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18F-FDG PET/CT Metabolic Parameters Correlate with EIF2S2

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Journal of Cancer 2021, Vol. 12 5838 Ivyspring International Publisher Journal of Cancer 2021; 12(19): 5838-5847. doi: 10.7150/jca.57926 Research Paper 18F-FDG PET/CT metabolic parameters correlate with EIF2S2 expression status in colorectal cancer Jian-Wei Yang1,2*, Ling-Ling Yuan3*, Yan Gao2, Xu-Sheng Liu2, Yu-Jiao Wang6, Lu-Meng Zhou1,2, Xue-Yan Kui1,2, Xiao-Hui Li2, Chang-Bin Ke2, Zhi-Jun Pei1,2,4,5 1. Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China. 2. Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China. 3. Department of Pathology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China. 4. Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, Hubei, China. 5. Hubei Key Laboratory of WudangLocal Chinese Medicine Research, Shiyan, Hubei, China. 6. Department of Radiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China. *Contributed equally to this work. Corresponding authors: Zhijun Pei, E-mail: [email protected]; Changbin Ke, E-mail: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2021.01.07; Accepted: 2021.07.09; Published: 2021.08.03 Abstract Background: We sought to investigate whether the expression of the gene EIF2S2 is related to 18F-FDG PET/CT metabolic parameters in patients with colorectal cancer (CRC). Materials and methods: The expression of EIF2S2 in CRC and its relationship with clinicopathological features were obtained through the ONCOMINE, UALCAN and GEPIA databases. EIF2S2 and GLUT1 expression were examined by immunohistochemistry in 42 CRC patients undergoing preoperative PET-CT examination. Spearman correlation analysis was used to assess the relationship between EIF2S2 and GLUT1 levels and clinical parameters. Correlation analysis between EIF2S2 and Reactome-Glycolysis signatures was performed using GEPIA2. We describe the effect of EIF2S2 knockdown on lactate production and the mRNA levels of glycolysis-related genes in human colon cancer SW480 cells. Results: Immunohistochemistry revealed an upregulation of EIF2S2 protein expression in tumor tissues of colorectal cancer patients, which is consistent with the significant upregulation of EIF2S2 transcript levels in the database. These colorectal cancer patients included 24 cases of colon cancer and 18 cases of rectal cancer, ranging in age from 31 to 78 years. The transcription was significantly related to histological subtypes and TP53 mutations (P <0.05). The value of SUVmax in CRC significantly correlated with the expression of EIF2S2 (rho = 0.462, P <0.01). Although SUVmax and SUVmean was not correlate with the expression of GLUT1 (P <0.05), a significant correlation was observed between the expression of GLUT1 and the volumetric PET parameters, such as MTV and TLG (P < 0.01). GLUT1 expression in CRC was positively correlated with EIF2S2 status (rho = 0.470, P <0.01). In SW480 cells, RNAi-mediated depletion of EIF2S2 inhibited lactic acid production (P <0.05) and SLC2A1, SLC2A3, SLC2A10, HK2, PKM2, LDHA mRNA level (P <0.01). Conclusions: Primary CRC FDG uptake is strongly associated with the overexpression of EIF2S2, and EIF2S2 may promote glycolysis in CRC by mediating GLUT1. Key words: Colorectal cancer, EIF2S2, 18F-FDG, SUVmax, glucose transporter 1 Introduction Colorectal cancer (CRC) is the fourth most treatment can significantly reduce the mortality of common cancer [1]. Although the incidence and patients. There is a need for effective biomarkers of mortality of CRC have declined over the past two CRC for screening and early detection. Cancer cells decades, unresectable locally advanced CRC has a mainly obtain energy by breaking down glucose into poor prognosis. Early diagnosis and timely surgical ATP using aerobic glycolysis (the Warburg effect) [2, http://www.jcancer.org Journal of Cancer 2021, Vol. 12 5839 3]. 