Gene Summary

Gene:SLC7A5; solute carrier family 7 member 5
Aliases: E16, CD98, LAT1, 4F2LC, MPE16, D16S469E
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:large neutral amino acids transporter small subunit 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SLC7A5 (cancer-related)

Ogawa H, Kaira K, Motegi Y, et al.
Role of Amino Acid Transporter Expression as a Prognostic Marker in Patients With Surgically Resected Colorectal Cancer.
Anticancer Res. 2019; 39(5):2535-2543 [PubMed] Related Publications
BACKGROUND/AIM: L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers. However, the clinicopathological significance of LAT1 and 4F2 cell surface antigen (4F2hc) in patients with colorectal cancer (CRC) is unknown. The aim of this study was to clarify the prognostic significance of LAT1 expression in CRC patients who underwent surgical resection.
MATERIALS AND METHODS: Samples from one hundred and forty-seven patients were examined by immunohistochemistry. The expression of LAT1 and 4F2hc, and the Ki-67 labeling index were assessed using resected tumor specimens.
RESULTS: The positive expression of LAT1 and 4F2c was 80% (118/147) and 58% (86/147) (p<0.01), respectively. The expression of LAT1 was identified as an independent significant marker linked to worse prognosis in patients with CRC, and was correlated with tumor cell proliferation, tumor aggressiveness, and metastasis. Moreover, LAT1 was closely associated with the expression of 4F2hc and phosphorylation of the mTOR pathway.
CONCLUSION: LAT1 is a significant molecular marker used to predict prognosis after surgical resection of CRC patients.

Ocak S, Kebudi R, Cebeci Z, et al.
Neuroblastoma of the Iris in Children.
J Pediatr Ophthalmol Strabismus. 2019; 56:e12-e16 [PubMed] Related Publications
Neuroblastoma of the iris is an extremely rare clinical entity. An otherwise healthy 2-month-old male infant presented to the oncology clinic with a nodular whitish iris lesion in his right eye. The excisional tumor biopsy was consistent with a pathological diagnosis of neuroblastoma with differentiation and negative MYCN gene mutation. Further systemic evaluation revealed a right adrenal mass with no metastatic lesion. The biopsy of the adrenal lesion was also consistent with neuroblastoma. After four courses of chemotherapy, the adrenal mass was completely resected. The patient underwent two additional courses of postoperative chemotherapy and continued retinoic acid treatment. The patient is under regular follow-up with no evidence of recurrence 36 months after the initial diagnosis. This is the first case report to present a histopathological verification of neuroblastoma of the iris. The authors suggest that neonates and infants who are diagnosed as having neuroblastoma undergo an ophthalmologic examination after the initial diagnosis to investigate the true incidence of small iris lesions in neuroblastoma that may have been unrecognized. Neuroblastoma should be included in the differential diagnosis of amelanotic iris lesions in infants and young children. [J Pediatr Ophthalmol Strabismus. 2019;56:e12-e16.].

El-Ansari R, Craze ML, Alfarsi L, et al.
The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer.
Breast Cancer Res Treat. 2019; 175(1):27-38 [PubMed] Related Publications
PURPOSE: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes.
METHODS: SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome.
RESULTS: Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5-/SLC7A5-/SLC3A2-), high SLC1A5 (SLC1A5+/SLC7A5-/SLC3A2-), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p < 0.001). The key regulator of tumour cell metabolism, c-MYC, was significantly expressed in tumours in the high SLC cluster (p < 0.001). When different BC subtypes were considered, the association with the poor outcome was observed in the ER+ high proliferation/luminal B class only (p = 0.003). In multivariate analysis, SLC clusters were independent risk factor for shorter BC-specific survival (p = 0.001).
CONCLUSION: The co-operative expression of SLC1A5, SLC7A5, and SLC3A2 appears to play a role in the aggressive subclass of ER+ high proliferation/luminal BC, driven by c-MYC, and therefore have the potential to act as therapeutic targets, particularly in synergism.

