miR-199a-5p/GPR89A axis modulates sorafenib resistance in hepatocellular carcinoma through glutamate metabolic reprogramming

Abstract

Objective

Sorafenib is a key targeted therapeutic agent for hepatocellular carcinoma (HCC). However, the emergence of drug resistance greatly limits its clinical efficacy. We found that GPR89A is markedly overexpressed in both sorafenib-resistant HCC cell lines and clinical tumor specimens. Nevertheless, the exact biological role of GPR89A in sorafenib-resistant HCC remains to be elucidated.

Methods

To generate sorafenib-resistant HCC cell lines, cells were cultured in medium with 10 μM sorafenib. GPR89A expression in these cells was examined by quantitative reverse transcription–polymerase chain reaction and Western blot. The impact of GPR89A inhibition on cell proliferation was assessed using cell counting kit-8 and colony formation assays. Bioinformatics predicted miR-199a-5p binding sites in the GPR89A promoter region; luciferase reporter assays were conducted with wild-type or mutant promoter sequences. Glutamate in culture supernatants was measured by enzyme-linked immunosorbent assay, and exogenous glutamate showed dose-dependent inhibition of resistant cell proliferation (MTT assay). Clinical correlation analysis involved 30 pairs of advanced HCC samples. Pearson analysis revealed significant inverse correlations among miR-199a-5p, GPR89A, and metabotropic glutamate receptor 1 (mGluR1) expression.

Results

We found that the cell surface transmembrane protein GPR89A was substantially overexpressed in both sorafenib-resistant HCC cell lines and clinical tumor specimens. Importantly, higher GPR89A expression levels were positively correlated with an increased degree of sorafenib resistance in clinical samples. In sorafenib-resistant HCC tissues, the expression of both GPR89A and mGluR1 was significantly upregulated, whereas miR-199a-5p levels were markedly reduced. Correlation analysis revealed a negative association between GPR89A and miR-199a-5p expression, and a positive association between GPR89A and mGluR1. Mechanistically, miR-199a-5p directly targets GPR89A mRNA to suppress its expression, thereby downregulating mGluR1 and reducing glutamate levels.

Conclusions

These findings uncover a novel regulatory axis linking GPR89A overexpression, glutamate metabolic reprogramming, and the development of acquired sorafenib-resistant HCC.

Introduction

Hepatocellular carcinoma (HCC) is the most common histological subtype of primary liver cancer and represents a highly aggressive malignancy characterized by multifactorial pathogenesis. ¹ The incidence and mortality rates of HCC have shown consistent annual increases, with this malignancy currently ranked as the fourth leading cause of cancer-related deaths globally. ² In its early stages, HCC typically manifests with nonspecific symptoms, leading to a majority of patients being diagnosed only at an advanced stage.^3,4 This delay deprives these patients of the opportunity for potentially curative treatments, including radical hepatectomy, tumor ablation, or liver transplantation.^5–7

The identification of effective systemic treatment strategies remains a critical objective in HCC. ⁸ Targeted cancer therapies have achieved transformative breakthroughs over the past decade, establishing their position as the vanguard of precision medicine development.^9,10 Sorafenib is an oral targeted therapeutic agent and the first approved treatment for advanced HCC.^11–13 As a small molecule multi-kinase inhibitor, it suppresses tumor progression by inhibiting the activity of receptor tyrosine kinases.^14,15 Two pivotal Phase III multicenter, double-blind, and randomized controlled trials—the SHARP and ORIENTAL clinical trials demonstrated sorafenib's capacity to significantly prolong median overall survival in advanced HCC patients.^16,17 These landmark findings led to sorafenib approval for the systemic management of advanced HCC. Notably, emerging clinical evidence reveals critical limitations in the efficacy of sorafenib. A substantial proportion of HCC patients develop acquired resistance following prolonged treatment, frequently culminating in tumor progression through recurrence or metastasis.^18–20 Particularly, patients exhibit intrinsic resistance patterns detectable during initial therapeutic phases. ²¹ Some research has been invested in elucidating mechanisms of sorafenib resistance and exploring combination therapies with other targeted or chemotherapeutic agents.^22–24 This clinical challenge needs to characterize the molecular pathways driving sorafenib resistance and develop therapeutic strategies to reverse these resistance mechanisms.

