Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Research

Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in lung adenocarcinoma

Authors: Junfeng Huang, Bingqi Hu, Ying Yang, Huanhuan Liu, Xingyu Fan, Jing Zhou, Liwen Chen

Published in: BMC Cancer | Issue 1/2023

Login to get access

Abstract

Background

Chaperonin-containing tailless complex polypeptide 1 (TCP1) subunit 3 (CCT3) has tumor-promoting effects in lung adenocarcinoma (LUAD). This study aims to investigate the molecular mechanisms of CCT3 in LUAD oncogenesis.

Methods

The UALCAN databases, Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) data were used to analyze CCT3 expression in LUAD. Both the Wilcoxon rank-sum test and the regression model were used to investigate the connection between clinicopathologic characteristics of LUAD patients and CCT3 expression. The prognostic value of CCT3 was determined by Cox regression models, the Kaplan-Meier method and Nomogram prediction. Next, we identified the most related genes with CCT3 via GeneMANIA and String databases, and the association between CCT3 and infiltrated immune cells using single-sample Gene Set Enrichment Analysis (ssGSEA). CCT3-related pathway enrichment analysis was investigated by GSEA. Finally, CCT3 roles in cell proliferation and apoptosis of LUAD A549 cells was verified by siRNA (small interfering RNA) mediated CCT3 knockdown.

Results

CCT3 was upregulated in LUAD both in mRNA and protein levels. CCT3 overexpression was associated with clinicopathological characteristics including sex, smoking, T- and N-categories, pathological staging, and a poor prognosis of LUAD patients. GeneMANIA and String databases found a set of CCT3-related genes that are connected to the assembly and stability of proteins involved in proteostasis of cytoskeletal filaments, DNA repair and protein methylation. Furthermore, CCT3 was found to be positively correlated with the infiltrating Th2 cells (r = 0.442, p < 0.01) while negatively correlated with mast cells (r = -0.49, p < 0.01) and immature dendritic cells (iDCs, r = -0.401, p < 0.001) according to ssGSEA analyzes. The pathway analysis based on GSEA method showed that the cell cycle pathway, the protein export pathway, the proteasome pathway and the ribosome pathway are enriched in CCT3 high group, whereas the JAK/STAT pathway, B cell receptor pathway, T cell receptor pathway and toll like receptor pathway were enriched in CCT3 low group. Finally, CCT3 knockdown substantially inhibited proliferation while promoted apoptosis of A549 cells.