Bröer A, Gauthier-Coles G, Rahimi F, et al.
Ablation of the
J Biol Chem. 2019; 294(11):4012-4026 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
The neutral amino acid transporter solute carrier family 1 member 5 (SLC1A5 or ASCT2) is overexpressed in many cancers. To identify its roles in tumors, we employed 143B osteosarcoma cells and HCC1806 triple-negative breast cancer cells with or without ASCT2 deletion. ASCT2ko 143B cells grew well in standard culture media, but ASCT2 was required for optimal growth at <0.5 mm glutamine, with tumor spheroid growth and monolayer migration of 143B ASCT2ko cells being strongly impaired at lower glutamine concentrations. However, the ASCT2 deletion did not affect matrix-dependent invasion. ASCT2ko 143B xenografts in nude mice exhibited a slower onset of growth and a higher number of small tumors than ASCT2wt 143B xenografts, but did not differ in average tumor size 25 days after xenotransplantation. ASCT2 deficiency was compensated by increased levels of sodium neutral amino acid transporter 1 (SNAT1 or SLC38A1) and SNAT2 (SLC38A2) in ASCT2ko 143B cells, mediated by a GCN2 EIF2α kinase (GCN2)-dependent pathway, but this compensation was not observed in ASCT2ko HCC1806 cells. Combined SNAT1 silencing and GCN2 inhibition significantly inhibited growth of ASCT2ko HCC1806 cells, but not of ASCT2ko 143B cells. Similarly, pharmacological inhibition of l-type amino acid transporter 1 (LAT1) and GCN2 significantly inhibited growth of ASCT2ko HCC1806 cells, but not of ASCT2ko 143B cells. We conclude that cancer cells with reduced transporter plasticity are more vulnerable to disruption of amino acid homeostasis than cells with a full capacity to up-regulate redundant transporters by an integrated stress response.

Muto Y, Furihata T, Kaneko M, et al.
Different Response Profiles of Gastrointestinal Cancer Cells to an L-Type Amino Acid Transporter Inhibitor, JPH203.
Anticancer Res. 2019; 39(1):159-165 [PubMed] Related Publications
BACKGROUND/AIM: L-type amino acid transporter 1 (LAT1) is a promising molecular target for cancer therapy. The present study aimed to characterize the anti-cancer effects of JPH203, an LAT1-selective inhibitor, on gastrointestinal cancer cells.
MATERIALS AND METHODS: Three esophageal, two gastric, and two colon cancer cell lines were used. Cytotoxic effects of JPH203 were assessed by a WST-8 assay. LAT1 mRNA levels were determined by quantitative PCR. The inhibitory property of JPH203 against LAT1 function was examined by a transport assay.
RESULTS: JPH203 treatment significantly reduced the viability of all gastric and colon cancer cells. While LAT1 expression levels and inhibitory potencies of JPH203 on LAT1 functions were comparable among the cells, all the esophageal cells were resistant to JPH203.
CONCLUSION: JPH203 was effective in reducing gastric and colon cancer cells. To clarify its cell type-dependent efficacy, identification of the causal factors for JPH203 resistance will be needed.

Poi MJ, Li J, Johnson JA, et al.
A Single Nucleotide Polymorphism in
Anticancer Res. 2019; 39(1):67-72 [PubMed] Related Publications
BACKGROUND/AIM: SLC7A5 is recognized as the major mediator of melphalan uptake into multiple myeloma (MM) cells; however, its contribution to the inter-patient variability of melphalan efficacy and toxicity is yet to be well elucidated. This study aimed to investigate the impact of a single nucleotide polymorphism (SNP) rs4240803 in SLC7A5 on the gene expression, ex vivo sensitivity to melphalan, and clinical outcomes in MM patients who were undergoing autologous stem cell transplantation with high-dose melphalan.
MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 108 MM patients prior to melphalan therapy. Clinical data were also collected from these patients following melphalan therapy.
RESULTS: rs4240803 was associated with elevated expression of SLC7A5 mRNA, higher ex vivo sensitivity to melphalan in PBMCs, and positive 90-day response in these patients (p=0.047, 0.10, 0.049, respectively).
CONCLUSION: rs4240803 impacted the expression of SLC7A5, thus contributing to the clinical response of MM patients to melphalan therapy.

