LAT1 is associated with poor prognosis and radioresistance in head and neck squamous cell carcinoma
- Authors:
- Published online on: March 13, 2023 https://doi.org/10.3892/ol.2023.13757
- Article Number: 171
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Copyright: © Kawasaki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Head and neck squamous cell carcinoma (HNSCC) has been identified as the sixth most common cancer in the world, with approximately 600,000 new cases diagnosed annually (1). Two-thirds of patients are diagnosed at an advanced stage, and the 5-year survival rate is 39–65%; thus, HNSCC has one of the worst prognoses compared to other cancer types (2). Worldwide, the standard treatments are surgery and chemoradiation (3–7). Unfortunately, recurrence and metastasis often occur even after these therapies. Recently, immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have exhibited better performance than standard chemotherapy in the Phase III CHECK-MATE-141 and KEYNOTE-040 studies (8,9). However, the response rate was only about 15%, and the median overall survival was 1.4-2.4 months, which is deemed unsatisfactory (10).
The L-type amino acid transporter (LAT1, SLC7A5) has been attracting the recent attention as a therapeutic target. Among the 50 types of mammalian cell membrane amino acid transporters, the expression of the following transporters is upregulated in malignant tumors: LAT1 (SLC7A5) (11), LAT3 (SLC43A1) (12), ASCT2 (SLC1A5) (13), ATB0+ (SLC6A14) (14), and xCT (SLC7A11) (15). LAT1 forms a heterodimeric complex with CD98 heavy chain (CD98hc) (4F2hc, SLC3A2) (16) and transports large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine. LAT1 is often upregulated in human cancer tissues, including colon, lung, prostate, gastric, breast, kidney, esophageal, and brain cancers. In non-small cell lung cancer, pancreatic cancer, brain tumor, prostate cancer, and breast cancer, high expression of LAT1 is associated with a poor prognosis, suggesting that the expression of LAT1 is related to cancer malignancy (17–22). LAT1 is upregulated in cancers, and its expression is highly specific to cancers. Inhibition of LAT1 often blocks the amino acid supply to tumor cells and evokes antitumor effects. Thus, LAT1 inhibitors are currently being developed as antitumor drugs. Intravenous administration of the LAT1 inhibitor, JPH203, inhibits tumor growth in nude mice (23).
Despite the high expression of LAT1 in various cancers, the function of LAT1 has not yet been elucidated in HNSCC. Therefore, this study aimed to characterize LAT1 in HNSCC and to investigate the relationship between LAT1 and prognosis in clinical samples. If LAT1 is a prognostic factor, the use of JPH203 will be improved significantly. If LAT1 can be used as a prognostic factor, tailor-made treatment based on the patient's background can be implemented instead of the current standard of care, which includes platinum-based agents combined with radiation therapy and surgery. For refractory and recurrent tumors, JPH203 may be an alternative treatment to nivolumab and pembrolizumab.
Materials and methods
Cell culture
Sa3 (gingiva), HSC2 (oral), and HSC4 (tongue) cell lines were used. Cells were grown in RPMI1640 (Nissui Pharmaceutical, Tokyo, Japan) supplemented with 10% fetal bovine serum (FBS) (Clontech Laboratories, Mountain View, CA) and 2 mM L-glutamine. The radioresistant cell lines were described previously (24).
Flow cytometry
For the analysis of the LAT1-positive fraction, cell pellets were incubated with FITC-conjugated SLC7A5/LAT1 antibody (BU53) (Novus Biologicals, Littleton). After washing with PBS twice, the cells were resuspended in 2 µg/ml propidium iodide/Hank's balanced salt solution and filtered through a cell strainer (BD Biosciences Discovery Labware, Bedford, MA). Flow cytometry was performed using a BD FACS Aria III instrument (Becton, Dickinson and Company Japan, Tokyo, Japan). To determine the negative fraction, FITC-conjugated mouse IgG2a isotype control (M2A) (Novus, Biologicals, Littleton, USA) was used.
Sphere formation assay
To avoid adhesion and subsequent development to non-CSCs, cells were cultured in serum-free semisolid medium. LAT1-positive and LAT1-negative cells (1×103 cells each) were seeded in 100 µl of PromoCell 3D Tumorsphere Medium XF (PromoCell GmbH, Heidelberg, Germany), containing 0.33% agar. The cells were then incubated for 14 days at 37°C in a humidified atmosphere containing 5% CO2.
