Abstract
Purpose
Colon cancer is the most common malignant tumor in the intestine. Abnormal Carboxylesterases 3 (CES3) expression had been reported to be correlated to multiple tumor progression. However, the association among CES3 expression and prognostic value and immune effects in colonic adenocarcinoma (COAD) were unclear.
Patients and methods
The transcription and expression data of CES3 and corresponding clinical information was downloaded from The Cancer Genome Atlas (TCGA). The CES3 protein expression and the prognostic value were verified based on tissue microarray data. The Cancer immune group Atlas (TCIA), Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the GSE78220 immunotherapy cohort were used to forecast immunotherapy efficacy. Finally, a prognostic immune signature was constructed and verified.
Results
Compared with normal colon tissues, the expression of mRNA and protein levels of CES3 were downregulated in tumor tissues. CES3 expression was associated with TIICs. Hihg-CES3 COAD patients had better efficacy of concurrent immunotherapy. CES3-related immune genes (CRIs) were identified and were then used to construct prognostic immune signature and had been successfully verified in GES39582.
Conclusion
CES3 might be a potential immune-related gene and promising prognostic biomarker in COAD.
Similar content being viewed by others
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
References
Almaimani RA, Aslam A, Ahmad J, El-Readi MZ, El-Boshy ME, Abdelghany AH et al (2022) In vivo and in vitro enhanced tumoricidal effects of metformin, active vitamin D(3), and 5-fluorouracil triple therapy against colon cancer by modulating the PI3K/Akt/PTEN/mTOR network. Cancers (basel) 14(6):1538
Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O et al (2021) Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 39(6):845–65.e7
Benson AB 3rd, Venook AP, Cederquist L, Chan E, Chen YJ, Cooper HS et al (2017) Colon cancer, Version 1.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 15(3):370–398
Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z (2021) Lipid metabolism and cancer. J Exp Med 218(1)
Boukhaled GM, Gadalla R, Elsaesser HJ, Abd-Rabbo D, Quevedo R, Yang SYC et al (2022) Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy. Nat Immunol 23(8):1273–1283
Chen J, Apizi A, Wang L, Wu G, Zhu Z, Yao H et al (2021) TCGA database analysis of the tumor mutation burden and its clinical significance in colon cancer. J Gastrointest Oncol 12(5):2244–2259
Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D et al (2016) TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 44(8):e71
Cui MY, Yi X, Zhu DX, Wu J (2022) The role of lipid metabolism in gastric cancer. Front Oncol 12:916661
Deng M, Sun S, Zhao R, Guan R, Zhang Z, Li S et al (2022) The pyroptosis-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma. Mol Med 28(1):16
Dolinsky VW, Sipione S, Lehner R, Vance DE (2001) The cloning and expression of a murine triacylglycerol hydrolase cDNA and the structure of its corresponding gene. Biochim Biophys Acta 1532(3):162–172
Dong Y, Ma WM, Shi ZD, Zhang ZG, Zhou JH, Li Y et al (2021) Role of NRP1 in bladder cancer pathogenesis and progression. Front Oncol 11:685980
Douyère M, Gong C, Richard M, Pellegrini-Moïse N, Daouk J, Pierson J et al (2022) NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells. Cancer Cell Int 22(1):377
Fonseca-Montaño MA, Blancas S, Herrera-Montalvo LA, Hidalgo-Miranda A (2022) Cancer genomics. Arch Med Res 53(8):723–731
Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P et al (2020) NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res 80(9):1846–1860
Fujishita T, Kojima Y, Kajino-Sakamoto R, Mishiro-Sato E, Shimizu Y, Hosoda W et al (2022) The cAMP/PKA/CREB and TGFβ/SMAD4 pathways regulate stemness and metastatic potential in colorectal cancer cells. Cancer Res 82(22):4179–4190
Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH et al (2019) Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 16(6):361–375
Ge L, Wang Q, He Y, Wu D, Zhou Q, Xu N et al (2022) Acupuncture for cancer pain: an evidence-based clinical practice guideline. Chin Med 17(1):8
Geyer N, Gerling M (2021) Hedgehog signaling in colorectal cancer: all in the stroma? Int J Mol Sci 22(3):1025
