Peroxisome proliferator activated receptors (PPARs) are a nuclear hormone receptors superfamily that is closely related to fatty acid (FA) metabolism and tumor progression. Solute carrier family 27 member 2 (SLC27A2) is important for FA transportation and metabolism and is related to cancer progression. This study aims to explore the mechanisms of how PPARs and SLC27A2 regulate FA metabolism in colorectal cancer (CRC) and find new strategies for CRC treatment.
Methods
Biological information analysis was applied to detect the expression and the correlation of PPARs and SLC27A2 in CRC. The protein–protein interaction (PPI) interaction networks were explored by using the STRING database. Uptake experiments and immunofluorescence staining were used to analyse the function and number of peroxisomes and colocalization of FA with peroxisomes, respectively. Western blotting and qRT‒PCR were performed to explore the mechanisms.
Results
SLC27A2 was overexpressed in CRC. PPARs had different expression levels, and PPARG was significantly highly expressed in CRC. SLC27A2 was correlated with PPARs in CRC. Both SLC27A2 and PPARs were closely related to fatty acid oxidation (FAO)‒related genes. SLC27A2 affected the activity of ATP Binding Cassette Subfamily D Member 3 (ABCD3), also named PMP70, the most abundant peroxisomal membrane protein. We found that the ratios of p-Erk/Erk and p-GSK3β/GSK3β were elevated through nongenic crosstalk regulation of the PPARs pathway.
Conclusions
SLC27A2 mediates FA uptake and beta-oxidation through nongenic crosstalk regulation of the PPARs pathway in CRC. Targeting SLC27A2/FATP2 or PPARs may provide new insights for antitumour strategies.
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Abkürzungen
PPARs
Peroxisome proliferator activated receptors
NHRs
Nuclear hormone receptors
FA
Fatty acid
SLC27A2
Solute carrier family 27 member 2
CRC
Colorectal cancer
PPI
Protein–protein interaction
FAO
Fatty acid oxidation
ABCD3
ATP Binding Cassette Subfamily D Member 3
TME
Tumor microenvironment
FAT
Fatty acid translocase
FABPs
Fatty acid binding proteins
FATPs
Fatty acid transport proteins
ISCs
Intestinal stem cells
HFD
High-fat diet
RXR
Retinoid X receptor
PPREs
Peroxisome proliferator response elements
FBS
Fetal bovine serum
PA
Palmitic acid
ORO
Oil-Red-O
RT
Room temperature
TBST
Tris Buffered Saline with Tween-20
qRT‒PCR
Quantitative reverse transcriptase-PCR
TCGA
The Cancer Genome Atlas
GTEx
Genotype-Tissue Expression
GEPIA
Gene Expression Profiling Interactive Analysis
FATP2
Fatty acid transport protein 2
MDSCs
Myeloid-derived suppressor cells
ICIs
Immune checkpoint inhibitors
dMMR
Mismatch-repair-deficient
MSI-H
Microsatellite instability-high
PD-L1
Programmed cell death ligand 1
scRNA-seq
Single-cell RNA sequencing
RNA-seq
RNA sequencing
NAFLD
Non-alcoholic fatty liver disease
T2DM
Type 2 diabetes mellitus
ROS
Reactive oxygen species
SLC39A1
Solute carrier family 39 member 1
RCC
Renal cell carcinoma
NC
Negative control
OE
Over expression
Background
Colorectal cancer (CRC), ranking as the third most frequent cancer and second leading cause of cancer‒related deaths, is a major challenge in healthcare worldwide [1]. Most patients are diagnosed with advanced or metastatic disease [2]. The proportion of patients younger than 50 years is rising, owing to hereditary or environmental risk factors [3]. Precise management of CRC, involving single or combined reagents, is needed [4]. Metabolic reprogramming of tumor and the tumor microenvironment (TME), including cells, cytokines, nutrients or metabolites, supports proliferation, migration, immune escape or resistance in cancers [5, 6].
