溶质载体SLC7A5及SLC7A11基因在恶性肿瘤中的研究进展

摘要/Abstract

摘要：

溶质载体（SLC）作为氨基酸的转运渠道，存在于各类细胞上，其作用为转运各种氨基酸，为细胞的生长发育提供所需的营养物质。近年来发现的SLC7家族成员中的SLC7A5及SLC7A11基因在各类恶性肿瘤中存在高表达，通过为肿瘤提供所需的氨基酸，促进肿瘤的发生发展。研究显示，上述基因与多种恶性肿瘤均存在相关性，其表达与肿瘤细胞的生长、转移、治疗及预后密切相关。并且，多项研究结果提示SLC7A5及SLC7A11基因可作为恶性肿瘤的治疗靶点应用于靶向治疗。明确上述基因在恶性肿瘤中的表达及临床意义、分子生物学机制以及分子靶向治疗研究的进展，有助于为恶性肿瘤的诊断和治疗提供新的途径。

关键词:溶质载体蛋白质类,肿瘤,基因表达,分子生物学,分子靶向治疗

Abstract:

As a transport channel for amino acids， solute carrier （SLC） exists in all kinds of cells， and its function is to transport various amino acids and provide necessary nutrients for the growth and development of cells. In recent years， SLC7A5 and SLC7A11 genes of SLC7 family members have been found to be highly expressed in various malignant tumors， which can promote the occurrence and development of tumors by providing necessary amino acids for tumors. Studies have shown that these genes are associated with a variety of malignant tumors， and their expression is closely related to the growth， metastasis， treatment and prognosis of tumor cells. Moreover， the results of multiple studies suggest that SLC7A5 and SLC7A11 genes can be used as therapeutic targets for malignant tumors. Clarifying the expression and clinical significance of the above genes in malignant tumors， the molecular biological mechanism and the progress of molecular targeted therapy are helpful to provide a new way for the diagnosis and treatment of malignant tumors.

Key words:Solute carrier proteins,Neoplasms,Gene expression,Molecular biology,Molecular targeted therapy

刘博翰, 黄俊星. 溶质载体SLC7A5及SLC7A11基因在恶性肿瘤中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(5): 280-284.

Liu Bohan, Huang Junxing. Research progress of solute carriers related genes in malignant tumors[J]. Journal of International Oncology, 2023, 50(5): 280-284.

