image: (A) Up-regulation of 311 genes in HNSCC tumor tissues compared with adjacent normal tissues across the TCGA HNSC, GSE127165, GSE10121, GSE37991, and GSE30784 datasets. (B) CCT2 was highly expressed in tumor tissues compared with adjacent normal tissues. (C) Identification of 45 common prognosis-associated genes through univariate Cox regression analysis in the GSE41613 and GSE42743 datasets. (D) Forest plot of univariate Cox regression analysis for 45 common prognosis-associated genes in the GSE41613 dataset. (E) High expression of CCT2 predicted poor prognosis in GSE41613, GSE42743, and TCGA datasets. (F) Representative immunohistochemistry images illustrating the expression levels of CCT2 and Ki-67 in HNSCC tissues and normal epithelium. (G) Distribution of CCT2 immunohistochemistry scores in tumor and adjacent normal tissues. (H) Western blotting analysis of CCT2 expression was performed on paired tumor and adjacent normal tissues from three HNSCC samples. (I, J) Western blotting and quantitative PCR analysis of CCT2 expression in HNSCC cell lines (HSC-3, CAL-27, and SAS) and normal epithelial cell lines (HOEC and HIEC6). Data were presented as mean ± standard deviation. ∗∗∗p < 0.001 and ∗∗∗∗p < 0.0001 for student's t-test and one-way ANOVA test. CCT2, chaperonin containing TCP1 subunit 2; HNSCC, head and neck squamous cell carcinoma.
Credit: Lin Lu, Yi Shen, Xuerong Li, Yiwei Zhao, Xuefan Zhai, Min Cai, Baicheng Bao, Guiqing Liao, Jianbo Sun
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by poor survival due to rapid progression, metastasis, and cisplatin resistance. The chaperonin containing TCP-1 subunit 2 (CCT2), a subunit of the chaperonin-containing TCP-1 (CCT) complex, has been previously implicated in several cancers, but its specific role and contribution to chemoresistance in HNSCC remain elusive.
This study in Genes & Diseases by researchers from Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, and Guangdong Medical University investigated the role of CCT2 in driving tumor growth, progression, and both cell-intrinsic and vesicle-mediated drug resistance in HNSCC.
Analysis of TCGA and multiple GEO datasets, together with examination of HNSCC tissues and cell lines, showed that CCT2 is overexpressed in HNSCC and associated with poor prognosis, advanced clinical stage, and aggressive tumor characteristics. Functional experiments demonstrated that CCT2 depletion suppressed HNSCC cell proliferation and tumor growth in vitro and in vivo. CCT2 knockdown also reduced migration and invasion, accompanied by increased E-cadherin and decreased N-cadherin, vimentin, and Slug, indicating suppression of epithelial–mesenchymal transition.
CCT2 expression positively correlated with cisplatin IC50 values across HNSCC cell lines, while CCT2 knockdown increased cisplatin sensitivity both in vitro and in vivo. Mechanistic analyses showed enrichment of MYC-related pathways in CCT2-high tumors. Co-immunoprecipitation demonstrated a direct interaction between CCT2 and c-Myc, and cycloheximide-chase experiments showed that CCT2 knockdown reduced c-Myc stability and shortened its half-life. CCT2 also influenced cell-cycle regulators, including CCND1 and CCNE1.
Functional experiments further established c-Myc as a downstream mediator of CCT2. c-Myc overexpression in CCT2-deficient cells restored cell-cycle progression and partially rescued impaired migration and invasion, whereas c-Myc knockdown increased cisplatin sensitivity. These findings indicate that CCT2 promotes HNSCC aggressiveness and chemoresistance, at least partly, by stabilizing c-Myc and regulating downstream cell-cycle programs.
The study also identified apoptotic vesicles (apoVs) as a mechanism for transferring chemoresistance between tumor cells. ApoVs released from cisplatin-treated HNSCC cells contained CCT2 and were internalized by recipient tumor cells. CCT2-containing apoVs increased CCT2 and c-Myc levels, altered cell-cycle regulators, accelerated cell-cycle progression, and enhanced cisplatin resistance in recipient cells, whereas apoVs from CCT2-depleted cells had weaker effects. These findings suggest that chemotherapy-induced apoVs can facilitate the non-genetic transfer of CCT2 and promote drug tolerance among neighboring tumor cells.
Overall, the study identifies CCT2 as a regulator of HNSCC progression and cisplatin resistance. CCT2 promotes proliferation, migration, and invasion while reducing cisplatin sensitivity through interaction with and stabilization of c-Myc. ApoV-mediated CCT2 transfer provides an additional mechanism for enhancing chemoresistance within tumor populations, supporting CCT2 as a potential therapeutic target for HNSCC.
Reference
Title of the original paper: CCT2 enhances c-Myc stabilization to drive tumor progression and chemoresistance in head and neck squamous cell carcinoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101795
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