Lipid metabolic hallmarks play a pivotal role in CRC. Fatty acids (FAs) as the essential molecules of lipid can maintain membrane homeostasis, and regulate cell signalling and energy metabolism [7]. FA can be taken up from the TME or de novo synthesized in cells. FA uptake occurs through transmembrane proteins, including fatty acid translocase (FAT, CD36), fatty acid binding proteins (FABPs) and fatty acid transport proteins (FATPs, SLC27s) [8]. The intracellular FA pool is the source of cell structural molecules and metabolism. Fatty acid beta-oxidation (FAO) is an important metabolic process in mitochondria or peroxisome [9]. For tumor progression, cancer cells reprogram to FAO to produce ATP more efficiently. Medium-chain FAs are mainly catabolized in mitochondria and long-chain or very long-chain FAs are primarily catabolized in peroxisome [10].
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Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors (NHR) and are ligand-dependent transcriptional regulators. Recent researches have revealed that PPAR agonists or antagonists can regulate cell metabolism, including the FAO process, exhibiting anticancer effects [11]. Recently, studies about single-cell genomic and transcriptomic landscapes of metastatic colorectal cancer (mCRC) patients and patient-derived tumor organoids have revealed that the PPAR signaling pathway was aberrantly activated in mCRC. PPAR inhibitors can suppress the proliferation and promote the apoptosis of CRC organoids, indicating it’s critical role in mCRC tumorigenesis [12]. The PPAR pathway can regulate FAO to induce tumorigenesis in intestinal stem cells (ISCs) in high-fat diet (HFD) feeding mouse models [13, 14]. Ligand-activated PPARs heterodimerize with retinoid X receptor (RXR) and bind to specific DNA response elements (PPREs), regulating lipids homeostasis and metabolism [15]. In previous studies, solute carrier family 27 member 2 (SLC27A2) was reported to regulate cancer proliferation, metastasis, inflammation and immunosuppression [16, 17]. We investigated the expression of SLC27A2 and PPARs aiming to find new metabolic therapies for CRC.
Materials and methods
Cell culture and transient transfection
The human colorectal cancer cell lines, HCT-15 and SW480 were purchased from ATCC and passed short tandem repeat (STR) detection. The cells were cultured in RPMI 1640 medium (CORNIN, USA) containing 10% fetal bovine serum (FBS, Gibco, USA), at 37 °C and 5% CO2. For further study, we cultured cells with palmitic acid (PA, 100 uM, Sigma, dissolved in DMSO, NaOH, BSA) and generated the fatty cells, in which lipid droplet accumulated in the cytosol and Oil-Red-O (ORO) staining were observed [18]. Transient transfections were conducted by MegaTran 2.0 or siTran 2.0 to overexpress or knock down SLC27A2 expression, according to the manufacturer’s protocol, respectively. And qRT‒PCR was used to test the efficacy. In our previous study we used two siRNAs to knock down SLC27A2 and the efficacy was tested by qRT‒PCR and western blotting. The sequence of siRNA-SLC27A2-3 in this study was 5'-CGACAGAGUUGGAGAUACATT- 3'.
