Abstract
The prognosis role of CCT3 in MM and the possible pathways it involved were studied in our research. By analyzing ten independent datasets (including 48 healthy donors, 2220 MM, 73 MGUS, and 6 PCL), CCT3 was found to express higher in MM than healthy donors, and the expression level was gradually increased from MGUS, SMM, MM to PCL (all Pā<ā0.01). By analyzing three independent datasets (GSE24080, GSE2658, and GSE4204), we found that CCT3 was a significant indicator of poor prognosis (all Pā<ā0.01). KEGG and GSEA analysis showed that CCT3 expression was associated with JAK-STAT3 pathway, Hippo signaling pathway, and WNT signaling pathway. In addition, different expressed genes analysis revealed MYC, which was one of the downstream genes regulated by JAK-STAT3 pathway, was upregulated in MM. This confirms that JAK-STAT3 signaling pathway may promote the progress of disease which was regulated by CCT3 expression. Our study revealed that CCT3 may play a supporting role at the diagnosis of myeloid, and high expression of CCT3 suggested poor prognosis in MM. CCT3 expression may promote the progression of MM mainly by regulating MYC through JAK-STAT3 signaling pathway.
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References
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl J Med. 2016;375:754ā66.
Chavan SS, He J, Tytarenko R, Deshpande S, Patel P, Bailey M, et al. Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J. 2017;7:e535.
Hideshima T, Cottini F, Nozawa Y, Seo HS, Ohguchi H, Samur MK, et al. p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood. 2017;129:1308ā19.
Zhang W, Lin Y, Liu X, He X, Zhang Y, Fu W, et al. Prediction and prognostic significance of BCAR3 expression in patients with multiple myeloma. J Transl Med. 2018;16:363.
Zhang W, Zhang Y, Yang Z, Liu X, Yang P, Wang J, et al. High expression of UBE2T predicts poor prognosis and survival in multiple myeloma. Cancer Gene Ther. 2019. https://doi.org/10.1038/s41417-018-0070-x.
Solimando AG, Brandl A, Mattenheimer K, Graf C, Ritz M, Ruckdeschel A, et al. JAM-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia. 2018;32:736ā43.
Hao M, Zang M, Wendlandt E, Xu Y, An G, Gong D, et al. Low serum miR-19a expression as a novel poor prognostic indicator in multiple myeloma. Int J Cancer. 2015;136:1835ā44.
Poon TCW, Wong N, Lai PBS, Rattray M, Johnson PJ, Sung JJY. A tumor progression model for hepatocellular carcinoma: bioinformatic analysis of genomic data. Gastroenterology. 2006;131:1262ā70.
Gu J, Xuan Z. Inferring the perturbed microRNA regulatory networks in cancer using hierarchical gene co-expression signatures. PLoS ONE. 2013;8:e81032.
Yamaguchi H, Wyckoff J, Condeelis J. Cell migration in tumors. Curr Opin Cell Biol. 2005;17:559ā64.
Yang X, Ren H, Shao Y, Sun Y, Zhang L, Li H, et al. Chaperonin-containing T-complex protein 1 subunit 8 promotes cell migration and invasion in human esophageal squamous cell carcinoma by regulating Ī±-Actin and Ī²-tubulin expression. Int J Oncol. 2018;52:2021ā30.
Shi X, Cheng S, Wang W. Suppression of CCT3 inhibits malignant proliferation of human papillary thyroid carcinoma cell. Oncol Lett. 2018;15:9202ā8.
Li LJ, Zhang LS, Han ZJ, He ZY, Chen H, Li YM. Chaperonin containing TCP-1 subunit 3 is critical for gastric cancer growth. Oncotarget. 2017;8:111470ā81.
Song Y, Li S, Ray A, Das DS, Qi J, Samur MK, et al. Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene. 2017;36:5631ā8.
Kang YJ, Zeng W, Song W, Reinhold B, Choi J, Brusic V, et al. Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DObeta as a novel target for multiple myeloma. Br J Haematol. 2013;163:343ā51.
Chauhan D, Tian Z, Nicholson B, Kumar KGS, Zhou B, Carrasco R, et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell. 2012;22:345ā58.
Zhan F, Barlogie B, Arzoumanian V, Huang Y, Williams DR, Hollmig K, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood. 2007;109:1692ā700.
Driscoll JJ, Pelluru D, Lefkimmiatis K, Fulciniti M, Prabhala RH, Greipp PR, et al. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood. 2010;115:2827ā34.
Chng WJ, Kumar S, Vanwier S, Ahmann G, Price-Troska T, Henderson K, et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 2007;67:2982ā9.
Tiedemann RE, Zhu YX, Schmidt J, Yin H, Shi C-X, Que Q, et al. Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. Blood. 2010;115:1594ā604.
Gutierrez NC, Sarasquete ME, Misiewicz-Krzeminska I, Delgado M, De Las Rivas J, Ticona FV, et al. Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling. Leukemia. 2010;24:629ā37.