Invasion assay
Invasion assays were performed using an 8 µm Boyden chamber (Falcon, USA). The filter was coated with 100 µl of Matrigel (1 mg/ml). The upper chamber was filled with 500 µl of serum-free RPMI 1640 medium with 5×103 cells, whereas the bottom chamber was filled with 1,000 µl of 10%-FBS-supplemented RPMI 1640 medium. After 72 h of incubation, the upside of the filter was swabbed off and fixed with formalin. Cells were stained with hematoxylin-eosin and counted under an optical microscope (Olympus, Tokyo, Japan).
Wound healing assay
Cells were grown to confluency with growth medium in a 60-mm dish, and a straight line was drawn with a 200-µl pipet tip. After 24 h of incubation with serum-free RPMI medium, the cells were fixed in formalin, and the residual area of wound gap after migration was analyzed using ImageJ and compared to that of the corresponding initial wound gap (set at 1).
Immunostaining
Immunohistochemical staining was performed on 173 preoperative untreated HNSCC biopsy specimens collected at our hospital from 2010 to 2019 for clinicopathological studies. The median follow-up period was 34 (range: 2–6) months. The anti-LAT-1 antibody was a monoclonal antibody purified from rabbit. Tissue sections (3 µm) were deparaffinized and treated with 3% hydrogen peroxide methanol for 10 min to inhibit endogenous peroxidase activity. After washing with the buffer, the sections were incubated with anti-LAT1 antibody (1:1,000; ab208776, Abcam, Cambridge, MA) for 90 min. The sections were then incubated with Dako EnVision+ System HRP and colorized with DAB (3,3-diaminobenzidine). The results were classified into four levels according to the degree of staining: score 0 (negative), score 1 (weak), score 2 (moderate), and score 3 (strong). A score of ≥2 was considered positive for LAT1 expression. The evaluation method was adopted from a study by Rietbergen et al (25). At least two skilled pathologists scored the staining while blinded to the clinical information.
Experiment using JPH203
JPH203 (Namiki, Tokyo, Japan) was used to inhibit LAT1 at a concentration of 100 µM, referring to the concentration used by Choi et al (26).
Statistical analysis
Significant differences in OS and PFS were assessed using the Kaplan-Meier method and log-rank test. The univariate and multivariate Cox proportional hazards modeling was used to evaluate prognostic significance. One-way ANOVA followed by Tukey's post hoc test was used to compare three unpaired groups, and unpaired Student's t-tests were used to compare two unpaired groups, respectively. All experiments were independently repeated at least three times. P<0.05 was considered significant.
Results
LAT1-positive cells in HNSCC have strong spheroid-forming and invasive potential
Three HNSCC cell lines, that is, Sa3, HSC2, and HSC4, were separated into LAT1-positive and -negative cells using a flow cytometer. The LAT1-positive cells had strong spheroid formation ability, whereas the LAT1-negative cells could hardly form spheroids (Fig. 1A). LAT1-positive cells from the three different cell lines also exhibited enhanced invasive ability (Fig. 1B).
Patients with LAT1-positive HNSCC have a poor prognosis and are refractory to chemoradiotherapy
According to TNM Classification of Malignant Tumours, 8th ed., Union for International Cancer Control (27), 78.0% of patients were at advanced stages (Table I). The intensity of LAT1 immunostaining of biopsy specimens was determined by skilled pathologists to be negative (Fig. 2A), weak (Fig. 2B), moderate (Fig. 2C), or strong (Fig. 2D). Specimens with negative and weak immunostaining were classified into the Low group, whereas specimens with moderate and strong immunostaining were classified into the High group. Of the 173 patients (Table I), 52 were in the Low group and 121 were in the High group. The 5-year OS was 56.8% in the Low group, whereas it was 45.3% in the High group (P=0.041) (Fig. 3A); moreover, PFS was 47.9% in the Low group and 36.2% in the High group (P=0.037) (Fig. 3B). Furthermore, multivariate analysis revealed that LAT1 was an independent prognostic factor for OS (Table IIA) and PFS (Table IIB) [OS, P=0.045, HR: 1.710, 95% confidence interval (95% CI): 1.013-2.887; PFS, P=0.037, HR: 1.749, 95% CI: 1.013-2.887].
