The diagnostic and prognostic value of CCTs in human hepatocellular carcinoma: a study based on integrated bioinformatics

doi:10.5246/jcps.2022.10.068

Abstract

Abstract:

Chaperonin-containing tailless complex polypeptide 1 (CCT) is a group of genes involved in protein folding. It has been reported to be associated with the genesis and development of multiple tumors. However, the expression levels and functions of distinct CCTs involved in carcinogenesis and progression of hepatocellular carcinoma (HCC) have not been systematically analyzed. In the present study, we aimed to investigate the expression and mutation patterns, diagnostic and prognostic value, and functional enrichment of CCTs in HCC using ONCOMINE, GEPIA, the Human Protein Atlas, cBioPortal, Kaplan-Meier Plotter, and R language. The transcriptional and translational levels of all CCT family members were remarkably higher in HCC patients and related to the tumor stage. All CCT family members, especially CCT2 and CCT8, might serve as promising diagnostic, prognostic markers as well as therapeutic targets for HCC.

Key words: CCT, Hepatocellular carcinoma, MicroRNAs, Target genes, Bioinformatics analysis

Supporting:

Weiwei Jiang, Haiyan Quan, Lu He, Xing Jiang. The diagnostic and prognostic value of CCTs in human hepatocellular carcinoma: a study based on integrated bioinformatics[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(10): 782-797.

Figures/Tables 10

Table 1. The transcriptional levels of CCT family members between HCC and normal liver tissues.

Table 2. Forest plot of OS and mRNA expressions of CCT family genes in HCC patients.