Shen L, Qian C, Cao H, et al.
Upregulation of the solute carrier family 7 genes is indicative of poor prognosis in papillary thyroid carcinoma.
World J Surg Oncol. 2018; 16(1):235 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: The solute carrier (SLC) 7 family genes comprise 14 members and function as cationic amino acid/glycoprotein transporters in many cells, they are essential for the maintenance of amino acid nutrition and survival of tumor cells. This study was conducted to analyze the associations of SLC7 family gene expression with mortality in papillary thyroid carcinoma (PTC).
METHODS: Clinical features, somatic mutations, and SLC7 family gene expression data were downloaded from The Cancer Genome Atlas database. Linear regression model analysis was performed to analyze the correlations between SLC7 family gene expression and clinicopathologic features. Kaplan-Meier survival and logistic regression analyses were performed to characterize the associations between gene expression and patients' overall survival.
RESULTS: Patient mortality was negatively associated with age and tumor size but positively increased cancer stage and absence of thyroiditis in PTC patients. Kaplan-Meier survival analysis indicated that patients with high SLC7A3, SLC7A5, and SLC7A11 expression levels exhibited poorer survival than those with low SLC7A3, SLC7A5, and SLC7A11 expression levels (P < 0.05 for all cases). Logistic regression analysis showed that SLC7A3, SLC7A5, and SLC7A11 were associated with increased mortality (odds ratio [OR] 8.61, 95% confidence interval [CI] 2.3-55.91; OR 3.87, 95% CI 1.18-17.31; and OR 3.87, 95% CI 1.18-17.31, respectively.
CONCLUSION: Upregulation of SLC7A3, SLC7A5, and SLC7A11 expression was associated with poor prognosis in PTC patients, and SLC7 gene expression levels are potentially useful prognostic biomarkers.

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 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Non-coding RNAs (ncRNAs) have been reported to participate in tumor progression by regulating gene expression. Previous studies showed that protein phosphatase Mg2
METHODS: The association between PPM1F or miR-490-3p expression and clinicopathological features and prognosis in patients with HCC was analyzed by TCGA RNA-sequencing data. CircSLC3A2 was identified to bind with miR-490-3p by bioinformatic analysis, and the binding sites between miR-490-3p and PPM1F or circSLC3A2 were confirmed by dual luciferase report and RNA immunoprecipitation (RIP) assays. The localization and clinical significance of miR-490-3p and circSLC3A2 in patients with HCC were investigated by fluorescence in situ hybridization (FISH). MTT, Agar, and Transwell assays were conducted to evaluate the effects of miR-490-3p or circSLC3A2 on cell proliferation and invasive potential.
RESULTS: The expression of PPM1F or miR-490-3p was associated with poor survival and tumor recurrence, and acted as an independent prognostic factor in patients with HCC. Re-expression of miR-490-3p inhibited HCC cell proliferation and invasion by targeting PPM1F, but its inhibitor reversed these effects. Moreover, circSLC3A2, predominantly localized in the cytoplasm, exhibited an oncogenic role by sponging miR-490-3p and regulating PPM1F expression, and harbored a positive correlation with poor survival in patients with HCC.
CONCLUSION: CircSLC3A2 acts as an oncogenic factor in HCC by sponging miR-490-3p and regulating PPM1F expression.

Dura B, Choi JY, Zhang K, et al.
scFTD-seq: freeze-thaw lysis based, portable approach toward highly distributed single-cell 3' mRNA profiling.
Nucleic Acids Res. 2019; 47(3):e16 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Cellular barcoding of 3' mRNAs enabled massively parallel profiling of single-cell gene expression and has been implemented in droplet and microwell based platforms. The latter further adds the value for compatibility with low input samples, optical imaging, scalability, and portability. However, cell lysis in microwells remains challenging despite the recently developed sophisticated solutions. Here, we present scFTD-seq, a microchip platform for performing single-cell freeze-thaw lysis directly toward 3' mRNA sequencing. It offers format flexibility with a simplified, widely adoptable workflow that reduces the number of preparation steps and hands-on time, with the quality of data and cost per sample matching that of the state-of-the-art scRNA-seq platforms. Freeze-thaw, known as an unfavorable lysis method resulting in possible RNA fragmentation, turns out to be fully compatible with 3' scRNA-seq. We applied it to the profiling of circulating follicular helper T cells implicated in systemic lupus erythematosus pathogenesis. Our results delineate the heterogeneity in the transcriptional programs and effector functions of these rare pathogenic T cells. As scFTD-seq decouples on-chip cell isolation and library preparation, we envision it to allow sampling at the distributed sites including point-of-care settings and downstream processing at centralized facilities, which should enable wide-spread adoption beyond academic laboratories.

