Research progress on functions and mechanisms of solute carrier family 3 member A2 in hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YU Guotao , CHEN Gang , YIN Yanfeng , YAN Chuntao , MA Li , ZHU Jiashun ,  HU Zongqiang

Department of Hepatobiliary Pancreatic Surgery, Kunming First People’s Hospital, Kunming 650011, P. R. China;

Corresponding author：

HU Zongqiang, Email: 2509484088@qq.com

Keywords：

solute carrier family 3 member A2; hepatocellular carcinoma; action mechanism; targeted therapy

DOI：

10.7507/1007-9424.202307011

Video：

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Objective To summarize the possible roles and relevant mechanisms of solute carrier family 3 member A2 (SLC3A2) gene in hepatocellular carcinoma (HCC), and explore its clinical application prospects and value in the diagnosis, treatment, and prognosis of patients with HCC. Method The literature on reseaches of the SLC3A2 gene and its association with HCC both domestically and internationally in recent years was reviewed and summarized. Results Notably, the SLC3A2 exhibited obviously elevated expression in the HCC tissue as compared with the normal liver tissue. It mainly affected the disease progression of HCC by regulating the intracellular and extracellular amino acids transport, inhibiting the ferroptosis of cells, activating the mechanistic target of rapamycin complex signaling pathways and integrin signaling pathway, and played an important role in the diagnosis, treatment, and prognosis of patients with HCC. Conclusion From the results of literature review collected, SLC3A2 might be closely associated with the migration, invasion, proliferation, and apoptosis of HCC cell, and it is expected to serve as an indicator for evaluating survival and prognosis of patients with HCC, and become one of the effective treatment targets for HCC in future.

Citation： YU Guotao, CHEN Gang, YIN Yanfeng, YAN Chuntao, MA Li, ZHU Jiashun, HU Zongqiang. Research progress on functions and mechanisms of solute carrier family 3 member A2 in hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(10): 1265-1272. doi: 10.7507/1007-9424.202307011 Copy