Western blot
Whole proteins were extracted by cell lysis buffer (Beyotime, P0013B, Shang hai) and quantified by a BCA protein assay kit (Thermo Fisher, 23,227, USA). Proteins were separated by a 10% SDS‒PAGE gel and transferred to a PVDF membrane. Then, the PVDF membrane was blocked with 5% nonfat milk for 2 h at room temperature (RT), and incubated with primary antibodies overnight (4 °C) and secondary HRP-conjugated antibodies for 2 h (RT), respectively. The PVDF membrane was washed with Tris buffered Saline with Tween-20 (TBST) buffer after every step. The blots were cut prior to hybridisation with antibodies. Western Blot Stripping Buffer (Bioss, C05-03,041) was used for breaking antibody-antigen interactions to detect multiple target protein by using different antibodies. The molecular weights of target proteins are very similar and we cropped the blots closely. The original gels and multiple exposure images was shown in Supplementary Fig. 1. Blots were detected by an enhanced chemiluminescence system (Bio-Rad, USA). The relative gray value was measured by Image J. We performed three independent repetitions of the experiments for each dataset. The specific primary antibodies as follows: anti-β-actin (42KD, 1:5000, 20,536–1-AP, Proteintech), anti-SLC27A2 (70KD, 1:2000, 14,048–1-AP, Proteintech), anti-PPARG (50KD, 1:2000, 16,643–1-AP, Proteintech), anti-Erk1/2 (42/44KD, 1:1000, 11,257–1-AP, Proteintech), anti-p-Erk1/2 (42/44KD, 1:2000, 28,733–1-AP, Proteintech), anti-GSK3β(47KD, 1:500, ET1607-71, HUABIO), and anti-p-GSK3β (47KD, 1:500, ET1607-60, HUABIO).
RNA extraction and quantitative reverse transcriptase-PCR (qRT‒PCR)
Total RNA was extracted by using TRIzol Reagent (Invitrogen, 15,596–018, USA). All steps were performed according to the manufacturer’s instructions. RNA concentrations were quantified with a Nanodrop 2000 system (Thermo Fisher Scientific, USA), and cDNAs were obtained with a reverse transcriptase kit (TaKaRa, Japan). qRT‒PCR was performed by SYBR Premix ExTaqTM II (Takara, Japan). The mRNA levels were normalized to β-actin and 2−ΔΔCt was calculated for analysis. The mRNA expression average three different experiments. The primers used in qRT‒PCR are listed in Table S1.
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Immunofluorescence staining and FA uptake
HCT-15 and SW480 cells were digested, collected and counted after transfection for 24 h. A total of 2 ~ 2.5 × 105 cells were seeded in 6-well culture plates per well, in which a slide had been placed. After attaching, the cells were cocultured with fluorescent BODIPYTM FL C16 fatty acid (24 h, 10 μM, Invitrogen, D3821, USA), which is a fluorescence labelled palmitic acid (PA). Slides with cells were collected, washed gently with PBS, fixed in 4% PFA for 15 min, incubated in 0.25% Triton X-100 for 10 min to rupture the cell membranes, and blocked for 1 h by using PBST (1% BSA). The cells were incubated in anti-PMP70 (1: 500, Abcam, ab3421) primary antibody (overnight, 4 °C). Next, the slides were washed with PBS and incubated with fluorescent secondary antibody (Alexa Fluor 568 goat anti-rabbit IgG, 1:100, Life Technologies, Waltham, MA USA) in the dark (1 h, RT). Finally, the slides were washed and stained with DAPI (sc-24941, Santa Cruz Biotechnology, Dallas, TX, USA) and imaged by using a confocal microscope (Olympus, IX83, FLUOVIEW FV1200, Tokyo, Japan). The relative fluorescence intensity was measured by Image J. We performed three independent repetitions of the experiments.
Biological information analysis
Extensive RNA sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were collected in the Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/) [19]. In our study, we explored the expression of SLC27A2 and PPARs in CRC through the GEPIA database (http://gepia2.cancer-pku.cn/#analysis) by ‘GEPIA2 Expression DIY on Box Plot’ mode. We explored the correlation of ‘SLC27A2 with PPARs’ and ‘SLC27A2 with FAO‒related genes’ in CRC through the GEPIA database by the ‘GEPIA2 Correlation Analysis’ mode. The protein–protein interaction (PPI) networks were analyzed on the STRING database Version 11.5 (https://cn.string-db.org/) [20]. The PPI networks of SLC27A2/PPARG in CRC were visualized by using the following steps: ‘STRING Protein by name’, ‘Organisms Homo sapiens’, and ‘Viewers by Network’. The graphic abstract was generated by the FigDraw database (https://www.figdraw.com/static/index.html#/, accession numbers: 788566346027118592; Figure ID:UWYWTc1d3c).
