{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T20:05:25Z","timestamp":1776456325455,"version":"3.51.2"},"reference-count":43,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81902513"],"award-info":[{"award-number":["81902513"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Natural Science Foundation of Shanghai Municipality","award":["22XD1422300"],"award-info":[{"award-number":["22XD1422300"]}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"crossref","award":["2022XD053"],"award-info":[{"award-number":["2022XD053"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n               <jats:title>Background<\/jats:title>\n               <jats:p>Disruptions in calcium homeostasis are associated with a wide range of diseases, and play a pivotal role in the development of cancer. However, the construction of prognostic models using calcium extrusion-related genes in colon adenocarcinoma (COAD) has not been well studied. We aimed to identify whether calcium extrusion-related genes serve as a potential prognostic biomarker in the COAD progression.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Methods<\/jats:title>\n               <jats:p>We constructed a prognostic model based on the expression of calcium extrusion-related genes (SLC8A1, SLC8A2, SLC8A3, SLC8B1, SLC24A2, SLC24A3 and SLC24A4) in COAD. Subsequently, we evaluated the associations between the risk score calculated by calcium extrusion-related genes and mutation signature, immune cell infiltration, and immune checkpoint molecules. Then we calculated the immune score, stromal score, tumor purity and estimate score using the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm. The response to immunotherapy was assessed using tumor immune dysfunction and exclusion (TIDE). Finally, colorectal cancer cells migration, growth and colony formation assays were performed in RKO cells with the overexpression or knockdown SLC8A3, SLC24A2, SLC24A3, or SLC24A4.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Results<\/jats:title>\n               <jats:p>We found that patients with high risk score of calcium extrusion-related genes tend to have a poorer prognosis than those in the low-risk group. Additionally, patients in high-risk group had higher rates of KRAS mutations and lower MUC16 mutations, implying a strong correlation between KRAS and MUC16 mutations and calcium homeostasis in COAD. Moreover, the high-risk group showed a higher infiltration of regulatory T cells (Tregs) in the tumor microenvironment. Finally, our study identified two previously unreported model genes (SLC8A3 and SLC24A4) that contribute to the growth and migration of colorectal cancer RKO cells.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Conclusions<\/jats:title>\n               <jats:p>Altogether, we developed a prognostic risk model for predicting the prognosis of COAD patients based on the expression profiles of calcium extrusion-related genes, Furthermore, we validated two previously unreported tumor suppressor genes (SLC8A3 and SLC24A4) involved in colorectal cancer progression.<\/jats:p>\n            <\/jats:sec>","DOI":"10.7717\/peerj.17582","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T09:17:24Z","timestamp":1720603044000},"page":"e17582","source":"Crossref","is-referenced-by-count":5,"title":["Identification and validation of calcium extrusion-related genes prognostic signature in colon adenocarcinoma"],"prefix":"10.7717","volume":"12","author":[{"given":"Mingpeng","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoning","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the 902nd Hospital of PLA Joint Service Support Force, Bengbu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, Shanxi Medical University, Taiyuan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4443","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"issue":"3","key":"10.7717\/peerj.17582\/ref-1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3892\/ijmm.2021.4847","article-title":"Emerging trends in colorectal cancer: dysregulated signaling pathways (Review)","volume":"47","author":"Ahmad","year":"2021","journal-title":"International Journal of Molecular Medicine"},{"issue":"1","key":"10.7717\/peerj.17582\/ref-2","doi-asserted-by":"publisher","first-page":"598","DOI":"10.3390\/ijms24010598","article-title":"Regulation