In total, 85 of the 173 patients were treated with chemoradiation, including 36 patients in the Low group and 49 patients in the High group (Table III). The 5-year OS for patients treated with chemoradiation was 58.7% in the Low group and 33.0% in the High group (P=0.003) (Fig. 3C). The PFS for the Low group was found to be better than the prognosis for the High group (46.4% in the Low group vs. 28.4% in the High group, P=0.001) (Fig. 3D). The multivariate analysis showed that LAT1 was an independent prognostic factor for OS and PFS in patients who underwent chemoradiotherapy (OS: P=0.008, HR: 2.697, 95% CI: 1.292-5.464; PFS: P=0.017, HR: 2.124, 95% CI: 1.147-3.933) (Table IV). Surgical treatment was available for 88 patients (Table V), but there were no significant differences in terms of OS (53.5% for Low and 53.6% for High) (Fig. 3E) or PFS (50.0% for Low and 41.4% for High) (Fig. 3F), (Table VI).
Radioresistant cells have an expanded LAT1-positive fraction and enhanced malignant potential
Because of the poor prognosis of LAT1-positive patients and their resistance to radiotherapy, we examined the expression of LAT1 in three cell lines, Sa3, HSC2, and HSC4, after irradiation with 60 Gy. The LAT1-positive fraction increased from 10–20% before irradiation to 60–80% after irradiation (Fig. 4A). After irradiation with 60 Gy, cells were separated into LAT1-positive and LAT1-negative cells using flow cytometry and cultured in serum-free semifluid medium. The LAT1-positive cells exhibited enhanced spheroid-forming and invasive abilities (Fig. 4B and C), indicating that radioresistant cells had high malignant potential.
LAT1 inhibition reduces the LAT1-positive fraction of normal and radioresistant cells and reduces the malignant potential
JPH203 was added to RPMI 1640 and incubated for 1 day, after which the LAT1-positive fractions were compared. Treatment with JPH203 reduced the fraction of LAT1-positive cells from 10–20% to 2–5% (Fig. 5A). In radioresistant cells (irradiated as described above), JPH203 reduced the LAT1-positive fraction from 80 to 20–40% (Fig. 5B). Thus, JPH203 reduced the LAT1-positive fraction in both the parental and radioresistant cells.
Parental and radioresistant cells were separated into LAT1-positive and LAT1-negative cells and cultured in serum-free semifluid medium supplemented with JPH203. After JPH203 treatment, the spheroid formation ability was not significantly different between LAT1-positive and LAT1-negative cells (Fig. 5C and D) Similarly, no differences in invasive ability were detected between LAT1-positive and LAT1-negative cells after JPH203 treatment in both normal and radioresistant cells (Fig. 5E and F).
JPH203 inhibits the migratory ability of normal and radioresistant cells
Wound healing assays were performed in both parental and radioresistant cells. JPH203 was effective in inhibiting the migration in both the parental (Fig. 5G) and radioresistant cells (Fig. 5H).
Discussion
We demonstrated that LAT1 is strongly involved in sphere formation, invasion, and migration in HNSCC. Furthermore, patients with LAT1-positive specimens had a worse prognosis and were more resistant to chemoradiotherapy compared to patients with low LAT1 expression. JPH203, a LAT1 inhibitor, suppressed sphere formation, invasion, and migration in radioresistant cells.
We have previously reported that CD98hc is a marker for cancer stem cells in HNSCC (24), and similar reports have been published by other investigators (28,29). Since CD98hc binds to amino acid transporters in the light chain, LAT1-positive cells may have cancer stem cell characteristics. LAT1-positive cells can form spheres in serum-free semifluid medium, which is a characteristic of cancer stem cells (30). Although other stem cell markers, such as Oct3/4, Nanog, and SOX2, need to be investigated, LAT1 may be an important therapeutic target because it induces chemoradiotherapy resistance.
The mTOR signaling pathway plays an important role in invasion and migration. Amino acids, including leucine or amino acid prodrugs, are transported into cells by LAT1 and cause activation of mTORC1, resulting in enhanced invasion and migration (31). In our study, the enhanced invasion and migration of LAT1-positive cells may result from the activation of mTOR signaling.