Statistical analysis
GraphPad Prism 5.0 software was used for statistical analysis. Data were expressed as the mean ± SEM. The differences between two groups were analyzed by Student’s t test, and three groups or more were analyzed by one-way ANOVA. P < 0.05 was considered statistically significant. *P < 0.05; **P < 0.01; ***P < 0.001.
Results
SLC27A2 was related to PPARs in colorectal cancer
SLC27A2 is a protein–coding gene, and the encoded protein FATP2 acts as a transporter to take up FAs or an isozyme to convert long-chain fatty acids into fatty acyl-CoA [21]. Studies have shown that SLC27A2 is elevated in cancers and promotes cancer progression [16]. We explored the GEPIA database and found that SLC27A2 was overexpressed in CRC compared to para-normal tissues (Fig. 1A). Our previous experiments elucidated that overexpression or knockdown of SLC27A2 could promote or suppress CRC cells proliferation, cell cycle or migration. PPARs were also expressed differently in CRC, and PPARG was highly expressed with statistical significance (Fig. 1B). PPARs are pivotal factors in regulating lipid metabolism. We performed correlation analysis between SLC27A2 and PPARs and the protein–protein interaction (PPI) networks showed that SLC27A2 was related to PPARs in CRC (Fig. 1C). The original data was provided in Supplementary Fig. 2.
Fig. 1
SLC27A2 was related to PPARs in colorectal cancer. A SLC27A2 was overexpressed in CRC from (GEPIA) database. B PPARs had different expressions in colorectal cancer, and PPARG was significantly highly expressed in CRC from (GEPIA) database. C SLC27A2 had a relationship with PPARs in CRC from GEPIA database. *P < 0.05; **P < 0.01; ***P < 0.001. T: tumor; N: normal; COAD: colon adenocarcinoma; READ: rectum adenocarcinoma; SLC27A2: Solute carrier family 27 member 2; PPARA: Peroxisome proliferator activated receptor A; PPARD: Peroxisome proliferator activated receptor D; PPARG: Peroxisome proliferator activated receptor G
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SLC27A2 was associated with the PPARs pathway
We explored the protein–protein interaction (PPI) networks between proteins on the STRING database (https://cn.string-db.org/). The results showed that SLC27A2 was correlated with FAO metabolic genes, whether in mitochondria or peroxisome (Fig. 2A). PPARG is a nuclear hormone receptor (NHR), that is mainly located in the nucleus, cytosol, or peroxisome. Additionally, PPARG is involved in energy metabolism. As a ligand–inducible transcriptional regulator, PPARG can be activated by FA. We investigated the proteins correlated with PPARG in the STRING database and found that it had a relationship with other NHRs (Fig. 2B). Through gene correlation analysis in the GEPIA database (http://gepia.cancer-pku.cn/), we revealed that the expression level of SLC27A2 was significantly correlated with FAO metabolic genes (Fig. 2C).
Fig. 2
SLC27A2 was associated with the PPARs pathway. A SLC27A2 correlated with genes encoding proteins associated with FAO metabolism on the STRING database. B The correlated proteins with PPARG in CRC from the STRING database. C SLC27A2 had a close relationship with FAO metabolic genes in CRC, both in mitochondria and peroxisomes on the STRING database
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SLC27A2 was associated with FAO metabolic genes in colorectal cancer
To investigate the influence of SLC27A2 on FAO–related gene expression, we overexpressed SLC27A2 by plasmids, and the efficiency was tested by qRT–PCR (Fig. 3A ~ B). We extracted RNA from HCT-15 and SW480 cells transfected with plasmids and demonstrated that the mRNA levels of FAO–related genes were increased (Fig. 3C ~ D). Similarly, we knocked down SLC27A2 by siRNAs (Fig. 3E ~ F) and the mRNA levels of FAO–related genes concomitantly decreased (Fig. 3G ~ H).