18F-FDG PET/CT has been widely used in the Methods detection, treatment monitoring, and prognostic evaluation of various tumors [4-7]. 18F-FDG is glucose ONCOMINE database analysis radiolabeled with 18F. Drawn in by glucose The ONCOMINE database (www.oncomine.org) transporters (GLUTs) and phosphorylated by is an integrated online cancer microarray database for hexokinases (HK), it cannot be metabolized further, DNA or RNA sequence analysis, designed to facilitate allowing its irreversible entry into cells. 18F-FDG is discoveries from whole gene expression analysis[32]. used to detect the amount of glucose uptake in In this study, using the ONCOMINE database, we tumors. The mechanism may be mediated by the obtained data on the transcriptional expression increased number of GLUTs [8] and HK [9, 10] in differences of EIF2 between CRC and normal malignant cells. The relationship between expression colorectal tissues. The cutoff values were as follows: P of GLUT-1 or HK2 and degree of 18F-FDG uptake has value: 1E-4; fold change: 2; gene rank: 10%; data type: been extensively studied [11-16]. High expression of mRNA. GLUT-1 is a crucial factor for 18F-FDG uptake in many malignant tumors. GLUT1 is encoded by the SLC2A1 UALCAN gene and plays an important role in the development UALCAN (http://ualcan.path.uab.edu) is a of many tumors, such as nonsmall cell lung cancer comprehensive, user-friendly, and interactive web [17] and breast cancer [18]. In previous reports, it was resource for analyzing cancer omics data from the found that the relationship between 18F-FDG uptake TCGA database [33]. Differences in EIF2S2 transcript and GLUT-1 expression in different malignant tumors levels were identified through the UALCAN website, is not entirely consistent [19, 20]. It has been reported including 286 colon cancer tissues and 41 normal that 18F-FDG uptake correlates with GLUT1 colon tissues; 166 rectal cancer tissues and normal expression in patients with liver metastasis from CRC rectal tissues in the TCGA database. At the same time, [21]. In addition, it showed that SUVmax may be we analyzed the relative expression of EIF2S2 in useful for predicting the NPM1 expression of lung different groups with variations in sex, age, tumor adenocarcinoma [22] and METTL3 expression of histology, tumor grade, tumor stage, and lymphnode esophageal cancer [23]. status). P < 0.05 was considered statistically RNA binding protein (RBP) is widely recognized significant. as a protein that plays an important role in regulating GEPIA gene expression [24]. At present, more and more RBPs have been discovered, which play an important role Gene Expression Profiling Interactive Analysis in promoting the occurrence and development of (http://gepia.cancer-pku.cn/index.html) is a tool to tumors [25]. Some RBPs can also mediate energy analyze RNA sequence expression data of 9736 metabolism [26]. EIF2 is a heterotrimer consisting of tumors and 8587 normal tissues [34]. We found 83 eIF2α, eIF2β and eIF2γ [27, 28]. EIF2S2 (Eukaryotic Reactome-Glycolysis signaling molecules from the Translation. Reactome database [35]. The correlation between Initiation Factor 2 Subunit β) showed a EIF2S2 and glycolysis and glucose transport-related significant relationship between DNA copy number proteins was analyzed. levels and mRNA expression in luminal breast tumors Study population [29]. The eIF2β gene is highly expressed in lung cancer The study included 42 patients with CRC and can indicate the prognosis of patients with lung undergoing 18F-FDG PET/CT examination and adenocarcinoma [30]. EIF2S2 may play a role in surgical resection from February 2015 to October 2019. promoting tumors by regulating the WNT signaling Inclusion criteria were as follows: (a) CRC confirmed pathway [31]. But whether