Glutamate receptor-mediated signaling pathways demonstrate significant associations with tumorigenic progression and acquired resistance to molecularly targeted therapies. ²⁵ Glutamate receptors are classified into two main types: metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs).^26,27 mGluRs orchestrate glutamate metabolic cycles through ligand binding. mGluRs are highly expressed in neural tissues, and their roles in gliomas, neuroblastomas, and medulloblastomas have been extensively studied. Glioma cells secrete elevated levels of glutamate to promote their own proliferation, whereas glutamate antagonists have been shown to inhibit tumor growth.^28–30 mGluR expression extends beyond neural tissues and is detectably expressed in diverse cell types, including hepatocytes, melanocytes, keratinocytes, cardiomyocytes, pancreatic cells, and embryonic stem cells.^31,32 Recent studies highlight that mGluR is involved in non-neurogenic cancers, including colon cancer, melanoma, lung cancer, thyroid cancer, breast cancer, and prostate cancer.^33–37 Different mGluR subtypes play diverse roles in tumor biology. Previous studies have identified mGluR8 as a key mediator of chemotherapy resistance in gliomas, ³⁸ while other research has linked elevated glutamate levels to endocrine therapy resistance in hormone receptor-positive breast cancer. ³⁹ These findings suggest that targeting glutamate-related metabolic pathways may provide new strategies for overcoming resistance to targeted therapies.

Notably, the role of glutamate metabolic reprogramming in sorafenib-resistant (SR) HCC remains unexplored. Our research investigating the mechanisms underlying sorafenib resistance in HCC has identified GPR89A as a critical resistance-related gene (data not shown). GPR89A, an orphan G protein-coupled receptor, has emerged as a critical regulator in metabolic homeostasis and disease pathogenesis. ⁴⁰ Limited reports exist in the field of tumor research. MicroRNA dysregulation is a hallmark of carcinogenesis, including miR-199a-5p downregulation in HCC, which has been previously reported. ⁴⁰ In this study, we found that miR-199a-5p expression was significantly reduced in SR HCC specimens. GPR89A was identified as a direct target of miR-199a-5p. This study aims to investigate the mechanism of GPR89A-mediated glutamate signaling in SR HCC cells, to identify potential targets for combination therapy strategies.

Materials and methods

Cell culture

The HCC cell lines Huh7 (RRID: CVCL_0336) and Hep3B (RRID: CVCL_0326) used in this study were purchased from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, located in Shanghai, China. Human embryonic kidney cell line 293T (RRID: CVCL_0063) was purchased from the American Type Culture Collection (Manassas, VA, USA).

Both cell lines were cultured in Dulbecco's modified Eagle medium (Gibco, NY, USA) supplemented with 10% fetal bovine serum (Gibco), 100 μg/mL streptomycin sulfate, and 100 IU/mL penicillin G (both from Sigma–Aldrich, St Louis, MO, USA). The cells were maintained at 37 °C in a humidified incubator with 5% CO₂.

Establish SR cell line

To generate SR cell lines, Huh7 and Hep3B cells were exposed to increasing concentrations of sorafenib (Selleck Chemicals, Houston, USA), with doses gradually escalated from 0.25 μM to 12 μM in two-week intervals over a period of 16 weeks. The resulting resistant sublines were then maintained in medium containing 10 μM sorafenib. These stably resistant subclones were designated as Huh7/SR and Hep3B/SR cells.

Plasmid transfection

This experiment was conducted as previously described.^41,42 Huh7/SR and Hep3B/SR SR HCC cell lines were transfected with a miR-199a-5p mimic, inhibitor, or negative control at a final concentration of 50 nM in six-well plates following standard procedures. All miRNA reagents were sourced from Ribobio (Guangzhou, China). GPR89A overexpression constructs were generated by cloning the cDNA into pWPXL lentiviral vectors using double-enzyme digestion, and the sequences were confirmed by restriction analysis and Sanger sequencing. For gene knockdown, shRNA fragments targeting GPR89A were ligated into pLVTHM vectors (pLVTHM-shGPR89A), with subsequent sequence verification. Lentiviral particles were produced by co-transfecting HEK293T cells with psPAX2 (packaging), pMD2.G (envelope), and either the pWPXL-GPR89A or pLVTHM-shGPR89A plasmids using Lipofectamine 3000 (Invitrogen). Viral supernatants were collected to infect the SR HCC cell lines, and stable polyclonal populations were established through puromycin selection.