Fig. 3
SLC27A2 was associated with FAO metabolic genes in colorectal cancer. A ~ B SLC27A2 was overexpressed in HCT-15 and SW480 by plasmids and tested by qRT‒PCR. C ~ D The expression of FAO related genes were measured when SLC27A2 was overexpressed in CRC and the mRNA expression of CPT1A, SLC35G1, ACOX1, EHHADH, ABCD3, HADHA, HADHB, ETFA, and EPHX2 elevated in HCT-15 and SW480. E ~ F SLC27A2 was knocked down in HCT-15 and SW480 by siRNAs and verified using qRT‒PCR. G ~ H The mRNA expression levels of FAO–related genes were measured when SLC27A2 was knocked down in CRC and the mRNA expression of SLC25A20, ACOX1, ABCG2, ABCD3, HADHA, HADHB, HADH, and ETFA decreased in HCT-15 and SW480. NC: negative control; OE: over expression
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SLC27A2 regulated the function and number of peroxisomes in colorectal cancer
ABCD3 (ATP Binding Cassette Subfamily D Member 3), also named PMP70, belongs to the superfamily of ATP-binding cassette (ABC) transporters. Peroxisomal ABC transporters are involved in lipid metabolism and the PPARs pathway, particularly in FAO metabolism [22]. The expression level of ABCD3 increased or decreased upon SLC27A2 overexpression or knockdown, respectively (Fig. 3). We conducted coculture experiments and found that FA uptake levels were elevated when SLC27A2 was overexpressed. The PMP70 level, which represents the number and function of peroxisomes [23], increased in the overexpression group. Interestingly, fluorescence–labelled FAs colocalized with PMP70 (Fig. 4A ~ B). Similar results were observed when SLC27A2 was knocked down (Fig. 4C ~ D).
Fig. 4
SLC27A2 regulated the function and number of peroxisomes in colorectal cancer. A ~ B The function and number of peroxisomes were enhanced, and the uptake levels of fluorescent FA (BODIPY FL C16, PA, 10 μM) were elevated and the colocalization of FA with peroxisomes were enhanced when SLC27A2 was overexpressed in CRC. C ~ D The function and number of peroxisomes, uptake level of fluorescent FA, and colocalization diminished when SLC27A2 was knocked down in CRC. NC: negative control; OE: over expression; PMP70: belonged to the superfamily of ATP-binding cassette (ABC) transporters, also named ABCD3 (ATP Binding Cassette Subfamily D Member 3)
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SLC27A2 reprogrammed colorectal cancer non-genic crosstalk regulation of PPARG
PPARG is a nuclear hormone receptor (NHR). Activated PPARG can regulate lipid homeostasis and metabolism [15]. We detected the the ratios of p-Erk/Erk and p-GSK3β/GSK3β when cells were transfected with plasmids or siRNAs to overexpress or knock down SLC27A2 (encoding FATP2), respectively. Additionally, the efficiencies were verified by western blotting. The results showed that the ratios of p-Erk/Erk and p-GSK3β/GSK3β were elevated when SLC27A2 was overexpressed (Fig. 5A ~ B). Conversely, the ratios were reduced when SLC27A2 was knocked down (Fig. 5C ~ D). Non-genic crosstalk regulation of PPARs through p-Erk/Erk and p-GSK3β/GSK3β influenced FA metabolic reprogramming in CRC (Fig. 5E, Graphic abstract).