Feng M, Xiong G, Cao Z, et al.
LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.
J Exp Clin Cancer Res. 2018; 37(1):274 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na
METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated.
RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTOR
CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.

Häfliger P, Graff J, Rubin M, et al.
The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model.
J Exp Clin Cancer Res. 2018; 37(1):234 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential amino acids across the plasma membrane. While LAT1 is overexpressed in a variety of human neoplasms, its expression and its role in thyroid cancer is currently unknown. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy for which no effective therapy exists. The purpose of this study was to explore whether the inhibition of LAT1 in ATC would affect tumor growth both in vitro and in vivo.
METHODS: LAT1 was pharmacologically blocked by JPH203 in human ATC and papillary thyroid cancer (PTC) cell lines. The effects on proliferation and mTORC1 activity were addressed in vitro. A genetically engineered mouse model of ATC was used to address the effect of blocking LAT1 on tumor growth in vivo. SLC7A5 transcription was measured in patient-derived ATC samples to address the clinical relevance of the findings.
RESULTS: LAT1 block by JPH203 reduced proliferation and mTORC1 signaling in human thyroid cancer cell lines. SLC7A5 transcription was upregulated in ATC tissues derived from a genetically engineered mouse model and in ATC samples recovered from patients. JPH203 treatment induced thyroid tumor growth arrest in vivo in a fully immunocompetent mouse model of thyroid cancer. Additionally, analysis of publicly available datasets of thyroid carcinomas revealed that high LAT1 expression is associated with potentially untreatable PTC presenting reduced NIS/SLC5A5 transcription and with ATC.
CONCLUSIONS: These preclinical results show that LAT1 inhibition is a novel therapeutic approach in the context of thyroid cancers, and more interestingly in untreatable thyroid cancers.

Salisbury TB, Arthur S
The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer.
Int J Mol Sci. 2018; 19(8) [PubMed] Article available free on PMC after 15/03/2020 Related Publications
The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.

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) [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeutic targets, nine unique short hairpin RNA (shRNA) vectors were used to stably suppress transporter expression in human epithelial (Hep3B) and mesenchymal (SK-Hep1) hepatocellular carcinoma (HCC) cell lines. In addition, six unique CRISPR-Cas9 vectors were used to edit the ASCT2 (

Ji X, Yang X, Wang N, et al.
Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia.
Cell Physiol Biochem. 2018; 48(2):731-740 [PubMed] Related Publications
BACKGROUND/AIMS: Y+LAT1 protein, encoded by the SLC7A7 gene (a member of the SLC7 family), forms the cationic amino acid transport system y+L (system y+L). This system transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response.
METHODS: We analyzed the role of the SLC7A7 gene in the cellular activities of Jurkat cells, specifically the cell cycle and cell proliferation, apoptosis, migration, and invasion. Cell proliferation was assessed using the Cell Counting Kit-8. Apoptosis and the cell cycle were determined with a FACSCalibur flow cytometer. A Transwell chamber was used to measure cell invasion and migration.
RESULTS: The proliferative ability of Jurkat cells was not significantly altered by transfection with SLC7A7 overexpression vectors. However, SLC7A7 overexpression significantly decreased the percentage of apoptotic Jurkat cells (P = 0.007) but significantly increased the proportion of G1 phase cells (P = 0.029) and cell migration (P < 0.001) and invasion (P < 0.001). Knockdown of SLC7A7 increased the cell apoptosis rate (P = 0.006) but decreased the G1 phase ratio (P = 0.002) and cell migration (P < 0.001) and invasion (P < 0.001).
CONCLUSIONS: SLC7A7 plays a significant role in the pathogenesis of T-cell acute lymphoblastic leukemia.