1.	王晓昊, 李虎, 张露, 等. CSCO《原发性肝癌诊疗指南(2022年版)》内科治疗部分研读. 中国普外基础与临床杂志, 2023, 30(4): 403-407.
2.	Pizzagalli MD, Bensimon A, Superti-Furga G. A guide to plasma membrane solute carrier proteins. FEBS J, 2021, 288(9): 2784-2835.
3.	Zhu B, Cheng D, Hou L, et al. SLC3A2 is upregulated in human osteosarcoma and promotes tumor growth through the PI3K/Akt signaling pathway. Oncol Rep, 2017, 37(5): 2575-2582.
4.	Zhao M, Li M, Zheng Y, et al. Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma. J Cancer, 2022, 13(5): 1611-1622.
5.	Ichinoe M, Mikami T, Yanagisawa N, et al. Prognostic values of L-type amino acid transporter 1 and CD98hc expression in breast cancer. J Clin Pathol, 2021, 74(9): 589-595.
6.	Lee D, Kim HS, Kim HU, et al. Expression profile of CD98 heavy chain and L-type amino acid transporter 1 and its prognostic significance in colorectal cancer. Pathol Res Pract, 2022, 229: 153730.
7.	Hayashi N, Yamasaki A, Ueda S, et al. Oncogenic transformation of NIH/3T3 cells by the overexpression of L-type amino acid transporter 1, a promising anti-cancer target. Oncotarget, 2021, 12(13): 1256-1270.
8.	Cano-Crespo S, Chillarón J, Junza A, et al. CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression. Sci Rep, 2019, 9(1): 14065.
9.	Console L, Scalise M, Salerno S, et al. N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98). Sci Rep, 2022, 12(1): 14570.
10.	Kahlhofer J, Teis D. The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: physiological and pathophysiological implications. Basic Clin Pharmacol Toxicol, 2022 Dec 2. doi: 10.1111/bcpt.13821.
11.	Häfliger P, Charles RP. The L-type amino acid transporter LAT1—an emerging target in cancer. Int J Mol Sci, 2019, 20(10): 2428.
12.	Yan R, Li Y, Müller J, et al. Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Cell Discov, 2021, 7(1): 16.
13.	Nachef M, Ali AK, Almutairi SM, et al. Targeting SLC1A5 and SLC3A2/SLC7A5 as a potential strategy to strengthen anti-tumor immunity in the tumor microenvironment. Front Immunol, 2021, 12: 624324.
14.	Digomann D, Linge A, Dubrovska A. SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed. Autophagy, 2019, 15(10): 1850-1851.
15.	Seo E, Jee B, Chung JH, et al. Repression of SLC22A3 by the AR-V7/YAP1/TAZ axis in enzalutamide-resistant castration-resistant prostate cancer. FEBS J, 2023, 290(6): 1645-1662.
16.	Hou J, Yan D, Liu Y, et al. The roles of integrin α5β1 in human cancer. Onco Targets Ther, 2020, 13: 13329-13344.
17.	Poettler M, Unseld M, Braemswig K, et al. CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior. Mol Cancer, 2013, 12: 169.
18.	Wang H, Chen W, Jin M, et al. CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression. Mol Cancer, 2018, 17(1): 165.
19.	Singh N, Ecker GF. Insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, LAT1. Int J Mol Sci, 2018, 19(5): 1278.
20.	Wu F, Xiong G, Chen Z, et al. SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway. Hereditas, 2022, 159(1): 6.
21.	Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell, 2021, 12(8): 599-620.
22.	Wang L, Liu Y, Du T, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ, 2020, 27(2): 662-675.
23.	He J, Liu D, Liu M, et al. Characterizing the role of SLC3A2 in the molecular landscape and immune microenvironment across human tumors. Front Mol Biosci, 2022, 9: 961410.
24.	Rochette L, Dogon G, Rigal E, et al. Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis. Int J Mol Sci, 2022, 24(1): 449.
25.	Yin J, Meng X, Peng L, et al. Ferroptosis and cancer immunotherapy. Curr Mol Med, 2023, 23(5): 401-409.
26.	王雅乐. 鼠肝癌治疗性单克隆抗体的靶标鉴定及SLC3A2作为肝癌潜在诊疗靶点的初步评估. 厦门: 厦门大学, 2019.
27.	Pellizzari G, Martinez O, Crescioli S, et al. Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2. J Immunother Cancer, 2021, 9(6): e002140.
28.	Kong R, Wang N, Han W, et al. IFNγ-mediated repression of system Xc^- drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells. J Leukoc Biol, 2021, 110(2): 301-314.
29.	Liang J, Sun Z. Overexpression of membranal SLC3A2 regulates the proliferation of oral squamous cancer cells and affects the prognosis of oral cancer patients. J Oral Pathol Med, 2021, 50(4): 371-377.
30.	Alfarsi LH, El-Ansari R, Craze ML, et al. Co-expression effect of SLC7A5/SLC3A2 to predict response to endocrine therapy in oestrogen-receptor-positive breast cancer. Int J Mol Sci, 2020, 21(4): 1407.
31.	Zhang L, Liu W, Liu F, et al. IMCA induces ferroptosis mediated by SLC7A11 through the AMPK/mTOR pathway in colorectal cancer. Oxid Med Cell Longev, 2020, 2020: 1675613.
32.	Grzes KM, Sanin DE, Kabat AM, et al. Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters. Immunity, 2021, 54(11): 2514-2530.
33.	Ikeda K, Kinoshita M, Kayama H, et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep, 2017, 21(7): 1824-1838.
34.	Bothwell PJ, Kron CD, Wittke EF, et al. Targeted suppression and knockout of ASCT2 or LAT1 in epithelial and mesenchymal human liver cancer cells fail to inhibit growth. Int J Mol Sci, 2018, 19(7): 2093.
35.	Zou J, Du K, Li S, et al. Glutamine metabolism regulators associated with cancer development and the tumor microenvironment: a pan-cancer multi-omics analysis. Genes (Basel), 2021, 12(9): 1305.
36.	Zhang L, Huang Y, Ling J, et al. Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma. Future Oncol, 2018, 14(10): 927-936.
37.	Bo T, Kobayashi S, Inanami O, et al. LAT1 inhibitor JPH203 sensitizes cancer cells to radiation by enhancing radiation-induced cellular senescence. Transl Oncol, 2021, 14(11): 101212.
38.	Deng J, Chernikova SB, Wang Y, et al. A novel brain-permeant chemotherapeutic agent for the treatment of brain metastasis in triple-negative breast cancer. Mol Cancer Ther, 2021, 20(11): 2110-2116.
39.	Kanai Y. Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther, 2022, 230: 107964.
40.	Kim DH, Kim WD, Kim SK, et al. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis, 2020, 11(5): 406.
41.	Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res, 2021, 399(1): 112453.
42.	Su Y, Zhao B, Zhou L, et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett, 2020, 483: 127-136.
43.	Li W, Dong X, He C, et al. LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. J Exp Clin Cancer Res, 2019, 38(1): 183.
44.	Huang W, Chen K, Lu Y, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia, 2021, 23(12): 1227-1239.
45.	Gao R, Kalathur RKR, Coto-Llerena M, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med, 2021, 13(12): e14351.
46.	Li ZJ, Dai HQ, Huang XW, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin, 2021, 42(2): 301-310.
47.	Potla R, Hirano-Kobayashi M, Wu H, et al. Molecular mapping of transmembrane mechanotransduction through the β1 integrin-CD98hc-TRPV4 axis. J Cell Sci, 2020, 133(20): jcs248823.
48.	Wu B, Zhou Y, Wang Y, et al. Dominant suppression of β1 integrin by ectopic CD98-ICD inhibits hepatocellular carcinoma progression. Int J Mol Sci, 2016, 17(11): 1882.

