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. 2023 Apr 11;23(1):335.
doi: 10.1186/s12885-023-10816-3.

SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway

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SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway

Kun Shang et al. BMC Cancer. .

Abstract

Background: 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.

Keywords: Colorectal cancer; FAO; PPARs; SLC27A2.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
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
Fig. 2
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
Fig. 3
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
Fig. 4
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)
Fig. 5
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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