Fuchs R, Stracke A, Holzmann V, et al.
Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(9):1211-1229 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The quinazoline based drug prazosin (PRZ) is a potent inducer of apoptosis in human cancer cells. We recently reported that PRZ enters cells via endocytosis and induces tubulation of the endolysosomal system. In a proteomics approach aimed at identifying potential membrane proteins with binding affinity to quinazolines, we detected the oncoprotein CD98hc. We confirmed shuttling of CD98hc towards lysosomes and upregulation of CD98hc expression in PRZ treated cells. Gene knockout (KO) experiments revealed that endocytosis of PRZ still occurs in the absence of CD98hc - suggesting that PRZ does not enter the cell via CD98hc but misroutes the protein towards tubular lysosomes. Lysosomal tubulation interfered with completion of cytokinesis and provoked endoreplication. CD98hc KO cells showed reduced endoreplication capacity and lower sensitivity towards PRZ induced apoptosis than wild type cells. Thus, loss of CD98hc does not affect endocytosis of PRZ and lysosomal tubulation, but the ability for endoreplication and survival of cells. Furthermore, we found that glutamine, lysomototropic agents - namely chloroquine and NH

Zacharakis N, Chinnasamy H, Black M, et al.
Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer.
Nat Med. 2018; 24(6):724-730 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as melanoma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary

Md Fuzi AA, Omar SZ, Mohamed Z, et al.
High throughput silencing identifies novel genes in endometrioid endometrial cancer.
Taiwan J Obstet Gynecol. 2018; 57(2):217-226 [PubMed] Related Publications
OBJECTIVE: To validate the gene expression profile obtained from the previous microarray analysis and to further study the biological functions of these genes in endometrial cancer. From our previous study, we identified 621 differentially expressed genes in laser-captured microdissected endometrioid endometrial cancer as compared to normal endometrial cells. Among these genes, 146 were significantly up-regulated in endometrial cancer.
MATERIALS AND METHODS: A total of 20 genes were selected from the list of up-regulated genes for the validation assay. The qPCR confirmed that 19 out of the 20 genes were up-regulated in endometrial cancer compared with normal endometrium. RNA interference (RNAi) was used to knockdown the expression of the upregulated genes in ECC-1 and HEC-1A endometrial cancer cell lines and its effect on proliferation, migration and invasion were examined.
RESULTS: Knockdown of MIF, SOD2, HIF1A and SLC7A5 by RNAi significantly decreased the proliferation of ECC-1 cells (p < 0.05). Our results also showed that the knockdown of MIF, SOD2 and SLC7A5 by RNAi significantly decreased the proliferation and migration abilities of HEC-1A cells (p < 0.05). Moreover, the knockdown of SLC38A1 and HIF1A by RNAi resulted in a significant decrease in the proliferation of HEC1A cells (p < 0.05).
CONCLUSION: We have identified the biological roles of SLC38A1, MIF, SOD2, HIF1A and SLC7A5 in endometrial cancer, which opens up the possibility of using the RNAi silencing approach to design therapeutic strategies for treatment of endometrial cancer.

El Ansari R, Craze ML, Miligy I, et al.
The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours.
Breast Cancer Res. 2018; 20(1):21 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: Breast cancer (BC) is a heterogeneous disease characterised by variant biology and patient outcome. The amino acid transporter, SLC7A5, plays a role in BC although its impact on patient outcome in different BC subtypes remains to be validated. This study aimed to determine whether the clinicopathological and prognostic value of SLC7A5 is different within the molecular classes of BC.
METHODS: SLC7A5 was assessed at the genomic level, using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data (n = 1980), and proteomic level, using immunohistochemical analysis and tissue microarray (TMA) (n = 2664; 1110 training and 1554 validation sets) in well-characterised primary BC cohorts. SLC7A5 expression correlated with clinicopathological and biological parameters, molecular subtypes and patient outcome.
RESULTS: SLC7A5 mRNA and protein expression were strongly correlated with larger tumour size and higher grade. High expression was observed in triple negative (TN), human epidermal growth factor receptor 2 (HER2)+, and luminal B subtypes. SLC7A5 mRNA and protein expression was significantly associated with the expression of the key regulator of tumour cell metabolism, c-MYC, specifically in luminal B tumours only (p = 0.001). High expression of SLC7A5 mRNA and protein was associated with poor patient outcome (p < 0.001) but only in the highly proliferative oestrogen receptor (ER)+/ luminal B (p = 0.007) and HER2+ classes of BC (p = 0.03). In multivariate analysis, SLC7A5 protein was an independent risk factor for shorter breast-cancer-specific survival only in ER+ high-proliferation tumours (p = 0.02).
CONCLUSIONS: SLC7A5 appears to play a role in the aggressive highly proliferative ER+ subtype driven by MYC and could act as a potential therapeutic target. Functional assessment is necessary to reveal the specific role played by this transporter in the ER+ highly proliferative subclass and HER2+ subclass of BC.