Cell proliferation ability detection

Cells were incubated with 50 μM EdU for 6 h, followed by nuclear staining with 4′,6-diamidino-2-phenylindole (1 mg/mL) for 20 min. The proportion of proliferating cells was then assessed under a fluorescence microscope. For cell viability analysis, cell counting kit-8 (CCK-8) reagent (A311-01, Vazyme) or MTT was added to the cell cultures, which were then incubated at 37 °C for 2 h. Optical density was measured at 450 nm or 570 nm using a microplate reader at 24 h intervals. The mean absorbance values were calculated and plotted as time-course proliferation curves using GraphPad Prism software (version 9.0).

Quantitative reverse transcription–polymerase chain reaction (qRT–PCR) analysis

Total RNA was extracted with TRIzol reagent (Invitrogen, CA, USA) according to the manufacturer's protocol. cDNA was synthesized using Moloney Murine Leukemia Virus reverse transcriptase (Tiangen Biotech, Beijing, China). qRT–PCR was carried out on a StepOnePlus™ system (Applied Biosystems). Mature miRNA levels were measured using the TaqMan microRNA assay kit (Applied Biosystems), with U6 serving as the reference gene for normalization. All primers used in this study are listed in Supplemental Table 1.

Western blot analysis

Western blot analysis was performed as previously described.^41,42 Briefly, equal amounts of protein were separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes (Millipore). Membranes were blocked with 5% nonfat milk in Tris-buffered saline with 0.4% Tween-20 (TBS-T) for 2 h at room temperature, then incubated overnight at 4 °C with primary antibodies (1:1000 dilution). After three washes with TBS-T, membranes were incubated with horseradish peroxidase-conjugated secondary antibodies for 2 h at room temperature, followed by three additional 10 min washes in TBS-T. Protein bands were visualized using enhanced chemiluminescence substrate (Proteintech). The antibodies used for immunoblotting included those against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (ab181602, Abcam), metabotropic glutamate receptor 1 (mGluR1) (861702, Biolegend), and GPR89A (PA5-118817, Invitrogen). GAPDH was used as the endogenous control for normalization.

Enzyme-linked immunosorbent assay (ELISA)

Serum glutamate concentrations were measured in HCC patients (n = 15 paired samples) with either SR or sorafenib-sensitive phenotypes using an ELISA. Samples were processed following the manufacturer's instructions (Proteintech, China), and absorbance was measured at 450 nm with a microplate reader.

Dual-luciferase reporter assay

Dual-luciferase reporter gene constructs containing either wild-type or mutant GPR89A 3′-untranslated region (3′-UTR) sequences were generated using the psiCHECK2 vector (C8021, Promega). These plasmids were co-transfected with miR-199a-5p mimics into Huh7/SR and Hep3B/SR cells using Lipofectamine 3000 (Thermo Fisher Scientific), following the manufacturer's instructions. Luciferase activity was measured using the Dual-Luciferase Reporter Assay System (Promega), with firefly luciferase activity normalized to Renilla luciferase activity for data analysis.

Clinical sample analysis

Patients with advanced HCC commonly acquire resistance to sorafenib treatment within about six months. We conducted our study in accordance with the Helsinki Declaration of 1975 as revised in 2024. Between January 2016 and December 2022, paired SR and sorafenib-sensitive tumor tissues were obtained via ultrasound-guided biopsy from 60 HCC patients, all of whom provided written informed consent in compliance with institutional ethical guidelines. The inclusion criteria were as follows: availability of complete clinical case data, no history of therapy, and pathological confirmation by a certified pathologist. Clinical information of HCC patients included in this study is detailed in Supplemental Table 2. Immediately after collection, all tissues were snap-frozen in liquid nitrogen to preserve RNA integrity and stored at −80 °C until further processing. For subsequent molecular analysis, total RNA was extracted from each specimen using TRIzol^® reagent (Invitrogen) following the manufacturer's recommended protocol to ensure consistency and minimize sample degradation. The extracted RNA was subjected to rigorous quality control using two complementary techniques. First, 1.0% agarose gel electrophoresis was performed to verify RNA integrity, as indicated by a clear 28S and 18S ribosomal RNA band with a ratio >1.8. Second, ultraviolet spectrophotometric analysis was conducted using a NanoDrop 2000 instrument (Thermo Scientific), with RNA purity assessed by measuring the absorbance ratio at 260/280 nm; samples displaying an A260/A280 ratio between 1.8 and 2.1 were considered suitable for the following experiments.

