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SLC7A9 as a Potential Biomarker for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC).

Methods

SLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters.

Results

The expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence.

Conclusions

SLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-386.

    Article  CAS  Google Scholar 

  2. Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are C. Global trends in esophageal cancer. J Surg Oncol. 2017;115:564–79.

    Article  Google Scholar 

  3. Dubecz A, Kern M, Solymosi N, Schweigert M, Stein HJ. Predictors of lymph node metastasis in surgically resected T1 esophageal cancer. Ann Thorac Surg. 2015;99:1879–85.

    Article  Google Scholar 

  4. Duan XF, Tang P, Shang XB, Jiang HJ, Yu ZT. The prevalence of lymph node metastasis for pathological T1 esophageal cancer: a retrospective study of 143 cases. Surg Oncol. 2018;27:1–6.

    Article  Google Scholar 

  5. Wu J, Chen QX, Shen DJ, Zhao Q. A prediction model for lymph node metastasis in T1 esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2018;155:1902–8.

    Article  Google Scholar 

  6. Chapman BC, Weyant M, Hilton S, et al. Analysis of the National Cancer Database esophageal squamous cell carcinoma in the United States. Ann Thorac Surg. 2019;S0003–4975:31006–9.

    Google Scholar 

  7. Yamashita K, Watanabe M, Mine S, et al. Patterns and outcomes of recurrent esophageal cancer after curative esophagectomy. World J Surg. 2017;41:2337–44.

    Article  Google Scholar 

  8. Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res. 2015;75:1782–8.

    Article  CAS  Google Scholar 

  9. Bhutia YD, Ganapathy V. Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochim Biophys Acta. 2016;1863:2531–9.

    Article  CAS  Google Scholar 

  10. Ichinoe M, Mikami T, Yoshida T, et al. High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: comparison with non-cancerous lesions. Pathol Int. 2011;61:281–9.

    Article  CAS  Google Scholar 

  11. Yanagisawa N, Ichinoe M, Mikami T, et al. High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas. J Clin Pathol. 2012;65:1019–23.

    Article  Google Scholar 

  12. Sakata T, Ferdous G, Tsuruta T, et al. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathol Int. 2009;59:7–18.

    Article  CAS  Google Scholar 

  13. Robert SM, Buckingham SC, Campbell SL, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015; 7: 289ra86.

  14. Takeuchi S, Wada K, Toyooka T, et al. Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. Neurosurgery. 2013;72:33–41.

    Article  Google Scholar 

  15. National Cancer Institute: The Cancer Genome Atras Program. https://www.cancer.gov/tcga. Accessed on 8 January 2021.

  16. Tsunoo H, Komura S, Ohishi N, et al. Effect of transfection with human interferon-beta gene entrapped in cationic multilamellar liposomes in combination with 5-fluorouracil on the growth of human esophageal cancer cells in vitro. Anticancer Res. 2002;22:1537–43.

    CAS  PubMed  Google Scholar 

  17. TNM Classification of Malignant Tumours, 8th Edition. James DB, Mary KG, Christian W, eds. New York: Wiley, 2016: 57-62.

  18. Kanda M, Shimizu D, Tanaka H, et al. Significance of SYT8 for the detection, prediction, and treatment of peritoneal metastasis from gastric cancer. Ann Surg. 2018;267:495–503.

    Article  Google Scholar 

  19. Umeda S, Kanda M, Miwa T, et al. Expression of sushi domain containing two reflects the malignant potential of gastric cancer. Cancer Med. 2018;7:5194–204.

    Article  CAS  Google Scholar 

  20. Baba H, Kanda M, Sawaki K, et al. PRAME expression as a potential biomarker for hematogenous recurrence of esophageal squamous cell carcinoma. Anticancer Res. 2019;39:5943–51.

    Article  CAS  Google Scholar 

  21. Kanda M, Tanaka H, Shimizu D, et al. SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells. Oncogene. 2018;37:5355–66.

    Article  CAS  Google Scholar 

  22. Kanda M, Shimizu D, Sawaki K, et al. Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer. Mol Cancer. 2020;19:131.

    Article  CAS  Google Scholar 

  23. Baba H, Kanda M, Sato Y, et al. Expression and malignant potential of B4GALNT4 in esophageal squamous cell carcinoma. Ann Surg Oncol. 2020;27:3247–56.

    Article  Google Scholar 

  24. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. http://www.linkedomics.org. Accessed on 19 January 2021.

  25. Vasaikar SV, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2018;46:D956–63.

    Article  CAS  Google Scholar 

  26. Chillarón J, Font-Llitjós M, Fort J, Zorzano A, Goldfarb DS, Nunes V, Palacín M. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol. 2010;6:424–34.

    Article  Google Scholar 

  27. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–47.

    Article  CAS  Google Scholar 

  28. Liu J, Xia X, Huang P. xCT: a critical molecule that links cancer metabolism to redox signaling. Mol Ther. 2020;28:2358–66.