Furness CL, Mansur MB, Weston VJ, et al.
The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.
Leukemia. 2018; 32(9):1984-1993 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

El Ansari R, Craze ML, Diez-Rodriguez M, et al.
The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes.
Br J Cancer. 2018; 118(8):1115-1122 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity and patient outcome. This study aimed to evaluate the biological and prognostic value of the membrane solute carrier, SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. SLC3A2 was assessed at the genomic level, using METABRIC data (n = 1980), and at the proteomic level, using immunohistochemistry on tissue microarray (TMA) sections constructed from a large well-characterised primary BC cohort (n = 2500). SLC3A2 expression was correlated with clinicopathological parameters, molecular subtypes and patient outcome. SLC3A2 mRNA and protein expression were strongly correlated with higher tumour grade and poor Nottingham prognostic index (NPI). High expression of SLC3A2 was observed in triple-negative (TN), HER2+ and ER+ high-proliferation subtypes. SLC3A2 mRNA and protein expression were significantly associated with the expression of c-MYC in all BC subtypes (p < 0.001). High expression of SLC3A2 protein was associated with poor patient outcome (p < 0.001), but only in the ER+ high-proliferation (p = 0.01) and TN (p = 0.04) subtypes. In multivariate analysis SLC3A2 protein was an independent risk factor for shorter BC-specific survival (p < 0.001). SLC3A2 appears to play a role in the aggressive BC subtypes driven by MYC and could act as a potential prognostic marker. Functional assessment is necessary to reveal its potential therapeutic value in the different BC subtypes.

Ding K, Tan S, Huang X, et al.
GSE1 predicts poor survival outcome in gastric cancer patients by SLC7A5 enhancement of tumor growth and metastasis.
J Biol Chem. 2018; 293(11):3949-3964 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Gastric cancer remains a malignancy with poor survival outcome. We herein report that GSE1, a proline-rich protein, possesses a role in the progression of human gastric cancer. The expression of GSE1 was observed to be much higher in human gastric cancer tissues compared with normal gastric tissues, and GSE1 expression correlated positively with lymph node metastasis, histological grade, depth of invasion, and clinical stage in gastric cancer patients. Moreover, GSE1 expression was also associated with decreased post-operative relapse-free survival and overall survival in the cohort. The forced expression of GSE1 in gastric cancer cell lines resulted in increased cell proliferation, increased colony formation, enhanced cell migration, and invasion. Furthermore, forced expression of GSE1 also increased tumor size and enhanced lung metastasis in xenograft models. The depletion of endogenous GSE1 with shRNAs decreased the oncogenicity and invasiveness of gastric cancer cells both

Cormerais Y, Massard PA, Vucetic M, et al.
The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5).
J Biol Chem. 2018; 293(8):2877-2887 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The transporters for glutamine and essential amino acids, ASCT2 (solute carrier family 1 member 5, SLC1A5) and LAT1 (solute carrier family 7 member 5, SLC7A5), respectively, are overexpressed in aggressive cancers and have been identified as cancer-promoting targets. Moreover, previous work has suggested that glutamine influx via ASCT2 triggers essential amino acids entry

Wada Y, Hirose K, Harada T, et al.
Impact of oxygen status on 10B-BPA uptake into human glioblastoma cells, referring to significance in boron neutron capture therapy.
J Radiat Res. 2018; 59(2):122-128 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Boron neutron capture therapy (BNCT) can potentially deliver high linear energy transfer particles to tumor cells without causing severe damage to surrounding normal tissue, and may thus be beneficial for cases with characteristics of infiltrative growth, which need a wider irradiation field, such as glioblastoma multiforme. Hypoxia is an important factor contributing to resistance to anticancer therapies such as radiotherapy and chemotherapy. In this study, we investigated the impact of oxygen status on 10B uptake in glioblastoma cells in vitro in order to evaluate the potential impact of local hypoxia on BNCT. T98G and A172 glioblastoma cells were used in the present study, and we examined the influence of oxygen concentration on cell viability, mRNA expression of L-amino acid transporter 1 (LAT1), and the uptake amount of 10B-BPA. T98G and A172 glioblastoma cells became quiescent after 72 h under 1% hypoxia but remained viable. Uptake of 10B-BPA, which is one of the agents for BNCT in clinical use, decreased linearly as oxygen levels were reduced from 20% through to 10%, 3% and 1%. Hypoxia with <10% O2 significantly decreased mRNA expression of LAT1 in both cell lines, indicating that reduced uptake of 10B-BPA in glioblastoma in hypoxic conditions may be due to reduced expression of this important transporter protein. Hypoxia inhibits 10B-BPA uptake in glioblastoma cells in a linear fashion, meaning that approaches to overcoming local tumor hypoxia may be an effective method of improving the success of BNCT treatment.