参考文献35

[1]	Fairweather SJ, Shah N, Bröer S. Heteromeric solute carriers: function, structure, pathology and pharmacology[J]. Adv Exp Med Biol, 2021, 21: 13-127. DOI: 10.1007/5584_2020_584. doi:10.1007/5584_2020_584pmid:33052588
[2]	汤志全, 石丽, 熊晶. 溶质载体SLC家族在非酒精性脂肪性肝病中的研究进展[J]. 遗传, 2022, 44(10): 881-898. DOI: 10.16288/j.yczz.22-238. doi:10.16288/j.yczz.22-238
[3]	Lu X. The role of large neutral amino acid transporter (LAT1) in cancer[J]. Curr Cancer Drug Targets, 2019, 19(11): 863-876. DOI: 10.2174/1568009619666190802135714. doi:10.2174/1568009619666190802135714pmid:31376820
[4]	Pizzagalli MD, Bensimon A, Superti-Furga G. A guide to plasma membrane solute carrier proteins[J]. FEBS J, 2021, 288(9): 2784-2835. DOI: 10.1111/febs.15531. doi:10.1111/febs.15531
[5]	Scalise M, Scanga R, Console L, et al. Chemical approaches for studying the biology and pharmacology of membrane transporters: the histidine/large amino acid transporter SLC7A5 as a benchmark[J]. Molecules, 2021, 26(21): 6562. DOI: 10.3390/molecules26216562. doi:10.3390/molecules26216562
[6]	Kanai Y. Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics[J]. Pharmacol Ther, 2022, 230: 107964. DOI: 10.1016/j.pharmthera.2021.107964. doi:10.1016/j.pharmthera.2021.107964
[7]	Liu Y, Ma G, Liu J, et al. SLC7A5 is a lung adenocarcinoma-specific prognostic biomarker and participates in forming immunosuppressive tumor microenvironment[J]. Heliyon, 2022, 8(10): e10866. DOI: 10.1016/j.heliyon.2022.e10866. doi:10.1016/j.heliyon.2022.e10866
[8]	Huang P, Xia L, Guo Q, et al. Genome-wide association studies identify miRNA-194 as a prognostic biomarker for gastrointestinal cancer by targeting ATP6V1F, PPP1R14B, BTF3L4 and SLC7A5[J]. Front Oncol, 2022, 12: 1025594. DOI: 10.3389/fonc.2022.1025594. doi:10.3389/fonc.2022.1025594
[9]	Najumudeen AK, Ceteci F, Fey SK, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer[J]. Nat Genet, 2021, 53(1): 16-26. DOI: 10.1038/s41588-020-00753-3. doi:10.1038/s41588-020-00753-3pmid:33414552
[10]	Kurozumi S, Kaira K, Matsumoto H, et al. Association of L-type amino acid transporter 1 (LAT1) with the immune system and prognosis in invasive breast cancer[J]. Sci Rep, 2022, 12(1): 2742. DOI: 10.1038/s41598-022-06615-8. doi:10.1038/s41598-022-06615-8pmid:35177712
[11]	Bodoor K, Almomani R, Alqudah M, et al. LAT1 (SLC7A5) overexpression in negative Her2 group of breast cancer: a potential therapy target[J]. Asian Pac J Cancer Prev, 2020, 21(5): 1453-1458. DOI: 10.31557/APJCP.2020.21.5.1453. doi:10.31557/APJCP.2020.21.5.1453
[12]	Wang Q, Liu H, Liu Z, et al. Circ-SLC7A5, a potential prognostic circulating biomarker for detection of ESCC[J]. Cancer Genet, 2020, 240: 33-39. DOI: 10.1016/j.cancergen.2019.11.001. doi:10.1016/j.cancergen.2019.11.001
[13]	Lin W, Wang C, Liu G, et al. SLC7A11/xCT in cancer: biological functions and therapeutic implications[J]. Am J Cancer Res, 2020, 10(10): 3106-3126. pmid:33163260
[14]	Kim DH, Kim WD, Kim SK, et al. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells[J]. Cell Death Dis, 2020, 11(5): 406. DOI: 10.1038/s41419-020-2618-6. doi:10.1038/s41419-020-2618-6pmid:32471991
[15]	Feng L, Zhao K, Sun L, et al. SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis[J]. J Transl Med, 2021, 19(1): 367. DOI: 10.1186/s12967-021-03042-7. doi:10.1186/s12967-021-03042-7pmid:34446045
[16]	Hu K, Li K, Lv J, et al. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma[J]. J Clin Invest, 2020, 130(4): 1752-1766. DOI: 10.1172/JCI124049. doi:10.1172/JCI124049pmid:31874110
[17]	Chen MC, Hsu LL, Wang SF, et al. ROS mediate xCT-dependent cell death in human breast cancer cells under glucose deprivation[J]. Cells, 2020, 9(7): 1598. DOI: 10.3390/cells9071598. doi:10.3390/cells9071598