1. 王晓昊, 李虎, 张露, 等. CSCO《原发性肝癌诊疗指南(2022年版)》内科治疗部分研读. 中国普外基础与临床杂志, 2023, 30(4): 403-407.
2. Pizzagalli MD, Bensimon A, Superti-Furga G. A guide to plasma membrane solute carrier proteins. FEBS J, 2021, 288(9): 2784-2835.
3. Zhu B, Cheng D, Hou L, et al. SLC3A2 is upregulated in human osteosarcoma and promotes tumor growth through the PI3K/Akt signaling pathway. Oncol Rep, 2017, 37(5): 2575-2582.
4. Zhao M, Li M, Zheng Y, et al. Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma. J Cancer, 2022, 13(5): 1611-1622.
5. Ichinoe M, Mikami T, Yanagisawa N, et al. Prognostic values of L-type amino acid transporter 1 and CD98hc expression in breast cancer. J Clin Pathol, 2021, 74(9): 589-595.
6. Lee D, Kim HS, Kim HU, et al. Expression profile of CD98 heavy chain and L-type amino acid transporter 1 and its prognostic significance in colorectal cancer. Pathol Res Pract, 2022, 229: 153730.
7. Hayashi N, Yamasaki A, Ueda S, et al. Oncogenic transformation of NIH/3T3 cells by the overexpression of L-type amino acid transporter 1, a promising anti-cancer target. Oncotarget, 2021, 12(13): 1256-1270.
8. Cano-Crespo S, Chillarón J, Junza A, et al. CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression. Sci Rep, 2019, 9(1): 14065.
9. Console L, Scalise M, Salerno S, et al. N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98). Sci Rep, 2022, 12(1): 14570.
10. Kahlhofer J, Teis D. The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: physiological and pathophysiological implications. Basic Clin Pharmacol Toxicol, 2022 Dec 2. doi: 10.1111/bcpt.13821.
11. Häfliger P, Charles RP. The L-type amino acid transporter LAT1—an emerging target in cancer. Int J Mol Sci, 2019, 20(10): 2428.
12. Yan R, Li Y, Müller J, et al. Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Cell Discov, 2021, 7(1): 16.
13. Nachef M, Ali AK, Almutairi SM, et al. Targeting SLC1A5 and SLC3A2/SLC7A5 as a potential strategy to strengthen anti-tumor immunity in the tumor microenvironment. Front Immunol, 2021, 12: 624324.
14. Digomann D, Linge A, Dubrovska A. SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed. Autophagy, 2019, 15(10): 1850-1851.
15. Seo E, Jee B, Chung JH, et al. Repression of SLC22A3 by the AR-V7/YAP1/TAZ axis in enzalutamide-resistant castration-resistant prostate cancer. FEBS J, 2023, 290(6): 1645-1662.
16. Hou J, Yan D, Liu Y, et al. The roles of integrin α5β1 in human cancer. Onco Targets Ther, 2020, 13: 13329-13344.
17. Poettler M, Unseld M, Braemswig K, et al. CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior. Mol Cancer, 2013, 12: 169.
18. Wang H, Chen W, Jin M, et al. CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression. Mol Cancer, 2018, 17(1): 165.
19. Singh N, Ecker GF. Insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, LAT1. Int J Mol Sci, 2018, 19(5): 1278.
20. Wu F, Xiong G, Chen Z, et al. SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway. Hereditas, 2022, 159(1): 6.
21. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell, 2021, 12(8): 599-620.
22. Wang L, Liu Y, Du T, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ, 2020, 27(2): 662-675.
23. He J, Liu D, Liu M, et al. Characterizing the role of SLC3A2 in the molecular landscape and immune microenvironment across human tumors. Front Mol Biosci, 2022, 9: 961410.
24. Rochette L, Dogon G, Rigal E, et al. Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis. Int J Mol Sci, 2022, 24(1): 449.
25. Yin J, Meng X, Peng L, et al. Ferroptosis and cancer immunotherapy. Curr Mol Med, 2023, 23(5): 401-409.