Li H, Chen S, Liu J, et al.
Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer.
Biochem Biophys Res Commun. 2018; 495(3):2350-2355 [PubMed] Related Publications
Dysregulated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. The lncRNA plasmacytoma variant translocation 1 (PVT1) is reported to be an oncogene in a variety of cancers. However, the roles of PVT1-5 and its related miRNAs in lung cancer are poorly understood. In this study, we found that PVT1-5 expression was significantly increased in lung cancer tissues and cell lines. By using biotin-labeled lncRNA-PVT1-5 probe for miRNA in vivo precipitation (miRIP) in lung cancer cells and dual-luciferase reporterassays, we identified that miR-126 was associated with lncRNA-PVT1-5. Furthermore, knockdown of lncRNA-PVT1-5 in cells could down-regulate the expression of SLC7A5, the target of oncogenic miR-126, resulting in the cell proliferation. Conversely, inhibiting the expression of miR-126 markedly increased the expression of SLC7A5 and alleviated cell proliferation inhibition. Thus, our results indicated that lncRNA-PVT1-5 may function as a competing endogenous RNA (ceRNA) for miR-126 to promote cell proliferation by regulating the miR-126/SLC7A5 pathway, suggesting that lncRNA-PVT1-5 plays a crucial role in lung cancer progression and lncRNA-PVT1-5/miR-126/SLC7A5 regulatory network may shed light on tumorigenesis in lung cancer.

Popławski P, Wiśniewski JR, Rijntjes E, et al.
Restoration of type 1 iodothyronine deiodinase expression in renal cancer cells downregulates oncoproteins and affects key metabolic pathways as well as anti-oxidative system.
PLoS One. 2017; 12(12):e0190179 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Type 1 iodothyronine deiodinase (DIO1) contributes to deiodination of 3,5,3',5'-tetraiodo-L-thyronine (thyroxine, T4) yielding of 3,5,3'-triiodothyronine (T3), a powerful regulator of cell differentiation, proliferation, and metabolism. Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells. However, the global effects of DIO1 expression in various tissues affected by cancer remain unknown. Here, the effects of stable DIO1 re-expression were analyzed on the proteome of renal cancer cells, followed by quantitative real-time PCR validation in two renal cancer-derived cell lines. DIO1-induced changes in intracellular concentrations of thyroid hormones were quantified by L-MS/MS and correlations between expression of DIO1 and potential target genes were determined in tissue samples from renal cancer patients. Stable re-expression of DIO1, resulted in 26 downregulated proteins while 59 proteins were overexpressed in renal cancer cells. The 'downregulated' group consisted mainly of oncoproteins (e.g. STAT3, ANPEP, TGFBI, TGM2) that promote proliferation, migration and invasion. Furthermore, DIO1 re-expression enhanced concentrations of two subunits of thyroid hormone transporter (SLC7A5, SLC3A2), enzymes of key pathways of cellular energy metabolism (e.g. TKT, NAMPT, IDH2), sex steroid metabolism and anti-oxidative response (AKR1C2, AKR1B10). DIO1 expression resulted in elevated intracellular concentration of T4. Expression of DIO1-affected genes strongly correlated with DIO1 transcript levels in tissue samples from renal cancer patients as well as with their poor survival. This first study addressing effects of deiodinase re-expression on proteome of cancer cells demonstrates that induced DIO1 re-expression in renal cancer robustly downregulates oncoproteins, affects key metabolic pathways, and triggers proteins involved in anti-oxidative protection. This data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines.