EIF2S2 mediates aerobic by pathology; (b) no biopsy, radiotherapy or glycolysis has not been reported in CRC. chemotherapy before PET/CT; (c) surgery was Transcriptional data for EIF2S2 in CRC and its performed within 4 weeks after the scan; (d) tissue clinically relevant data were obtained from The samples were available for immunohistochemistry Cancer Genome Atlas (TCGA) database. We (IHC) staining; and (e) case records were complete. confirmed the high expression of EIF2S2 in CRC The age range of the 28 male patients was 31-78 with a through immunohistochemistry. The correlation mean age of 57.5 years. 14 female patients had an age between EIF2S2 and 18F-FDG uptake in colorectal range of 40-80 years with a mean age of 57.7 years. cancer and the effect of EIF2S2 knockdown on the They were pathologically diagnosed with CRC and levels of genes related to lactate production and did not receive radiotherapy or chemotherapy before partial glycolysis in SW480 cells were investigated. surgical resection and PET/CT imaging. http://www.jcancer.org Journal of Cancer 2021, Vol. 12 5840 18F-FDG PET/CT Table A. List of siRNA sequences PET/CT images (Biograph MCT; Siemens) were Name Sequence acquired 1 h after intravenous injection of 18F-FDG siEIF2S2 Forward 5’- GUCGUCCGAGUAGGAACCATT-3’ Reverse 5’- UGGUUCCUACUCGGACGACUU-3’ and fasting for at least 6 h. Regions of interest (ROIs) NC siRNA Forward 5’- UUCUCCGAACGUACGUTT-3’ were drawn around the contours of the primary Reverse 5’- ACGUGACACGUUCGGAGAATT-3’ tumors on the PET images. SUVmax, SUVmean, total lesion glycolysis (TLG), and metabolic tumor volume Quantitative real-time PCR assay (MTV) of each primary tumor were automatically calculated and recorded. SW480 cells in the logarithmic growth phase were inoculated with 1 × 105 cells in 24-well plates Immunohistochemistry and analysis and infected with siEIF2S2 or siCtrl. Total RNA was After the CRCs were resected, the tumor tissues extracted from cells and tissues with Trizol reagent and adjacent tissues were subjected to immuno- (Invitrogen) and a real-time polymerase chain histochemical analysis of the expression of EIF2S2 and reaction (RT-PCR) was performed with PrimeScript™ GLUT1.
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  • Supplementary Table 1

    Supplementary Table 1

    Up-regulated accession # Development M93275 ADFP, adipose differentiation related protein D43694 MATH-1, homolog of atonal 1 M64068 Bmi-1, zinc finger protein AW124785 Midnolin, midbrain nucleolar protein AI843178 Cla3, Cerebellar ataxia 3 D10712 Nedd1, Neural precursor cell expressed, developmentally down-regulated gene 1 AB011678 Doublecortin, for neurogenesis M57683 mPDGF-alpha-R, PDGF alpha receptor U41626 DSS1, deleted in split hand/split foot 1 homolog (Dss1), for limb development AB010833 PTCH2, patched 2, Mouse homolog of yeast CDC46 NP_034226 Ebf3, early B-cell factor 3 AI846695 Qk, Quaking U63386 Edr1 Early development regulator 1 (homolog of polyhomeotic 1), Mph1 AI043016 Rnf2, Ring finger protein 2 X69942 Enhancer-trap-locus 1, for transcription regulation AF100694 Ruvbl1, Ruv-B like protein 1, DNA helicase AW123618 Fzd2, Frizzled homolog 2 U88566 Sfrp1, secreted frizzled related protein 1 AA681520 Geminin-pending, for embryogenesis and morphogenesis U88567 Sfrp2, secreted frizzled related protein 2 AB025922 Gli1, GLI-Kruppel family member 1 AF089721 Smo, Smoothened X99104 Gli2, GLI-Kruppel family member 2 AF009414 SOX11, SRY-box containing gene 11 U61362 Grg1, groucho-related gene 1, Tle1, transducin-like enhancer of split 1 U85614 SRG3, Smarcc1, SWI/SNF related, matrix associated, action dependent regulator of chromatin, subfamily, member 1 M97506 Hen1, helix-loop-helix protein AI837838 Tmeff1, Transmembrane protein with EGF-like and two follistatin-like domains 1 U79748 Madh4, MAD homolog 4, for transcription regulation