Statistical analysis

All quantitative data are presented as the mean ± standard deviation, with values derived from four independent biological replicates to ensure reproducibility and reliability of the results. Statistical comparisons between treatment groups and control groups were performed using Student's t-test, allowing assessment of significant differences in experimental outcomes. For correlation analyses among GPR89A expression, miR-199a-5p levels, and glutamate concentrations, Pearson's correlation coefficient was applied to data sets exhibiting normal distribution, while Spearman's rank correlation was used for non-parametric data that did not meet normality assumptions. This dual approach ensured appropriate statistical analyses according to data distribution characteristics. All statistical analyses were conducted using standard software (such as GraphPad Prism version 9.0 or SPSS), and a two-tailed P value of <0.05 was considered indicative of statistical significance.

Results

GPR89A is involved in sorafenib resistance in HCC

To explore the potential role of GPR89A in mediating mechanisms of sorafenib resistance in HCC, we first quantified the relative mRNA expression levels in SR cells. Subsequent results revealed that SR HCC cells exhibited a significant upregulation of GPR89A expression compared to their respective control groups. qRT–PCR analysis showed a 4.2-fold increase in GPR89A mRNA expression (p < 0.01) (Figure 1A and B). Our results indicate that sorafenib exerts a dose-dependent modulatory effect on GPR89A expression, with corresponding changes observed at both the mRNA and protein levels (Figure 1C and D). We then performed knockdown of GPR89A in SR Huh7 and Hep3B cell lines (Figure 1E and F). In vitro functional assays, including CCK-8 assays (Figure 1G), colony formation assays (Figure 1H), and EdU cell proliferation assays (Figure 1I), demonstrated that specific knockdown of GPR89A significantly inhibited the proliferative capacity of the SR HCC cell lines. Collectively, these findings suggest that targeted knockdown of GPR89A may serve as a promising therapeutic strategy for reversing sorafenib resistance in HCC.

Figure 1.

GPR89A expression was elevated in SR cells, as determined by (A) qRT–PCR and (B) western blot analysis. (C) qRT–PCR and (D) western blot results showed that GPR89A expression increased in a dose-dependent manner with sorafenib treatment. The efficiency of GPR89A knockdown in resistant cells was confirmed by (E) qRT–PCR and (F) western blot. Knockdown of GPR89A in resistant cells suppressed cell proliferation, as demonstrated by (G) CCK-8 assays, (H) colony formation assays, and (I) EdU cell proliferation assays. All experiments were conducted in triplicate. *P < 0.05, **P < 0.01, ***P < 0.001; paired t-test.

GPR89A is directly regulated by miR-199a-5p in SR HCC cells

To further investigate the regulatory mechanism of GPR89A in SR HCC cell lines. TargetScan analysis (https://www.targetscan.org/vert_72/) predicted that miR-199a-5p could directly bind to the 3′-UTR region of the GPR89A. Mutations in the UTR region abolished this direct interaction (Figure 2A). Then, we performed a dual-luciferase reporter assay to investigate the activity of the GPR89A promoter in SR HCC cells (Figure 2B). Overexpression of miR-199a-5p via mimics significantly suppressed GPR89A mRNA expression, whereas inhibition of miR-199a-5p restored GPR89A expression levels (Figures 2C and D). These results demonstrate that miR-199a-5p directly interacts with the promoter region of GPR89A, thereby modulating its expression.

Figure 2.

miR-199a-5p directly regulates GPR89A in sorafenib-resistant HCC cells. (A) TargetScan database predicted that miR-199a-5p can bind to the promoter region of GPR89A. (B) Luciferase reporter assay was performed to assess the interaction between miR-199a-5p and the GPR89A promoter in sorafenib-resistant cells. (C) qRT–PCR analysis demonstrated that miR-199a-5p inhibited the expression of GPR89A. All experiments were conducted in triplicate. *P < 0.05, **P < 0.01, ***P < 0.001; unpaired t-test.

miR-199a-5p/GPR89A axis modulates mGluR1 expression in SR HCC cells

Previous data indicated that GPR89A acts as a regulator of metabolic homeostasis. Therefore, we assessed the mRNA expression levels of mGluR1–8 in SR HCC cells. The results revealed a significant association between mGluR1 expression and the two SR HCC cell lines (Figure 3A). Compared to the control groups, both miR-199a-5p mimics and GPR89A knockdown significantly suppressed mGluR1 mRNA expression, whereas inhibition of miR-199a-5p restored mGluR1 expression (Figures 3B and C). Colony formation assays further demonstrated that miR-199a-5p mimics and GPR89A knockdown reduced clonogenic capacity, and this anti-proliferative effect was similarly reversed by miR-199a-5p inhibition (Figure 3D). These findings indicate that GPR89A modulates mGluR1 expression, thereby contributing to sorafenib resistance in HCC. The underlying mechanism requires further investigation.