Tsai CY, Chen CY, Chiou YH, et al.
Epigallocatechin-3-Gallate Suppresses Human Herpesvirus 8 Replication and Induces ROS Leading to Apoptosis and Autophagy in Primary Effusion Lymphoma Cells.
Int J Mol Sci. 2017; 19(1) [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to induce cell death in cancer cells. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by human herpesvirus 8 (HHV8). In this study, we examined the role of EGCG on PEL cells in cell death and HHV8 replication. We performed trypan blue exclusion assay to assess the cell viability of PEL cells, flow cytometry analysis to examine the cell cycle distribution and reactive oxygen species (ROS) generation, caspase-3 activity to assay apoptosis, acridine orange staining to determine autophagy, and immunoblotting to detect the protein levels involved in apoptosis and autophagy as well as mitogen activated protein kinases (MAPKs) activation upon EGCG treatment. The expression of the HHV8 lytic gene was determined by luciferase reporter assay and reverse transcription-PCR, and viral progeny production was determined by PCR. Results revealed that EGCG induced cell death and ROS generation in PEL cells in a dose-dependent manner.

Altan B, Kaira K, Watanabe A, et al.
Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma.
Cancer Chemother Pharmacol. 2018; 81(1):141-153 [PubMed] Related Publications
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.

Hutterer M, Bumes E, Riemenschneider MJ, et al.
AIDS-Related Central Nervous System Toxoplasmosis With Increased 18F-Fluoroethyl-L-Tyrosine Amino Acid PET Uptake Due to LAT1/2 Expression of Inflammatory Cells.
Clin Nucl Med. 2017; 42(12):e506-e508 [PubMed] Related Publications
We report the case of a 40-year-old woman with a progressive right-sided hemiparesis. Standard MRI revealed a contrast-enhancing brain lesion within the left basal ganglia. Ffluoroethyl-L-tyrosine (F-FET) PET showed a distinct tracer uptake (lesion-to-brain ratio [LBR]: LBRmax = 2.03, LBRmean = 1.68) with a significant larger metabolic lesion volume than contrast-enhancement in MRI, indicating cerebral glioma. Surprisingly, histopathologic analysis demonstrated central nervous system toxoplasmosis with pronounced inflammatory reaction (reactive astrogliosis, microglia activation, macrophage, and T-lymphocyte infiltration), which was associated with strong LAT1/LAT2/CD98 expression. In conclusion, inflammatory brain lesions, such as cerebral toxoplasmosis, represent a potential pitfall of F-FET PET mimicking a brain tumor.

Honjo H, Toh Y, Sohda M, et al.
Clinical Significance and Phenotype of MTA1 Expression in Esophageal Squamous Cell Carcinoma.
Anticancer Res. 2017; 37(8):4147-4155 [PubMed] Related Publications
BACKGROUND/AIM: Metastasis-associated gene 1 (MTA1) is considered a potential prognostic factor in esophageal cancer. We investigated the clinical relationship between MTA1, LAT1, and tumor metabolism, as evaluated by positron emission tomography (PET) in esophageal squamous cell carcinoma.
MATERIALS AND METHODS: We analyzed 142 esophageal squamous cell carcinoma patients who underwent curative resection without preoperative treatment. MTA1 expression was assessed by immuno-zahistochemistry, and tested against standardized uptake values from preoperative PET-CT. The association among MTA1, LAT1, and
RESULTS: MTA1 staining was observed in 82 of 142 cancer tissues. Five-year overall survival was 69.9 % in the absence of MTA1, but 50.7% otherwise (p=0.021), while disease-free survival was 66.5% and 49.0% (p=0.071), respectively. Abnormal
CONCLUSION: MTA1 shows promise as a diagnostic and prognostic marker in esophageal cancer, and we anticipate that the gene will also prove to be a good therapeutic target.

Schmidt J, Bonzheim I, Steinhilber J, et al.
EMMPRIN (CD147) is induced by C/EBPβ and is differentially expressed in ALK+ and ALK- anaplastic large-cell lymphoma.
Lab Invest. 2017; 97(9):1095-1102 [PubMed] Related Publications
Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPβ, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPβ for the unusual phenotype of ALK+ ALCL cells, C/EBPβ was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK- cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPβ knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK- ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPβ knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK- ALCL, suggesting an additional role of C/EBPβ in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPβ plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL.

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