Greenlee H, DuPont-Reyes MJ, Balneaves LG, Carlson LE, Cohen MR, Deng G et al (2017) Clinical practice guidelines on the evidence-based use of integrative therapies during and after breast cancer treatment. CA Cancer J Clin 67(3):194–232
Hammid A, Fallon JK, Lassila T, Salluce G, Smith PC, Tolonen A et al (2021) Carboxylesterase activities and protein expression in rabbit and pig ocular tissues. Mol Pharm 18(3):1305–1316
Holmes RS, Cox LA, Vandeberg JL (2009) A new class of mammalian carboxylesterase CES6. Comp Biochem Physiol Part D Genom Proteom 4(3):209–217
Hou W, Yi C, Zhu H (2022) Predictive biomarkers of colon cancer immunotherapy: present and future. Front Immunol 13:1032314
Huang J, Li L, Lian J, Schauer S, Vesely PW, Kratky D et al (2016) Tumor-induced hyperlipidemia contributes to tumor growth. Cell Rep 15(2):336–348
Jiang J (2022) Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol 85:107–122
Liao Y, Zhao J, Bulek K, Tang F, Chen X, Cai G et al (2020) Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis. Nat Commun 11(1):900
Lichtenstern CR, Ngu RK, Shalapour S, Karin M (2020) Immunotherapy, inflammation and colorectal cancer. Cells 9(3):618
Liu F, Liang Y, Sun R, Yang W, Liang Z, Gu J et al (2022) Astragalus mongholicus Bunge and Curcuma aromatica Salisb. inhibits liver metastasis of colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway. Chin Med 17(1):91
Long H, Jia Q, Wang L, Fang W, Wang Z, Jiang T et al (2022) Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell 40(6):674–93.e7
Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A et al (2013) Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med 210(13):2851–2872
Lv B, Wang Y, Ma D, Cheng W, Liu J, Yong T et al (2022) Immunotherapy: reshape the tumor immune microenvironment. Front Immunol 13:844142
Maki T, Hosokawa M, Satoh T, Sato K (1991) Changes in carboxylesterase isoenzymes of rat liver microsomes during hepatocarcinogenesis. Jpn J Cancer Res 82(7):800–806
Matsubara T, Tanaka N, Krausz KW, Manna SK, Kang DW, Anderson ER et al (2012) Metabolomics identifies an inflammatory cascade involved in dioxin- and diet-induced steatohepatitis. Cell Metab 16(5):634–644
Motta R, Cabezas-Camarero S, Torres-Mattos C, Riquelme A, Calle A, Figueroa A et al (2021) Immunotherapy in microsatellite instability metastatic colorectal cancer: Current status and future perspectives. J Clin Transl Res 7(4):511–522
Müller D (2023) Targeting co-stimulatory receptors of the TNF superfamily for cancer immunotherapy. BioDrugs 37(1):21–33
Niekamp P, Kim CH (2023) Microbial metabolite dysbiosis and colorectal cancer. Gut Liver. 17(2):190
Ooki A, Shinozaki E, Yamaguchi K (2021) Immunotherapy in colorectal cancer: current and future strategies. J Anus Rectum Colon 5(1):11–24
Peng S, Xiao F, Chen M, Gao H (2022) Tumor-microenvironment-responsive nanomedicine for enhanced cancer immunotherapy. Adv Sci (weinh) 9(1):e2103836
Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A et al (2020) TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat Commun 11(1):2608
Philip M, Schietinger A (2022) CD8(+) T cell differentiation and dysfunction in cancer. Nat Rev Immunol 22(4):209–223
Quintanilha JCF, Graf RP, Fisher VA, Oxnard GR, Ellis H, Panarelli N et al (2023) Comparative effectiveness of immune checkpoint inhibitors vs chemotherapy in patients with metastatic colorectal cancer with measures of microsatellite instability, mismatch repair, or tumor mutational burden. JAMA Netw Open 6(1):e2252244
Raskov H, Orhan A, Christensen JP, Gögenur I (2021) Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy. Br J Cancer 124(2):359–367
Sanghani SP, Quinney SK, Fredenburg TB, Davis WI, Murry DJ, Bosron WF (2004) Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3. Drug Metab Dispos 32(5):505–511
Santos CR, Schulze A (2012) Lipid metabolism in cancer. FEBS J 279(15):2610–2623
Schulze A, Harris AL (2012) How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491(7424):364–373
Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H et al (2022) Immune checkpoint inhibitors in cancer therapy. Curr Oncol 29(5):3044–3060