According to the LAT1 immunostaining of HNSCC patient biopsies, high LAT1 expression was associated with poor prognosis and chemoradiotherapy resistance. In a previous report, high LAT1 expression was associated with an extremely poor prognosis in resected tongue cancer (32). However, in our study, no significant differences were detected in the LAT1 expression groups after surgical treatment. The lack of differences may be due to the staging based on clinical imaging diagnosis rather than pathological indicators and grouping head and neck cancers together. We believe that the ability to predict chemoradiotherapy resistance at the biopsy stage based on LAT1 expression is a significant finding of this study.
About half of HNSCC patients relapse after chemoradiotherapy or surgery, and immune checkpoint inhibitors have achieved some success. However, their efficacy is limited, and HNSCC remains a disease with a poor prognosis (33). Therefore, JPH203, a LAT1 inhibitor, is expected to be a new therapeutic agent. The expression of LAT1 increased from 10–20% to 60–80% after irradiation. Sphere formation, invasion, and migration are enhanced in LAT1-positive cells, even in radioresistant cell lines. The high fraction of LAT1-positive cells in resistant cell lines indicates high malignancy (34). Recurrent tumors may need to utilize more amino acids to survive and proliferate; however, the mechanism must be clarified.
JPH203 suppressed sphere formation, invasion, and migration in both the parental and radioresistant cells. After the addition of JPH203, the LAT1-positive cell fraction was noted to decrease to 2–5% in the parental cells and significantly decreased to 20–40% in the radioresistant cells. The expression of LAT1 was also suppressed by BCH, which is an inhibitor of LAT1 and LAT2. However, the expression of LAT1 is upregulated by feedback with prolonged exposure to JPH203 (35). In this study, the results were obtained after 24 h. The long-term expression of LAT1 requires further investigation.
In HNSCC, LAT1-positive cells are highly malignant and capable of sphere formation, invasion, and migration. Targeting these cells will improve the prognosis of HNSCC. Furthermore, LAT1 expression at the biopsy stage can be used to determine radiosensitivity. This will play an important role in designing tailor-made treatment strategies. For instance, patients with high LAT1 expression can undergo surgery first, whereas patients with low LAT1 expression can undergo chemoradiation first. JPH203 concomitant radiation therapy may be an alternative to platinum-based agents. JPH203 may also be an effective treatment for recurrent tumors that have become radioresistant, and the availability of other options, in addition to nivolumab and pembrolizumab, will improve the prognosis of HNSCC patients. In addition to treatment, 18F-FAMT, a LAT1-selective amino acid PET, has been found to be effective in cancer diagnosis (36). In the HNSCC field, the function of LAT1 needs to be clarified urgently and actively applied in the future.
In conclusion, LAT1-positive cells in HNSCC are those with enhanced spheroid formation, invasion, and migration, as well as those in radioresistant cell lines. Immunostaining of HNSCC patient specimens showed that LAT1 is an independent prognostic factor and resistant to chemoradiotherapy. JPH203, a LAT1 inhibitor, could strongly suppress spheroid formation, invasion, and migration of LAT1 positive cells. Therefore, JPH203 should also be used in the field of HNSCC, as LAT1 is a prognostic factor and can be used to predict therapeutic efficacy.
Acknowledgements
The authors would like to thank Mr. Yusuke Ono (Department of Molecular and Tumour Pathology, Akita University Graduate School of Medicine, Akita, Japan) and Ms. Reiko Ito (Department of Molecular and Tumour Pathology, Akita University Graduate School of Medicine, Akita, Japan) for their technical assistance, and Ms. Eriko Kumagai (Department of Molecular and Tumour Pathology, Akita University Graduate School of Medicine, Akita, Japan) for her secretarial work.
Funding
The present study was supported by JSPS KAKENHI (grant nos. 18K09311 and 19K07497).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
YK and YO designed the outline of the study. HS, YK, MM, HH, SS, TY, MS and AI conducted the experiments and data analyses. YK, SH and YO confirmed the authenticity of all raw data. YK and YO interpreted the data and wrote the draft. YO revised the draft before the submission. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Written informed consent was obtained from all patients. All procedures used in this research were approved by the Ethical Committee of Akita University Hospital (approval no. 2532; Akita, Japan). The study was performed according to the Declaration of Helsinki.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
HNSCC |
head and neck squamous cell carcinoma |
|
HR |
hazard ratio |
|
LAT1 |
L-type amino acid transporter 1 |
|
OS |
overall survival |
|
PFS |
progression-free survival |
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