References 52

[1]	Chen, W.Q.; Zheng, R.S.; Baade, P.D.; Zhang, S.W.; Zeng, H.M.; Bray, F.; Jemal, A.; Yu, X.Q.; He, J. Cancer statistics in China, 2015. CA A Cancer J. Clin. 2016, 66, 115–132.
[2]	Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA A Cancer J. Clin. 2015, 65, 87–108.
[3]	Huang, Y.L.; Wang, H.B.; Lian, Y.F.; Wu, X.J.; Zhou, L.; Wang, J.L.; Deng, M.H.; Huang, Y.H. Upregulation of kinesin family member 4A enhanced cell proliferation via activation of Akt signaling and predicted a poor prognosis in hepatocellular carcinoma. Cell Death Dis. 2018, 9, 141.
[4]	Ning, G.; Huang, Y.L.; Zhen, L.M.; Xu, W.X.; Jiao, Q.; Yang, F.J.; Wu, L.N.; Zheng, Y.Y.; Song, J.; Wang, Y.S.; Xie, C.; Peng, L. Transcriptional expressions of Chromobox 1/2/3/6/8 as independent indicators for survivals in hepatocellular carcinoma patients. Aging. 2018, 10, 3450–3473.
[5]	Vallin, J.; Grantham, J. The role of the molecular chaperone CCT in protein folding and mediation of cytoskeleton-associated processes: implications for cancer cell biology. Cell Stress. Chaperones. 2019, 24, 17–27.
[6]	Kaisari, S.; Sitry-Shevah, D.; Miniowitz-Shemtov, S.; Teichner, A.; Hershko, A. Role of CCT chaperonin in the disassembly of mitotic checkpoint complexes. PNAS. 2017, 114, 956–961.
[7]	Tracy, C.M.; Gray, A.J.; Cuéllar, J.; Shaw, T.S.; Howlett, A.C.; Taylor, R.M.; Prince, J.T.; Ahn, N.G.; Valpuesta, J.M.; Willardson, B.M. Programmed cell death protein 5 interacts with the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT) to regulate β-tubulin folding. J. Biol. Chem. 2014, 289, 4490–4502.
[8]	Kasembeli, M.; Lau, W.C.Y.; Roh, S.H.; Eckols, T.K.; Frydman, J.; Chiu, W.; Tweardy, D.J. Modulation of STAT3 folding and function by TRiC/CCT chaperonin. PLoS Biol. 2014, 12, e1001844.
[9]	Svanström, A.; Grantham, J. The molecular chaperone CCT modulates the activity of the actin filament severing and capping protein gelsolin in vitro. Cell Stress. Chaperones. 2016, 21, 55–62.
[10]	Echbarthi, M.; Vallin, J.; Grantham, J. Interactions between monomeric CCTδ and p150^Glued: a novel function for CCTδ at the cell periphery distinct from the protein folding activity of the molecular chaperone CCT. Exp. Cell Res. 2018, 370, 137–149.
[11]	Rhodes, D.R.; Yu, J.J.; Shanker, K.; Deshpande, N.; Varambally, R.; Ghosh, D.; Barrette, T.; Pander, A.; Chinnaiyan, A.M. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004, 6, 1–6.
[12]	Tang, Z.F.; Li, C.W.; Kang, B.X.; Gao, G.; Li, C.; Zhang, Z.M. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017, 45, W98–W102.
[13]	Asplund, A.; Edqvist, P.H.D.; Schwenk, J.M.; Pontén, F. Antibodies for profiling the human proteome-The Human Protein Atlas as a resource for cancer research. Proteomics. 2012, 12, 2067–2077.
[14]	Nagy, Á.; Lánczky, A.; Menyhárt, O.; Győrffy, B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci. Rep. 2018, 8, 9227.
[15]	Menyhárt, O.; Nagy, Á.; Győrffy, B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. Royal Soc. Open Sci. 2018, 5, 181006.
[16]	Gao, J.J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.C.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sander, C.; Schultz, N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 2013, 6, pl1.
[17]	Cerami, E.; Gao, J.J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; Antipin, Y.; Reva, B.; Goldberg, A.P.; Sander, C.; Schultz, N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012, 2, 401–404.
[18]	Liu, J.F.; Lichtenberg, T.; Hoadley, K.A.; Poisson, L.M.; Lazar, A.J.; Cherniack, A.D.; Kovatich, A.J.; Benz, C.C.; Levine, D.A.; Lee, A.V.; Omberg, L.; Wolf, D.M.; Shriver, C.D.; Thorsson, V. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018, 173, 400–416.e11.
[19]	Yu, G.C.; Wang, L.G.; Han, Y.Y.; He, Q.Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS A J. Integr. Biol. 2012, 16, 284–287.