    Article  CAS  Google Scholar 

  29. Sugano K, Maeda K, Ohtani H, Nagahara H, Shibutani M, Hirakawa K. Expression of xCT as a predictor of disease recurrence in patients with colorectal cancer. Anticancer Res. 2015;35:677–82.

    PubMed  Google Scholar 

  30. Minafra L, Bravatà V, Forte GI, Cammarata FP, Gilardi MC, Messa C. Gene expression profiling of epithelial-mesenchymal transition in primary breast cancer cell culture. Anticancer Res. 2014;34:2173–83.

    CAS  PubMed  Google Scholar 

  31. Thomson S, Petti F, Sujka-Kwok I, et al. A systems view of epithelial-mesenchymal transition signaling states. Clin Exp Metastasis. 2011;28:137–55.

    Article  CAS  Google Scholar 

  32. Foley KG, Christian A, Fielding P, Lewis WG, Roberts SA. Accuracy of contemporary oesophageal cancer lymph node staging with radiological-pathological correlation. Clin Radiol. 2017;72(693):e1-693.e7.

    Google Scholar 

  33. Aoyama J, Kawakubo H, Mayanagi S, et al. Discrepancy between the clinical and final pathological findings of lymph node metastasis in superficial esophageal cancer. Ann Surg Oncol. 2019;26:2874–81.

    Article  Google Scholar 

  34. Akutsu Y, Kato K, Igaki H, et al. The prevalence of overall and initial lymph node metastases in clinical T1N0 thoracic esophageal cancer: from the results of JCOG0502, a prospective multicenter study. Ann Surg. 2016;264:1009–15.

    Article  Google Scholar 

  35. Kawamoto T, Nihei K, Sasai K, Karasawa K. Clinical outcomes and prognostic factors of chemoradiotherapy for postoperative lymph node recurrence of esophageal cancer. Jpn J Clin Oncol. 2018;48:259–64.

    Article  Google Scholar 

  36. Sun ZG, Wang Z. Clinical study on lymph node metastatic recurrence in patients with N0 esophageal squamous cell cancer. Dis Esophagus. 2011;24:182–8.

    Article  Google Scholar 

  37. Sun ZG, Wang Z, Liu XY, Liu FY. Mucin 1 and vascular endothelial growth factor C expression correlates with lymph node metastatic recurrence in patients with N0 esophageal cancer after Ivor-Lewis esophagectomy. World J Surg. 2011;35:70–7.

    Article  Google Scholar 

  38. Sun Z, Liu X, Song JH, et al. TNFAIP8 overexpression: a potential predictor of lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma after Ivor Lewis esophagectomy. Tumour Biol. 2016;37:10923–34.

    Article  CAS  Google Scholar 

  39. Kanda M, Murotani K, Tanaka H, et al. Integrated multigene expression panel to prognosticate patients with gastric cancer. Oncotarget. 2018;9:18775–85.

    Article  Google Scholar 

  40. Cobler L, Zhang H, Suri P, Park C, Timmerman LA. xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction. Oncotarget. 2018;9:32280–97.

    Article  Google Scholar 

  41. Okazaki S, Umene K, Yamasaki J, et al. Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma. Cancer Sci. 2019;110:3453–63.

    Article  CAS  Google Scholar 

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Acknowledgment

We would like to thank Editage (www.editage.com) for English language editing.

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Authors and Affiliations

  1. Department of Surgery and Science, Academic Assembly, University of Toyama, Toyama, Japan

    Hayato Baba MD & Tsutomu Fujii MD, PhD, FACS

  2. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Hayato Baba MD, Mitsuro Kanda MD, PhD, FACS, Koichi Sawaki MD, PhD, Shunsuke Nakamura MD, PhD, Sei Ueda MD, Dai Shimizu MD, PhD, Masahiko Koike MD, PhD & Yasuhiro Kodera MD, PhD, FACS

  3. Department of Maxillofacial Surgery, School of Dentistry, Aichi-gakuin University Graduate School of Medicine, Nagoya, Japan

    Sei Ueda MD

  4. Department of Surgery, School of Dentistry, Aichi-gakuin University Graduate School of Medicine, Nagoya, Japan

    Sei Ueda MD

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  1. Hayato Baba MD
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  2. Mitsuro Kanda MD, PhD, FACS
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  3. Koichi Sawaki MD, PhD
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  6. Dai Shimizu MD, PhD
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  9. Tsutomu Fujii MD, PhD, FACS
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Correspondence to Mitsuro Kanda MD, PhD, FACS.

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Baba, H., Kanda, M., Sawaki, K. et al. SLC7A9 as a Potential Biomarker for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 29, 2699–2709 (2022). https://doi.org/10.1245/s10434-021-11001-1

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  • DOI: https://doi.org/10.1245/s10434-021-11001-1

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