26. 王雅乐. 鼠肝癌治疗性单克隆抗体的靶标鉴定及SLC3A2作为肝癌潜在诊疗靶点的初步评估. 厦门: 厦门大学, 2019.
27. Pellizzari G, Martinez O, Crescioli S, et al. Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2. J Immunother Cancer, 2021, 9(6): e002140.
28. Kong R, Wang N, Han W, et al. IFNγ-mediated repression of system Xc^- drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells. J Leukoc Biol, 2021, 110(2): 301-314.
29. Liang J, Sun Z. Overexpression of membranal SLC3A2 regulates the proliferation of oral squamous cancer cells and affects the prognosis of oral cancer patients. J Oral Pathol Med, 2021, 50(4): 371-377.
30. Alfarsi LH, El-Ansari R, Craze ML, et al. Co-expression effect of SLC7A5/SLC3A2 to predict response to endocrine therapy in oestrogen-receptor-positive breast cancer. Int J Mol Sci, 2020, 21(4): 1407.
31. Zhang L, Liu W, Liu F, et al. IMCA induces ferroptosis mediated by SLC7A11 through the AMPK/mTOR pathway in colorectal cancer. Oxid Med Cell Longev, 2020, 2020: 1675613.
32. Grzes KM, Sanin DE, Kabat AM, et al. Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters. Immunity, 2021, 54(11): 2514-2530.
33. Ikeda K, Kinoshita M, Kayama H, et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep, 2017, 21(7): 1824-1838.
34. Bothwell PJ, Kron CD, Wittke EF, et al. Targeted suppression and knockout of ASCT2 or LAT1 in epithelial and mesenchymal human liver cancer cells fail to inhibit growth. Int J Mol Sci, 2018, 19(7): 2093.
35. Zou J, Du K, Li S, et al. Glutamine metabolism regulators associated with cancer development and the tumor microenvironment: a pan-cancer multi-omics analysis. Genes (Basel), 2021, 12(9): 1305.
36. Zhang L, Huang Y, Ling J, et al. Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma. Future Oncol, 2018, 14(10): 927-936.
37. Bo T, Kobayashi S, Inanami O, et al. LAT1 inhibitor JPH203 sensitizes cancer cells to radiation by enhancing radiation-induced cellular senescence. Transl Oncol, 2021, 14(11): 101212.
38. Deng J, Chernikova SB, Wang Y, et al. A novel brain-permeant chemotherapeutic agent for the treatment of brain metastasis in triple-negative breast cancer. Mol Cancer Ther, 2021, 20(11): 2110-2116.
39. Kanai Y. Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther, 2022, 230: 107964.
40. Kim DH, Kim WD, Kim SK, et al. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis, 2020, 11(5): 406.
41. Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res, 2021, 399(1): 112453.
42. Su Y, Zhao B, Zhou L, et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett, 2020, 483: 127-136.
43. Li W, Dong X, He C, et al. LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. J Exp Clin Cancer Res, 2019, 38(1): 183.
44. Huang W, Chen K, Lu Y, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia, 2021, 23(12): 1227-1239.
45. Gao R, Kalathur RKR, Coto-Llerena M, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med, 2021, 13(12): e14351.
46. Li ZJ, Dai HQ, Huang XW, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin, 2021, 42(2): 301-310.
47. Potla R, Hirano-Kobayashi M, Wu H, et al. Molecular mapping of transmembrane mechanotransduction through the β1 integrin-CD98hc-TRPV4 axis. J Cell Sci, 2020, 133(20): jcs248823.
48. Wu B, Zhou Y, Wang Y, et al. Dominant suppression of β1 integrin by ectopic CD98-ICD inhibits hepatocellular carcinoma progression. Int J Mol Sci, 2016, 17(11): 1882.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on functions and mechanisms of solute carrier family 3 member A2 in hepatocellular carcinoma

Abstract Full text Figures/Tables Video References Cited by

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