Figure 3.

Increased mGluR1 expression is associated with sorafenib resistance in HCC cells. (A) mRNA levels of mGluR1-8 in Huh7/SR and Hep3B/SR cells. (B, C) The miR-199a-5p/GPR89A pathway regulates mGluR1 mRNA and protein expression in sorafenib-resistant HCC cells. (D) Modulation of mGluR1 expression via the miR-199a-5p/GPR89A pathway reduces proliferation of sorafenib-resistant HCC cells. All experiments were conducted in triplicate. **P < 0.01, ***P < 0.001; paired t-test.

miR-199a-5p/GPR89A axis regulates glutamate expression in SR HCC cells

To further investigate the molecular mechanisms of GPR89A in SR HCC cells, we found that miR-199a-5p mimics and GPR89A knockdown suppressed intracellular glutamate levels in SR HCC cells. This effect could be reversed by inhibiting miR-199a-5p expression (Figure 4A), suggesting that glutamate is involved in sorafenib resistance and is regulated by the miR-199a-5p/GPR89A axis. Glutamate promoted tumor cell proliferation in SR HCC cells, while its restored proliferative capacity following GPR89A knockdown (Figure 4B). Colony formation assays confirmed glutamate in promoting SR cell proliferation (Figure 4C). Clinically, serum glutamate levels were significantly higher in SR HCC patients (n = 15) compared to the control group (Figure 4D). These findings indicate that GPR89A regulates intracellular glutamate levels to promote sorafenib resistance in HCC.

Figure 4.

Glutamate levels are regulated by the miR-199a-5p/GPR89A pathway. (A) Glutamate concentrations in sorafenib-resistant HCC cells were measured by ELISA. The effects of glutamate on the proliferation and clonogenicity of sorafenib-resistant cells were evaluated by (B) MTT assays and (C) colony formation assays. (D) Serum glutamate levels were significantly higher in sorafenib-resistant HCC patients, as determined by ELISA (n = 15). All experiments were conducted in triplicate. **P < 0.01, ***P < 0.001; unpaired t-test.

Differential expression of GPR89A, miR-199a-5p, and mGluR1 in SR HCC patients and analysis of their clinical significance

Based on the above findings, we investigated the correlation among GPR89A, miR-199a-5p, and mGluR1. Analysis of 30 paired SR HCC specimens revealed elevated expression levels of GPR89A and mGluR1, while miR-199a-5p levels were reduced in the SR HCC samples (Figure 5A to C). We found a negative correlation between GPR89A and miR-199a-5p (Figure 5D), and a positive correlation between GPR89A and mGluR1 (Figure 5E). These data suggest that the miR-199a-5p/GPR89A axis promotes metabolic reprogramming involved in sorafenib resistance in HCC.

Figure 5.

miR-199a-5p expression is negatively correlated with GPR89A and mGluR1 levels in sorafenib-resistant HCC patients. (A) mRNA levels of GPR89A, (B) miR-199a-5p, and (C) mGluR1 in 30 pairs of sorafenib-resistant and sorafenib-sensitive HCC samples. (D, E) Correlations among GPR89A, miR-199a-5p, and mGluR1 mRNA expression were analyzed in sorafenib-resistant HCC samples (n = 30). Pearson's correlation coefficient (r) and statistical significance are indicated. All experiments were performed in triplicate. **P < 0.01, ***P < 0.001; unpaired t-test.