Heuck CJ, Szymonifka J, Hansen E, Shaughnessy JDJ, Usmani SZ, van Rhee F, et al. Thalidomide in total therapy 2 overcomes inferior prognosis of myeloma with low expression of the glucocorticoid receptor gene NR3C1. Clin Cancer Res. 2012;18:5499ā506.
Popovici V, Chen W, Gallas BG, Hatzis C, Shi W, Samuelson FW, et al. Effect of training-sample size and classification difficulty on the accuracy of genomic predictors. Breast Cancer Res. 2010;12:R5.
Shi L, Campbell G, Jones WD, Campagne F, Wen Z, Walker SJ, et al. The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models. Nat Biotechnol. 2010;28:827ā38.
Mitchell JS, Li N, Weinhold N, Forsti A, Ali M, van Duin M, et al. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun. 2016;7:12050.
Hanamura I, Huang Y, Zhan F, Barlogie B, Shaughnessy J. Prognostic value of cyclin D2 mRNA expression in newly diagnosed multiple myeloma treated with high-dose chemotherapy and tandem autologous stem cell transplantations. Leukemia. 2006;20:1288ā90.
Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020ā8.
Chen L, Wang S, Zhou Y, Wu X, Entin I, Epstein J, et al. Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma. Blood. 2010;115:61ā70.
Qiang Y-W, Ye S, Huang Y, Chen Y, Van Rhee F, Epstein J, et al. MAFb protein confers intrinsic resistance to proteasome inhibitors in multiple myeloma. BMC Cancer. 2018;18:724.
Went M, Sud A, Forsti A, Halvarsson B-M, Weinhold N, Kimber S, et al. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun. 2018;9:3707.
Papanikolaou X, Alapat D, Rosenthal A, Stein C, Epstein J, Owens R, et al. The flow cytometry-defined light chain cytoplasmic immunoglobulin index and an associated 12-gene expression signature are independent prognostic factors in multiple myeloma. Leukemia. 2015;29:1713ā20.
Yu G, Wang L-G, Han Y, He Q-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284ā7.
Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267ā73.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545ā50.
Yasui W, Oue N, Phyu PA, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8:86ā94.
Midorikawa Y, Sugiyama Y, Aburatani H. Molecular targets for liver cancer therapy: from screening of target genes to clinical trials. Hepatol Res. 2010;40:49ā60.
Cui X, Hu ZP, Li Z, Gao PJ, Zhu JY. Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma. World J Gastroenterol. 2015;21:8588ā604.
Zhang Z, Xu L, Sun C. Comprehensive characterization of cancer genes in hepatocellular carcinoma genomes. Oncol Lett. 2018;15:1503ā10.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Multiple myeloma Version 3. 2019. https://www.nccn.org/professionals/physician_gls/default.aspx#. Accessed 19 June 2019.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues (Revised 4th edition). Lyon: IARC; 2017.
Qian EN, Han SY, Ding SZ, Lv X. Expression and diagnostic value of CCT3 and IQGAP3 in hepatocellular carcinoma. Cancer Cell Int. 2016;16:55.
Bournazou E, Bromberg J. Targeting the tumor microenvironment: JAK-STAT3 signaling. JAK-STAT. 2013;2:e23828.
Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trends Biochem Sci. 2000;25:496ā502.
Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol. 2012;30:1005ā14.
CuƩllar J, Ludlam WG, Tensmeyer NC, Aoba T, Dhavale M, Santiago C, et al. Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly. Nat Commun. 2019;10:2865.
Morales JK, Falanga YT, Depcrynski A, Fernando J, Ryan JJ. Mast cell homeostasis and the JAK-STAT pathway. Genes Immun. 2010;11:599ā608.
Barron DA, Kagey JD. The role of the Hippo pathway in human disease and tumorigenesis. Clin Transl Med. 2014;3:25.
Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491ā505.
Staal FJT, Clevers HC. WNT signalling and haematopoiesis: A WNT-WNT situation. Nat Rev Immunol. 2005;5:21ā30.
Acknowledgements
This work was supported by grants from Xinjiang Joint Fund of National Natural Science Foundation of China (U1903117), the National Natural Science Foundation of China (81500118) to LF; and the National Natural Science Foundation of China (81600089) to JC. We thank the GEO Database and all the providers of datasets used in this report. Including GSE39754, GSE5900, GSE2113, GSE6477, GSE16558, GSE82307, GSE38627, GSE24080, GSE2658, and GSE4204.
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Qian, T., Cui, L., Liu, Y. et al. High expression of chaperonin-containing TCP1 subunit 3 may induce dismal prognosis in multiple myeloma. Pharmacogenomics J 20, 563ā573 (2020). https://doi.org/10.1038/s41397-019-0145-6
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DOI: https://doi.org/10.1038/s41397-019-0145-6