Fig. 5
SLC27A2 reprogrammed colorectal cancer nongenic crosstalk regulation of PPARs. A The protein expression levels of SLC27A2, PPARG, p-GSK3β, GSK3β, p-Erk, and Erk when SLC27A2 was overexpressed. The grouping of blots cropped from diferent gels. The blots were cut prior to hybridisation with antibodies. The raw data with detail description and multiple exposure images was shown in Supplementary Fig. 1. The relative levels of SLC27A2, PPARG, p-GSK3β/GSK3β, and p-Erk/Erk in HCT-15 and SW480 between NC group and OE group. C The protein expression levels of SLC27A2, PPARG, p-GSK3β, GSK3β, p-Erk, and Erk when SLC27A2 wasknocked down. The grouping of blots cropped from diferent gels. The blots were cut prior to hybridisation with antibodies. The raw data with detail description and multiple exposure images was shown in Supplementary Fig. 1. D The relative levels of SLC27A2, PPARG, p-GSK3β/GSK3β, and p-Erk/Erk in HCT-15 and SW480 between siNC group and siR3 group. E The graphic abstract of SLC27A2 reprogramming colorectal cancer. SLC27A2: Solute carrier family 27 member 2; NC: negative control; OE: over expression; PPARG: Peroxisome proliferator activated receptor G; GSK3β:Glycogen Synthase Kinase 3 Beta; PPARG: Peroxisome proliferator activated receptor G; RXR: retinoid X receptor; FAs: Fatty acids; FATP2: Fatty acid transport protein 2
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Discussion
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear hormone receptors (NHRs) and pivotal regulators in a series of lipid metabolic bioactivities, including adipocyte differentiation, lipid transportation and energy metabolism. PPARs isoforms can act as pro- or anti-tumorigenic factors. Preclinical or clinical evidence has proven that PPAR agonists or antagonists play critical roles in tumor metabolic reprogramming, cellular environmental homeostasis, and drug response [24, 25]. High-fat diet (HFD) was reported to contribute to CRC progression and liver metastasis, and PPARD antagonists could reverse this condition and might be beneficial for CRC treatment [26]. PPARs can induce FAO programming to maintain renewal of intestinal stem cells (ISCs) under HFD conditions [13]. In addition, HFD could also affect intestinal stem cell homeostasis through PPARs, mTORC1, Wnt/GSK-3β, or PTEN pathways [27]. Controversially, PPARs play different roles in tumor progression. In our previous study, we have demonstrated that SLC27A2 regulated FA uptake and cell biological behavior in a metabolic manner in CRC cell lines. Previous studies revealed that SLC27A2 regulated FAO to support ISC renewal [28], and mediated immune suppressive activity for myeloid-derived suppressor cells (MDSCs) in CRC mouse models [17]. We investigated the expression of PPARs and found differentially expressed levels in CRC. PPARs had a relatively close relationship with SLC27A2 in CRC (Fig. 1). As important factors for proliferation, apoptosis and energy metabolism, the ratios of p-Erk/Erk and p-GSK3β/GSK3β varied when SLC27A2 was overexpressed or knocked down via non-genic crosstalk regulation of PPARG (Fig. 5). Additionally, immune checkpoint inhibitors (ICIs) effective for CRC patients when the genetic phenotypes are mismatch-repair-deficient or microsatellite instability-high (dMMR/MSI-H) [29]. Recent studies have shown that PPARG induces programmed cell death ligand 1 (PD-L1) expression in CRC [30]. Encouragingly, targeting PPARs may be a new anti-tumor strategy.
The solute carrier protein (SLC) family is the second largest class of transmembrane transporters and is a potential drug target [31]. SLC27s (SLC27A1 ~ 6) are protein-encoding families involved in lipids metabolism. Fatty acid transport proteins (FATP1 ~ 6) play pivotal roles in fatty acid uptake and fatty acyl-CoA synthetase activity [32]. In this study, we found that SLC27A2 was elevated in CRC (Fig. 1). Additionally, we have proved that SLC27A2 played a critical role in biological behavior and was mechanically regulated via the FA metabolic pathway in CRC cell lines. Consistently, the expression of SLC27A2 in colorectal cancer tissues was also higher to paired para-cancerous tissues in our ongoing study. The preliminary results indicated that knockdown of SLC27A2 may reduce tumor burden in preclinical animal model. The differences between isolated cancer cells and paired normal colon cells from the models can be further analyzed by single-cell RNA sequencing (scRNA-seq), RNA sequencing (RNA-seq) or metabonomics analysis. By protein–protein interaction (PPI) network analysis, we found that SLC27A2 had an obvious correlation with FAO–related genes (Fig. 2) and demonstrated that the mRNA expression levels of the genes were elevated when SLC27A2 was overexpressed or reduced when SLC27A2 was knocked down (Fig. 3). Considerable evidence has revealed that SLC27A2 is related to various metabolic disorders or diseases, such as lipotoxicity, oxidative stress and energy production, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), kidney fibrosis, and cancers [33, 34]. Additionally, SLC27A2 regulated the function and number of peroxisomes in CRC (Fig. 4). Peroxisomes are metabolic organelles. Extensive studies have revealed the functional significance of peroxisomes, which are involved in FAO, cellular redox homeostasis, lipolysis and immunometabolism. The pathogenesis of cancer can be mediated by peroxisomes [35, 36]. SLC27A2 could regulate cells peroxisomes and mitochondria FAO in melanoma cells to induce drug resistance [37]. In addition, SLC27A2 regulated peroxisomes and mitochondria FAO to maintain ISC renewal [28]. Investigation of peroxisomes might provide new targeted therapeutic strategies. In our study, we explored the relationship between SLC27A2 and FAO metabolic genes, and found SLC27A2 could regulate FAO metabolic genes expression (Fig. 3). Metabolic reprogramming is a hallmark of malignant cells or the tumor microenvironment (TME), and cells adapt their metabolism to sustain biological processes [38]. Infiltrating immune cells play pivotal roles in the TME and coordinate immunosurveillance [39]. MDSCs mediates immune escape in cancer progression. FATP2 was exclusively elevated in MDSCs and regulated the function of MDSCs via the lipid metabolic pathways [17]. Targeting FATP2 could modulate lipid metabolism and reduce reactive oxygen species (ROS) production in MDSCs, thus enhancing ICIs efficacy [40]. In addition, FATP2 regulated lipids metabolism in melanoma and induced resistance to targeted therapy. Inhibiting FATP2 strongly overcame the phenotype [37]. PPARs regulate cancer cell progression through crosstalk with oncogenes or suppressor genes [41]. Previous study showed that SLC39A1 impaired tumor metabolism and regulated ell proliferation, migration, and cell cycle through the PPAR crosstalk regulation in renal cell carcinoma (RCC) [42]. In our research, we investigated the crosstalk between PPARs and SLC27A2, and found non-genic crosstalk regulation of PPARs through p-Erk/Erk and p-GSK3β/GSK3β to influence FA metabolic reprogramming in CRC. Taken together, these findings might provide novel insights for cancer treatment. Targeting SLC27A2/FATP2 or PPARs may identify new anti-tumor strategies, especially in metabolic therapy, immunotherapy, targeted therapy, immunometabolism or combinations.
Conclusions
In our study, we verified that SLC27A2 was overexpressed in CRC and that SLC27A2 mediated FAO metabolism through non-genic crosstalk regulation of the PPAR pathway in CRC. Targeting metabolic reprogramming in cancers might provide new insights for anti-tumor strategies. Targeting SLC27A2/FATP2 or PPARs might be a new strategy for cancer treatment.
Acknowledgements
We would like to thank Bangwei Cao for supporting the work.
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Declarations
Ethics approval and consent to participate
The databases are publicly available and freely available. This study did not involve any human or animal experiments, so this study did not need the approval from the ethics committee.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
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In einer Leseranfrage in der Zeitschrift Journal of the American Academy of Dermatology möchte ein anonymer Dermatologe bzw. eine anonyme Dermatologin wissen, ob er oder sie einen Patienten behandeln muss, der eine rassistische Tätowierung trägt.
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