of K(+)-dependent Na(+)\/Ca(2+)-exchangers (NCKX)","volume":"24","author":"Al-Khannaq","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"key":"10.7717\/peerj.17582\/ref-3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signalling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nature Reviews Molecular Cell Biology"},{"issue":"12","key":"10.7717\/peerj.17582\/ref-4","doi-asserted-by":"publisher","first-page":"3085","DOI":"10.3390\/cancers13123085","article-title":"Ca(2+) signaling and its potential targeting in pancreatic ductal carcinoma","volume":"13","author":"Bettaieb","year":"2021","journal-title":"Cancers"},{"key":"10.7717\/peerj.17582\/ref-5","doi-asserted-by":"publisher","first-page":"721644","DOI":"10.3389\/fonc.2021.721644","article-title":"CDT1 is a novel prognostic and predictive biomarkers for hepatocellular carcinoma","volume":"11","author":"Cai","year":"2021","journal-title":"Frontiers in Oncology"},{"issue":"9","key":"10.7717\/peerj.17582\/ref-6","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.3390\/biom10091257","article-title":"Role of sodium\/calcium exchangers in tumors","volume":"10","author":"Chovancova","year":"2020","journal-title":"Biomolecules"},{"key":"10.7717\/peerj.17582\/ref-7","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.cmet.2023.01.009","article-title":"Sodium perturbs mitochondrial respiration and induces dysfunctional tregs","volume":"35","author":"C\u00f4rte-Real","year":"2023","journal-title":"Cell Metabolism"},{"key":"10.7717\/peerj.17582\/ref-8","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1615\/CritRevOncog.2020035067","article-title":"Colorectal cancer biology, diagnosis, and therapeutic approaches","volume":"25","author":"Dariya","year":"2020","journal-title":"Critical Reviews in Oncogenesis"},{"key":"10.7717\/peerj.17582\/ref-9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.canlet.2020.01.026","article-title":"Plasma membrane Ca(2+)-permeable channels and sodium\/calcium exchangers in tumorigenesis and tumor development of the upper gastrointestinal tract","volume":"475","author":"Ding","year":"2020","journal-title":"Cancer Letters"},{"key":"10.7717\/peerj.17582\/ref-10","doi-asserted-by":"publisher","first-page":"2767","DOI":"10.1152\/physrev.00042.2022","article-title":"Physiology of intracellular calcium buffering","volume":"103","author":"Eisner","year":"2023","journal-title":"Physiological Reviews"},{"key":"10.7717\/peerj.17582\/ref-11","doi-asserted-by":"publisher","first-page":"102667","DOI":"10.1016\/j.ceca.2022.102667","article-title":"The mitochondrial sodium\/calcium exchanger NCLX (Slc8b1) in B lymphocytes","volume":"108","author":"Emrich","year":"2022","journal-title":"Cell Calcium"},{"key":"10.7717\/peerj.17582\/ref-12","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1152\/physrev.00041.2020","article-title":"Mitochondrial calcium exchange in physiology and disease","volume":"102","author":"Garbincius","year":"2022","journal-title":"Physiological Reviews"},{"key":"10.7717\/peerj.17582\/ref-13","doi-asserted-by":"publisher","first-page":"102135","DOI":"10.1016\/j.ceca.2019.102135","article-title":"Potassium-dependent sodium-calcium exchanger (NCKX) isoforms and neuronal function","volume":"86","author":"Hassan","year":"2020","journal-title":"Cell Calcium"},{"key":"10.7717\/peerj.17582\/ref-14","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1113\/JP272844","article-title":"Molecular mechanisms of tumour invasion: regulation by calcium signals","volume":"595","author":"Iamshanova","year":"2017","journal-title":"The Journal of Physiology"},{"key":"10.7717\/peerj.17582\/ref-15","doi-asserted-by":"publisher","first-page":"102153","DOI":"10.1016\/j.ceca.2019.102153","article-title":"Structure-function relationships of K(+)-dependent Na(+)\/Ca(2+) exchangers (NCKX)","volume":"86","author":"Jalloul","year":"2020","journal-title":"Cell Calcium"},{"key":"10.7717\/peerj.17582\/ref-16","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nature Medicine"},{"key":"10.7717\/peerj.17582\/ref-17","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.mam.2012.07.003","article-title":"The SLC8 gene family of sodium-calcium exchangers (NCX)\u2014structure, function, and regulation in health and