[20]	Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; von Mering, C. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2018, 47, D607–D613.
[21]	Roessler, S.; Jia, H.L.; Budhu, A.; Forgues, M.; Ye, Q.H.; Lee, J.S.; Thorgeirsson, S.S.; Sun, Z.T.; Tang, Z.Y.; Qin, L.X.; Wang, X.W. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010, 70, 10202–10212.
[22]	Wurmbach, E.; Chen, Y.B.; Khitrov, G.; Zhang, W.J.; Roayaie, S.; Schwartz, M.; Fiel, I.; Thung, S.; Mazzaferro, V.; Bruix, J.; Bottinger, E.; Friedman, S.; Waxman, S.; Llovet, J.M. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology. 2007, 45, 938–947.
[23]	Chen, X.; Cheung, S.T.; So, S.; Fan, S.T.; Barry, C.; Higgins, J.; Lai, K.M.; Ji, J.F.; Dudoit, S.; Ng, I.O.L.; van de Rijn, M.; Botstein, D.; Brown, P.O. Gene expression patterns in human liver cancers. Mol. Biol. Cell. 2002, 13, 1929–1939.
[24]	Pereira, J.H.; McAndrew, R.P.; Sergeeva, O.A.; Ralston, C.Y.; King, J.A.; Adams, P.D. Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy. Sci. Rep. 2017, 7, 3673.
[25]	Tang, N.H.; Cai, X.L.; Peng, L.R.; Liu, H.K.; Chen, Y.Z. TCP1 regulates Wnt7b/β-catenin pathway through P53 to influence the proliferation and migration of hepatocellular carcinoma cells. Signal Transduct. Target. Ther. 2020, 5, 169.
[26]	Yang, J.P.; Zhang, Z.P.; Zhao, Y.; Cheng, J.Z.; Zhao, C.; Wang, Z.G. CCT α is a novel biomarker for diagnosis of laryngeal squamous cell cancer. Sci. Rep. 2019, 9, 11823.
[27]	Guest, S.T.; Kratche, Z.R.; Bollig-Fischer, A.; Haddad, R.; Ethier, S.P. Two members of the TRiC chaperonin complex, CCT2 and TCP1 are essential for survival of breast cancer cells and are linked to driving oncogenes. Exp. Cell Res. 2015, 332, 223–235.
[28]	Liu, Y.J.; Chang, Y.J.; Kuo, Y.T.; Liang, P.H. Targeting β-tubulin/CCT-β complex induces apoptosis and suppresses migration and invasion of highly metastatic lung adenocarcinoma. Carcinogenesis. 2019, 41, 699–710.
[29]	Liu, Y.J.; Kumar, V.; Lin, Y.F.; Liang, P.H. Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation. Cell Death Dis. 2017, 8, e3052.
[30]	Showalter, A.E.; Martini, A.C.; Nierenberg, D.; Hosang, K.; Fahmi, N.A.; Gopalan, P.; Khaled, A.S.; Zhang, W.; Khaled, A.R. Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis. Sci. Rep. 2020, 10, 798.
[31]	Chang, Y.X.; Lin, Y.F.; Chen, C.L.; Huang, M.S.; Hsiao, M.; Liang, P.H. Chaperonin-containing TCP-1 promotes cancer chemoresistance and metastasis through the AKT-GSK3β-β-catenin and XIAP-survivin pathways. Cancers. 2020, 12, 3865.
[32]	Qu, H.B.; Zhu, F.; Dong, H.Y.; Hu, X.Q.; Han, M.L. Upregulation of CCT-3 induces breast cancer cell proliferation through miR-223 competition and Wnt/β-catenin signaling pathway activation. Front. Oncol. 2020, 10, 533176.
[33]	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.
[34]	Cui, X. Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma. World J. Gastroenterol. 2015, 21, 8588.
[35]	Liu, Y.; Zhang, X.; Lin, J.F.; Chen, Y.X.; Qiao, Y.X.; Guo, S.S.; Yang, Y.Y.; Zhu, G.Q.; Pan, Q.H.; Wang, J.Y.; Sun, F.Y. CCT3 acts upstream of YAP and TFCP₂ as a potential target and tumour biomarker in liver cancer. Cell Death Dis. 2019, 10, 644.
[36]	Kim, A.R.; Choi, K.W. TRiC/CCT chaperonins are essential for organ growth by interacting with insulin/TOR signaling in Drosophila. Oncogene. 2019, 38, 4739–4754.
[37]	Ryu, H.G.; Kim, S.; Lee, S.; Lee, E.; Kim, H.J.; Kim, D.Y.; Kim, K.T. HNRNP Q suppresses polyglutamine huntingtin aggregation by post-transcriptional regulation of vaccinia-related kinase 2. J. Neurochem. 2019, 149, 413–426.
[38]	Pavel, M.; Imarisio, S.; Menzies, F.M.; Jimenez-Sanchez, M.; Siddiqi, F.H.; Wu, X.T.; Renna, M.; O’Kane, C.J.; Crowther, D.C.; Rubinsztein, D.C. CCT complex restricts neuropathogenic protein aggregation via autophagy. Nat. Commun. 2016, 7, 13821.