[18]	Ruiu R, Rolih V, Bolli E, et al. Fighting breast cancer stem cells through the immune-targeting of the xCT cystine-glutamate antiporter[J]. Cancer Immunol Immunother, 2019, 68(1): 131-141. DOI: 10.1007/s00262-018-2185-1. doi:10.1007/s00262-018-2185-1pmid:29947961
[19]	Badgley MA, Kremer DM, Maurer HC, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice[J]. Science, 2020, 368(6486): 85-89. DOI: 10.1126/science.aaw9872. doi:10.1126/science.aaw9872pmid:32241947
[20]	Bröer S. Amino acid transporters as targets for cancer therapy: why, where, when, and how[J]. Int J Mol Sci, 2020, 21(17): 6156. DOI: 10.3390/ijms21176156. doi:10.3390/ijms21176156
[21]	Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia[J]. Am J Cancer Res, 2015, 5(4): 1281-1294. pmid:26101697
[22]	Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620. DOI: 10.1007/s13238-020-00789-5. doi:10.1007/s13238-020-00789-5
[23]	Quan L, Ohgaki R, Hara S, et al. Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation[J]. J Exp Clin Cancer Res, 2020, 39(1): 266. DOI: 10.1186/s13046-020-01762-0. doi:10.1186/s13046-020-01762-0
[24]	Cormerais Y, Giuliano S, LeFloch R, et al. Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth[J]. Cancer Res, 2016, 76(15): 4481-4492. DOI: 10.1158/0008-5472.CAN-15-3376. doi:10.1158/0008-5472.CAN-15-3376pmid:27302165
[25]	Galan-Cobo A, Sitthideatphaiboon P, Qu X, et al. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma[J]. Cancer Res, 2019, 79(13): 3251-3267. DOI: 10.1158/0008-5472.CAN-18-3527. doi:10.1158/0008-5472.CAN-18-3527pmid:31040157
[26]	Liu X, Olszewski K, Zhang Y, et al. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer[J]. Nat Cell Biol, 2020, 22(4): 476-486. DOI: 10.1038/s41556-020-0496-x. doi:10.1038/s41556-020-0496-xpmid:32231310
[27]	Wu Z, Xu J, Liang C, et al. Emerging roles of the solute carrier family in pancreatic cancer[J]. Clin Transl Med, 2021, 11(3): e356. DOI: 10.1002/ctm2.356. doi:10.1002/ctm2.356pmid:33783998
[28]	Häfliger P, Charles RP. The L-type amino acid transporter LAT1—an emerging target in cancer[J]. Int J Mol Sci, 2019, 20(10): 2428. DOI: 10.3390/ijms20102428. doi:10.3390/ijms20102428
[29]	Maekawa-Matsuura M, Fujieda K, Maekawa Y, et al. LAT1-targeting thermoresponsive liposomes for effective cellular uptake by cancer cells[J]. ACS Omega, 2019, 4(4): 6443-6451. DOI: 10.1021/acsomega.9b00216. doi:10.1021/acsomega.9b00216
[30]	Wang Y, Qin L, Chen W, et al. Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1[J]. Eur J Med Chem, 2021, 226: 113806. DOI: 10.1016/j.ejmech.2021.113806. doi:10.1016/j.ejmech.2021.113806
[31]	Zhang Y, Shi J, Liu X, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression[J]. Nat Cell Biol, 2018, 20(10): 1181-1192. DOI: 10.1038/s41556-018-0178-0. doi:10.1038/s41556-018-0178-0pmid:30202049
[32]	Lang X, Green MD, Wang W, et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11[J]. Cancer Discov, 2019, 9(12): 1673-1685. DOI: 10.1158/2159-8290.CD-19-0338. doi:10.1158/2159-8290.CD-19-0338pmid:31554642
[33]	Wang W, Green M, Choi JE, et al. CD8⁺T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569(7755): 270-274. DOI: 10.1038/s41586-019-1170-y. doi:10.1038/s41586-019-1170-y
[34]	Lei G, Zhang Y, Koppula P, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression[J]. Cell Res, 2020, 30(2): 146-162. DOI: 10.1038/s41422-019-0263-3. doi:10.1038/s41422-019-0263-3pmid:31949285
[35]	Ye LF, Chaudhary KR, Zandkarimi F, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers[J]. ACS Chem Biol, 2020, 15(2): 469-484. DOI: 10.1021/acschembio.9b00939. doi:10.1021/acschembio.9b00939pmid:31899616