disease","volume":"34","author":"Khananshvili","year":"2013","journal-title":"Molecular Aspects of Medicine"},{"issue":"2","key":"10.7717\/peerj.17582\/ref-18","doi-asserted-by":"publisher","first-page":"901","DOI":"10.3390\/ijms23020901","article-title":"Suppressing effect of Na(+)\/Ca(2+) exchanger (NCX) inhibitors on the growth of melanoma cells","volume":"23","author":"Liu","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"key":"10.7717\/peerj.17582\/ref-19","doi-asserted-by":"publisher","first-page":"671211","DOI":"10.3389\/fcell.2021.671211","article-title":"Identification of ZNF26 as a prognostic biomarker in colorectal cancer by an integrated bioinformatic analysis","volume":"9","author":"Liu","year":"2021","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"10.7717\/peerj.17582\/ref-20","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nature22082","article-title":"The mitochondrial Na(+)\/Ca(2+) exchanger is essential for Ca(2+) homeostasis and viability","volume":"545","author":"Luongo","year":"2017","journal-title":"Nature"},{"key":"10.7717\/peerj.17582\/ref-21","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1042\/BJ20070619","article-title":"Na+\/Ca2+ exchangers: three mammalian gene families control Ca2+ transport","volume":"406","author":"Lytton","year":"2007","journal-title":"Biochemical Journal"},{"key":"10.7717\/peerj.17582\/ref-22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.coph.2016.03.002","article-title":"Alterations of calcium homeostasis in cancer cells","volume":"29","author":"Marchi","year":"2016","journal-title":"Current Opinion in Pharmacology"},{"key":"10.7717\/peerj.17582\/ref-23","doi-asserted-by":"publisher","first-page":"e2301940","DOI":"10.1002\/advs.202301940","article-title":"NLRP14 safeguards calcium homeostasis via regulating the K27 ubiquitination of Nclx in oocyte-to-embryo transition","volume":"10","author":"Meng","year":"2023","journal-title":"Advanced Science"},{"key":"10.7717\/peerj.17582\/ref-24","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrc.2017.18","article-title":"The calcium-cancer signalling nexus","volume":"17","author":"Monteith","year":"2017","journal-title":"Nature Reviews Cancer"},{"key":"10.7717\/peerj.17582\/ref-25","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.juro.2014.11.097","article-title":"Down-regulation of SLC8A1 as a putative apoptosis evasion mechanism by modulation of calcium levels in penile carcinoma","volume":"194","author":"Mu\u00f1oz","year":"2015","journal-title":"Journal of Urology"},{"key":"10.7717\/peerj.17582\/ref-26","doi-asserted-by":"publisher","first-page":"e59686","DOI":"10.7554\/eLife.59686","article-title":"Dichotomous role of the human mitochondrial Na(+)\/Ca2(+)\/Li(+) exchanger NCLX in colorectal cancer growth and metastasis","volume":"9","author":"Pathak","year":"2020","journal-title":"Elife"},{"key":"10.7717\/peerj.17582\/ref-27","doi-asserted-by":"publisher","first-page":"761","DOI":"10.14348\/molcells.2017.0104","article-title":"The candidate tumor suppressor gene SLC8A2 inhibits invasion, angiogenesis and growth of glioblastoma","volume":"40","author":"Qu","year":"2017","journal-title":"Molecular Cell"},{"key":"10.7717\/peerj.17582\/ref-28","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.semcdb.2019.05.015","article-title":"Interorganellar calcium signaling in the regulation of cell metabolism: a cancer perspective","volume":"98","author":"Rimessi","year":"2020","journal-title":"Seminars in Cell & Developmental Biology"},{"key":"10.7717\/peerj.17582\/ref-29","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.bcp.2019.02.032","article-title":"Na(+)\/Ca(2+) exchangers: unexploited opportunities for cancer therapy?","volume":"163","author":"Rodrigues","year":"2019","journal-title":"Biochemical Pharmacology"},{"key":"10.7717\/peerj.17582\/ref-30","doi-asserted-by":"publisher","first-page":"102154","DOI":"10.1016\/j.ceca.2019.102154","article-title":"On the special role of NCX in astrocytes: translating Na(+)-transients into intracellular Ca(2+) signals","volume":"86","author":"Rose","year":"2020","journal-title":"Cell Calcium"},{"key":"10.7717\/peerj.17582\/ref-31","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.mam.2012.07.008","article-title":"The SLC24 gene family of Na+\/Ca2+-K+ exchangers: from sight and smell to memory