Discussion

HCC is a leading cause of cancer-related deaths worldwide. MicroRNAs serve as crucial genetic regulators involved in numerous cellular functions, including those related to HCC. ⁴³ MiR-199a-5p is a multifunctional small non-coding RNA governing posttranscriptional gene regulation and has been established as a pivotal molecular regulator in tumor pathogenesis and malignant evolution. Its role exhibits tumor-suppressive effects in tumors. ⁴⁴ miR-199a-5p directly targets oncogenic signaling pathways, which are critical for sorafenib resistance in HCC.^45,46 In our study, analysis of 30 paired SR and sorafenib-sensitive HCC samples revealed decreased miR-199a-5p expression in SR HCC. Notably, miR-199a-5p exhibits tumor-suppressive effects in SR HCC. However, the role of miR-199a-5p in suppressing tumors in SR HCC animal models and its potential to enhance the anti-tumor effect of sorafenib require further investigation. We then used the TargetScan website to predict that miR-199a-5p could directly bind to the UTR region of the GPR89A gene. Furthermore, we confirmed that miR-199a-5p suppresses GPR89A expression by directly binding to its promoter region.

The GPR89A protein is localized to both the Golgi cisternae and Golgi-associated vesicular membranes, where it functions as a voltage-gated anion channel mediator. Previous studies have reported that knockout of GPR89A in cisplatin-resistant lung cancer cells promotes cell cycle arrest in the G2/M phase, increases polyploidy, and inhibits colony formation and cell migration. ⁴⁰ This study was the first to identify GPR89A as a potential therapeutic target for overcoming cisplatin resistance in non-small cell lung cancer Calu1 cells. ⁴⁰ Whether GPR89A plays a role in platinum-based chemotherapy resistance in HCC needs further investigation in the future.

Metabolic reprogramming has become a defining characteristic of cancer biology, representing a fundamental shift in our understanding of oncogenesis and tumor progression. Tumor cells orchestrate a complex metabolic rewiring characterized by enhanced glucose uptake through aerobic glycolysis (the Warburg effect), glutaminolysis-driven nitrogen metabolism, and accelerated lipid biosynthesis to meet their bioenergetic and biosynthetic demands. ⁴⁷ This metabolic plasticity supports not only rapid proliferation but also contributes to immune evasion and therapeutic resistance. Glutamate, as a crucial carbon source for the tricarboxylic acid cycle, is integral to metabolic pathways that impact tumor progression. ⁴⁸ Various factors can modulate the expression of glutamate receptors, which may function in either promoting or suppressing tumor development. ⁴⁹ Additionally, glutamate and its receptors participate in the regulation of diverse immune cell activities, as evidenced by the expression of these receptors on immune cells. ⁵⁰ Stimulation of glutamate receptors can boost T cell activity or diminish cytokine production in immunosuppressive myeloid-derived suppressor cells, ultimately enhancing the anti-tumor immune response. ⁵¹ Other studies have demonstrated that human lung cancer cells in the brain microenvironment develop a significant dependence on mGluR1 signaling. ⁵² In these cells, mGluR1 can directly interact with and stabilize the epidermal growth factor receptor in a glutamate-dependent fashion, rendering the cancer cells sensitive to mGluR1 inhibition. These results suggest that enhanced mGluR1 signaling serves as an adaptive mechanism and exposes a potential therapeutic vulnerability in brain metastases of human lung cancer. ⁵³ This is consistent with our research findings. In this study, we measured the mRNA expression levels of mGluR1–8 in SR HCC cells. Our results revealed a significant association between mGluR1 expression and the two SR HCC cell lines.

In summary, miR-199a-5p directly targets GPR89A mRNA to inhibit its expression, thereby downregulating mGluR1 and reducing glutamate levels, ultimately reversing sorafenib resistance. While the endogenous ligand of GPR89A remains unidentified, its constitutive activity requires further characterization. Our data indicate that further mechanistic and in vivo studies are needed to validate the therapeutic relevance of GPR89A in HCC.

Conclusion

In conclusion, GPR89A has been shown to promote sorafenib resistance in HCC by facilitating the reprogramming of mGluR1 and glutamate metabolism. Suppression of GPR89A expression can effectively reverse sorafenib resistance in HCC. These findings reveal a novel regulatory axis involving GPR89A overexpression in SR HCC.

Supplemental Material

sj-doc-1-sci-10.1177_00368504251381592 - Supplemental material for miR-199a-5p/GPR89A axis modulates sorafenib resistance in hepatocellular carcinoma through glutamate metabolic reprogramming

Supplemental material, sj-doc-1-sci-10.1177_00368504251381592 for miR-199a-5p/GPR89A axis modulates sorafenib resistance in hepatocellular carcinoma through glutamate metabolic reprogramming by Yao Li, Yi Cai, Guangliang Duan, Yulin Du, Junjie Hu, Xue Han, Xiaolong Tang, Liangxian Jiang, Junqi Ren and Qi Huo in Science Progress