[39]	Antona, V.; Scalia, F.; Giorgio, E.; Radio, F.C.; Brusco, A.; Oliveri, M.; Corsello, G.; Lo Celso, F.; Vadalà, M.; Conway de Macario, E.; Macario, A.J.L.; Cappello, F.; Giuffrè, M. A novel CCT5 missense variant associated with early onset motor neuropathy. Int. J. Mol. Sci. 2020, 21, 7631.
[40]	Darrow, M.C.; Sergeeva, O.A.; Isas, J.M.; Galaz-Montoya, J.G.; King, J.A.; Langen, R.; Schmid, M.F.; Chiu, W. Structural mechanisms of mutant huntingtin aggregation suppression by the synthetic chaperonin-like CCT5 complex explained by cryoelectron tomography. J. Biol. Chem. 2015, 290, 17451–17461.
[41]	He, J.C.; McLaughlin, R.P.; van der Beek, L.; Canisius, S.; Wessels, L.; Smid, M.; Martens, J.W.M.; Foekens, J.A.; Zhang, Y.H.; van de Water, B. Integrative analysis of genomic amplification-dependent expression and loss-of-function screen identifies ASAP1 as a driver gene in triple-negative breast cancer progression. Oncogene. 2020, 39, 4118–4131.
[42]	Zhu, Q.L.; Wang, T.F.; Cao, Q.F.; Zheng, M.H.; Lu, A.G. Inhibition of cytosolic chaperonin CCTζ-1 expression depletes proliferation of colorectal carcinoma in vitro. J. Surg. Oncol. 2010, 102, 419–423.
[43]	Li, B.; Lu, X.G.; Ma, C.; Sun, S.J.; Shu, X.Y.; Wang, Z.Y.; Sun, W.Q. Long non-coding RNA NEAT1 promotes human glioma tumor progression via miR-152-3p/CCT6A pathway. Neurosci. Lett. 2020, 732, 135086.
[44]	Hallal, S.; Russell, B.P.; Wei, H.; Lee, M.Y.T.; Toon, C.W.; Sy, J.; Shivalingam, B.; Buckland, M.E.; Kaufman, K.L. Extracellular vesicles from neurosurgical aspirates identifies chaperonin containing TCP1 subunit 6A as a potential glioblastoma biomarker with prognostic significance. Proteomics. 2019, 19, e1800157.
[45]	Zhang, T.; Shi, W.; Tian, K.; Kong, Y.S. Chaperonin containing t-complex polypeptide 1 subunit 6A correlates with lymph node metastasis, abnormal carcinoembryonic antigen and poor survival profiles in non-small cell lung carcinoma. World J. Surg. Oncol. 2020, 18, 156.
[46]	Zeng, G.F.; Wang, J.L.; Huang, Y.L.; Lian, Y.F.; Chen, D.M.; Wei, H.; Lin, C.S.; Huang, Y.H. Overexpressing CCT6A contributes to cancer cell growth by affecting the G1-to-S phase transition and predicts A negative prognosis in hepatocellular carcinoma. Oncotargets Ther. 2019, 12, 10427–10439.
[47]	Ying, Z.; Tian, H.; Li, Y.; Lian, R.; Li, W.; Wu, S.S.; Zhang, H.Z.; Wu, J.H.; Liu, L.; Song, J.W.; Guan, H.Y.; Cai, J.C.; Zhu, X.; Li, J.; Li, M.F. CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling. J. Clin. Investig. 2017, 127, 1725–1740.
[48]	Wang, L.W.; Zhou, W.; Li, H.; Yang, H.; Shan, N.C. Clinical significance, cellular function, and potential molecular pathways of CCT7 in endometrial cancer. Front. Oncol. 2020, 10, 1468.
[49]	Lin, X.D.; Lin, N.; Lin, T.T.; Wu, Y.P.; Huang, P.; Ke, Z.B.; Lin, Y.Z.; Chen, S.H.; Zheng, Q.S.; Wei, Y.; Xue, X.Y.; Lin, R.J.; Xu, N. Identification of marker genes and cell subtypes in castration-resistant prostate cancer cells. J. Cancer. 2021, 12, 1249–1257.
[50]	Liu, P.; Kong, L.M.; Jin, H.Y.; Wu, Y.H.; Tan, X.D.; Song, B. Differential secretome of pancreatic cancer cells in serum-containing conditioned medium reveals CCT8 as a new biomarker of pancreatic cancer invasion and metastasis. Cancer Cell Int. 2019, 19, 262.
[51]	Yang, X.J.; Ren, H.R.; Shao, Y.H.; Sun, Y.; Zhang, L.H.; Li, H.L.; Zhang, X.L.; Yang, X.M.; Yu, W.W.; Fu, J. Chaperonin-containing T‑complex protein 1 subunit 8 promotes cell migration and invasion in human esophageal squamous cell carcinoma by regulating α-actin and β-tubulin expression. Int. J. Oncol. 2018, 6, 2021–2030.
[52]	Huang, X.D.; Wang, X.X.; Cheng, C.; Cai, J.; He, S.; Wang, H.; Liu, F.; Zhu, C.L.; Ding, Z.M.; Huang, X.T.; Zhang, T.Y.; Zhang, Y.X. Chaperonin containing TCP1, subunit 8 (CCT8) is upregulated in hepatocellular carcinoma and promotes HCC proliferation. APMIS. 2014, 122, 1070–1079.