consolidation and skin pigmentation","volume":"34","author":"Schnetkamp","year":"2013","journal-title":"Molecular Aspects of Medicine"},{"key":"10.7717\/peerj.17582\/ref-32","first-page":"7","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"10.7717\/peerj.17582\/ref-33","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/s41585-023-00738-x","article-title":"Calcium signalling pathways in prostate cancer initiation and progression","volume":"20","author":"Silvestri","year":"2023","journal-title":"Nature Reviews Urology"},{"key":"10.7717\/peerj.17582\/ref-34","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.semcdb.2018.11.001","article-title":"Calcium signalling and breast cancer","volume":"94","author":"So","year":"2019","journal-title":"Seminars in Cell & Developmental Biology"},{"key":"10.7717\/peerj.17582\/ref-35","doi-asserted-by":"publisher","first-page":"101759","DOI":"10.1016\/j.redox.2020.101759","article-title":"Innate-adaptive immunity interplay and redox regulation in immune response","volume":"37","author":"Sun","year":"2020","journal-title":"Redox Biology"},{"key":"10.7717\/peerj.17582\/ref-36","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1038\/s41419-022-04668-1","article-title":"Lon upregulation contributes to cisplatin resistance by triggering NCLX-mediated mitochondrial Ca(2+) release in cancer cells","volume":"13","author":"Tangeda","year":"2022","journal-title":"Cell Death & Disease"},{"key":"10.7717\/peerj.17582\/ref-37","first-page":"A68","article-title":"The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge","volume":"19","author":"Tomczak","year":"2015","journal-title":"Contemporary Oncology"},{"issue":"5","key":"10.7717\/peerj.17582\/ref-38","doi-asserted-by":"publisher","first-page":"2645","DOI":"10.3390\/ijms22052645","article-title":"Loss of Nckx3 exacerbates experimental DSS-induced colitis in mice through p53\/NF-\u03baB pathway","volume":"22","author":"Tran","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"key":"10.7717\/peerj.17582\/ref-39","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.preteyeres.2018.06.001","article-title":"Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors","volume":"67","author":"Vinberg","year":"2018","journal-title":"Progress in Retinal and Eye Research"},{"key":"10.7717\/peerj.17582\/ref-40","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1097\/CM9.0000000000002108","article-title":"Cancer statistics in China and United States, 2022: profiles, trends, and determinants","volume":"135","author":"Xia","year":"2022","journal-title":"Chinese Medical Journal"},{"key":"10.7717\/peerj.17582\/ref-41","doi-asserted-by":"publisher","first-page":"116909","DOI":"10.1016\/j.lfs.2019.116909","article-title":"Pathogenic roles of altered calcium channels and transporters in colon tumorogenesis","volume":"239","author":"Yang","year":"2019","journal-title":"Life Sciences"},{"key":"10.7717\/peerj.17582\/ref-42","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1186\/s12935-021-02252-9","article-title":"Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer","volume":"21","author":"Zheng","year":"2021","journal-title":"Cancer Cell International"},{"key":"10.7717\/peerj.17582\/ref-43","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.tcb.2022.07.004","article-title":"Calcium homeostasis and cancer: insights from endoplasmic reticulum-centered organelle communications","volume":"33","author":"Zheng","year":"2023","journal-title":"Trends in Cell Biology"}],"container-title":["PeerJ"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/peerj.com\/articles\/17582.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/17582.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/17582.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/17582.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T09:17:39Z","timestamp":1720603059000},"score":1,"resource":{"primary":{"URL":"https:\/\/peerj.com\/articles\/17582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,10]]},"references-count":43,"alternative-id":["10.7717\/peerj.17582"],"URL":"https:\/\/doi.org\/10.7717\/peerj.17582","archive":["CLOCKSS","LOCKSS","Portico"],"relation":{},"ISSN":["2167-8359"],"issn-type":[{"value":"2167-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,10]]},"article-number":"e17582"}}