Conclusion

Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in LUAD and therefore, a prognostic factor for LUAD.
Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
Willison KR. The structure and evolution of eukaryotic chaperonin-containing TCP-1 and its mechanism that folds actin into a protein spring. Biochem J. 2018;475(19):3009–34.CrossRefPubMed
5.
Lin YF, Tsai WP, Liu HG, Liang PH. Intracellular beta-tubulin/chaperonin containing TCP1-beta complex serves as a novel chemotherapeutic target against drug-resistant tumors. Cancer Res. 2009;69(17):6879–88.CrossRefPubMed
6.
7.
Wang K, He J, Tu C, et al. Upregulation of CCT3 predicts poor prognosis and promotes cell proliferation via inhibition of ferroptosis and activation of AKT signaling in lung adenocarcinoma. BMC Mol Cell Biol. 2022;23(1):25.CrossRefPubMedPubMedCentral
8.
Shi H, Zhang Y, Wang Y, Fang P, Liu Y, Li W. Restraint of chaperonin containing T-complex protein-1 subunit 3 has antitumor roles in non-small cell lung cancer via affection of YAP1. Toxicol Appl Pharmacol. 2022;439:115926.CrossRefPubMed
9.
Danni X, Jiangzheng Z, Huamao S, Yinglian P, Changcheng Y, Yanda L. Chaperonin containing TCP1 subunit 3 (CCT3) promotes cisplatin resistance of lung adenocarcinoma cells through targeting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway. Bioengineered. 2021;12(1):7335–47.CrossRefPubMedPubMedCentral
10.
Chen S, Tian Y, Ju A, Li B, Fu Y, Luo Y. Suppression of CCT3 Inhibits Tumor Progression by Impairing ATP Production and Cytoplasmic Translation in Lung Adenocarcinoma.Int J Mol Sci. 2022. 23(7).
11.
Wang Y, Liu P, Zhang Z, Wang J, Cheng Z, Fan C. Identification of CCT3 as a prognostic factor and correlates with cell survival and invasion of head and neck squamous cell carcinoma.Biosci Rep. 2021. 41(10).
12.
Shi X, Cheng S, Wang W. Suppression of CCT3 inhibits malignant proliferation of human papillary thyroid carcinoma cell. Oncol Lett. 2018;15(6):9202–8.PubMedPubMedCentral
13.
Zhang Y, Wang Y, Wei Y, et al. Molecular chaperone CCT3 supports proper mitotic progression and cell proliferation in hepatocellular carcinoma cells. Cancer Lett. 2016;372(1):101–9.CrossRefPubMed
14.
15.
Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.CrossRefPubMed
16.
Uhlen M, Zhang C, Lee S et al. A pathology atlas of the human cancer transcriptome.Science. 2017. 357(6352).
17.
Chandrashekar DS, Bashel B, Balasubramanya S, et al. UALCAN: a portal for facilitating Tumor Subgroup Gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.CrossRefPubMedPubMedCentral
18.
19.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–W102.CrossRefPubMedPubMedCentral
20.
Warde-Farley D, Donaldson SL, Comes O et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function.Nucleic Acids Res. 2010. 38(Web Server issue):W214-20.
21.
Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–12.CrossRefPubMed
22.
Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–13.CrossRefPubMed
23.
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
24.
25.
26.
Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51(D1):D587–92.CrossRefPubMed
27.
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008.CrossRefPubMedPubMedCentral
28.
29.
Olson MF, Sahai E. The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis. 2009;26(4):273–87.CrossRefPubMed
30.
Kubota H, Hynes GM, Kerr SM, Willison KR. Tissue-specific subunit of the mouse cytosolic chaperonin-containing TCP-1. FEBS Lett. 1997;402(1):53–6.CrossRefPubMed
31.
32.
Kauko O, Westermarck J. Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer. Int J Biochem Cell Biol. 2018;96:157–64.CrossRefPubMed
33.
Goley ED, Welch MD. The ARP2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol. 2006;7(10):713–26.CrossRefPubMed
34.
Stirling PC, Cuéllar J, Alfaro GA, et al. PhLP3 modulates CCT-mediated actin and tubulin folding via ternary complexes with substrates. J Biol Chem. 2006;281(11):7012–21.CrossRefPubMed
35.
Seo S, Baye LM, Schulz NP, et al. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A. 2010;107(4):1488–93.CrossRefPubMedPubMedCentral
36.
Cannavo A, Liccardo D, Komici K, et al. Sphingosine Kinases and Sphingosine 1-Phosphate receptors: signaling and actions in the Cardiovascular System. Front Pharmacol. 2017;8:556.CrossRefPubMedPubMedCentral
37.
Gestaut D, Roh SH, Ma B, et al. The Chaperonin TRiC/CCT Associates with Prefoldin through a conserved electrostatic interface essential for Cellular Proteostasis. Cell. 2019;177(3):751–765e15.CrossRefPubMedPubMedCentral
38.
Xu L, Hu J, Zhao Y, et al. PDCD5 interacts with p53 and functions as a positive regulator in the p53 pathway. Apoptosis. 2012;17(11):1235–45.CrossRefPubMed
39.
40.
Mamrot J, Balachandran S, Steele EJ, Lindley RA. Molecular model linking Th2 polarized M2 tumour-associated macrophages with deaminase-mediated cancer progression mutation signatures. Scand J Immunol. 2019;89(5):e12760.CrossRefPubMedPubMedCentral
41.
42.
Ma Y, Shurin GV, Peiyuan Z, Shurin MR. Dendritic cells in the cancer microenvironment. J Cancer. 2013;4(1):36–44.CrossRefPubMed
43.
Liu Y, Zhang X, Lin J, et al. CCT3 acts upstream of YAP and TFCP2 as a potential target and tumour biomarker in liver cancer. Cell Death Dis. 2019;10(9):644.CrossRefPubMedPubMedCentral
44.
Dou L, Zhang X. Upregulation of CCT3 promotes cervical cancer progression through FN1.Mol Med Rep. 2021. 24(6).
45.
Temiz E, Koyuncu İ, Sahin E. CCT3 suppression prompts apoptotic machinery through oxidative stress and energy deprivation in breast and prostate cancers. Free Radic Biol Med. 2021;165:88–99.CrossRefPubMed
Metadata
Title
Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in lung adenocarcinoma
Authors
Junfeng Huang
Bingqi Hu
Ying Yang
Huanhuan Liu
Xingyu Fan
Jing Zhou
Liwen Chen
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10677-w

Other articles of this Issue 1/2023

BMC Cancer 1/2023 Go to the issue

Research

Investigating the functional role of SETD6 in lung adenocarcinoma

Research

Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients

Study Protocol

Protocol of the RACB study: a multicenter, single-arm, prospective study to evaluate the efficacy of resection of initially unresectable hepatocellular carcinoma with atezolizumab combined with bevacizumab

Study Protocol

Effect of a 1-year tailored exercise program according to cancer trajectories in patients with breast cancer: study protocol for a randomized controlled trial

Research

Evaluation of an eight marker-panel including long mononucleotide repeat markers to detect microsatellite instability in colorectal, gastric, and endometrial cancers

Research

Validation of hypermethylated DNA regions found in colorectal cancers as potential aging-independent biomarkers of precancerous colorectal lesions
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits