1 may be a prognostic marker for local progression of prostatic cancer under expectant management. Cancer biomarkers: section A of Disease markers. 2015;15(4):365–74. pmid:25835180
  55. 55. Hayase S, Kumamoto K, Saito K, Kofunato Y, Sato Y, Okayama H, et al. L-type amino acid transporter 1 expression is upregulated and associated with cellular proliferation in colorectal cancer. Oncology letters. 2017;14(6):7410–6. pmid:29344181
  56. 56. Ogawa H, Kaira K, Motegi Y, Yokobori T, Takada T, Katoh R, et al. Role of Amino Acid Transporter Expression as a Prognostic Marker in Patients With Surgically Resected Colorectal Cancer. Anticancer research. 2019;39(5):2535–43. pmid:31092450
  57. 57. Isoda A, Kaira K, Iwashina M, Oriuchi N, Tominaga H, Nagamori S, et al. Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. Cancer science. 2014;105(11):1496–502. pmid:25220100
  58. 58. Toyoda M, Kaira K, Ohshima Y, Ishioka NS, Shino M, Sakakura K, et al. Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. British journal of cancer. 2014;110(10):2506–13. pmid:24762957
  59. 59. Nikkuni O, Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, et al. Expression of Amino Acid Transporters (LAT1 and ASCT2) in Patients with Stage III/IV Laryngeal Squamous Cell Carcinoma. Pathology oncology research: POR. 2015;21(4):1175–81. pmid:26024742
  60. 60. Shimizu A, Kaira K, Kato M, Yasuda M, Takahashi A, Tominaga H, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in cutaneous melanoma. Melanoma research. 2015;25(5):399–405. pmid:26237765
  61. 61. Shimizu A, Kaira K, Okubo Y, Utsumi D, Yasuda M, Tominaga H, et al. Prognostic impact of LAT1 and CD98 expression in cutaneous angiosarcoma. Neoplasma. 2017;64(2):283–8. pmid:28052681
  62. 62. Kaira K, Oriuchi N, Takahashi T, Nakagawa K, Ohde Y, Okumura T, et al. L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma. Anticancer research. 2011;31(12):4075–82. pmid:22199264