Siegmund D, Wagner J, Wajant H (2022) TNF receptor associated factor 2 (TRAF2) signaling in cancer. Cancers (basel). 14(16):4055
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249
Tian K, Qi W, Yan Q, Lv M, Song D (2022) Signature constructed by glycolysis-immune-related genes can predict the prognosis of osteosarcoma patients. Invest New Drugs 40(4):818–830
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G et al (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71(4):1263–1271
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27(8):1386–1422
Wang X, Yang L, Huang F, Zhang Q, Liu S, Ma L et al (2017) Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett 184:7–14
Wang Z, Song J, Azami NLB, Sun M (2022a) Identification of a novel immune landscape signature for predicting prognosis and response of colon cancer to immunotherapy. Front Immunol 13:802665
Wang L, Li S, Luo H, Lu Q, Yu S (2022b) PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J Exp Clin Cancer Res 41(1):303
Yan R, Zhu H, Huang P, Yang M, Shen M, Pan Y et al (2022) Liquidambaric acid inhibits Wnt/β-catenin signaling and colon cancer via targeting TNF receptor-associated factor 2. Cell Rep 38(5):110319
Yang S, Wu Y, Deng Y, Zhou L, Yang P, Zheng Y et al (2019) Identification of a prognostic immune signature for cervical cancer to predict survival and response to immune checkpoint inhibitors. Oncoimmunology 8(12):e1659094
Yang D, Ma X, Song P (2022a) A prognostic model of non small cell lung cancer based on TCGA and ImmPort databases. Sci Rep 12(1):437
Yang T, Hui R, Nouws J, Sauler M, Zeng T, Wu Q (2022b) Untargeted metabolomics analysis of esophageal squamous cell cancer progression. J Transl Med 20(1):127
Yi M, Li A, Zhou L, Chu Q, Luo S, Wu K (2021) Immune signature-based risk stratification and prediction of immune checkpoint inhibitor’s efficacy for lung adenocarcinoma. Cancer Immunol Immunother 70(6):1705–1719
Zeng Y, Zhang Z, Chen H, Fan J, Yuan W, Li J et al (2021) Comprehensive analysis of immune implication and prognostic value of IFI44L in non-small cell lung cancer. Front Oncol 11:798425
Huang J, Li L, Lian J, Schauer S, Vesely PW, Kratky D, Hoefler G, Lehner R. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth. Cell Rep. 2016 Apr 12;15(2):336–48. https://doi.org/10.1016/j.celrep.2016.03.020. Epub 2016 Mar 31. PMID: 27050512; PMCID: PMC4984953.
Zhang Y, Zhang C, Yang Y, Wang G, Wang Z, Liu J et al (2022) Pyroptosis-related gene signature predicts prognosis and indicates immune microenvironment infiltration in glioma. Front Cell Dev Biol 10:862493
Zhao H, Li W, Lyu P, Zhang X, Liu H, Liang P et al (2021) TCGA-TCIA-based CT radiomics study for noninvasively predicting Epstein-Barr virus status in gastric cancer. AJR Am J Roentgenol 217(1):124–134
Zhao L, Zhou X, Xie F, Zhang L, Yan H, Huang J et al (2022) Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (lond) 42(2):88–116
Funding
This study was funded by grants from Suzhou Municipal Science and Technology Bureau (Grant Numbers SKY2022006, SLJ202011 and SLT201959), Jiangsu Commission of Health (Grant Number M2020043) and China Digestive Tumor Clinical Research Public Welfare Project (Grant Number P014-038).
Author information
Authors and Affiliations
Contributions
Authors HLL and ZCY conceived and designed the study. LWJ carried out the study. XJJ, LYJ, GY, GDY, and WXY analyzed the data. HLL wrote the manuscript. All authors have read and approved this manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical approval
TCGA and GEO belong to public databases. The patients involved in the database have obtained ethical approval. Users can download relevant data for free for research and public relevant articles. Shanghai Outdo Biotech Co. Ltd. obtained the ethical approval for research using human tissue, we purchased these microarrays for our research. Therefore, there are no ethical issues and other conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
He, L., Zhao, C., Xu, J. et al. A potential novel biomarker: comprehensive analysis of prognostic value and immune implication of CES3 in colonic adenocarcinoma. J Cancer Res Clin Oncol 149, 13239–13255 (2023). https://doi.org/10.1007/s00432-023-05156-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-05156-5