Our work revealed that CCT2 tends to be overexpression in tumor tissues compared with normal tissues, and express more in more malignant grades and molecular subtypes of breast cancer. Genes correlated with CCT2 expression were mainly enriched in cell cycle pathway and also P53 signaling pathway. To the clinical aspects, our results indicated CCT2 expression was independently associated with worse prognosis of patients with breast cancer patients, especially in luminal A subtype. Additionally, we also explored potential relationships between CCTs gene family and their prognostic role in breast cancer.
Many previous studies have focused on colorectal cancer, gallbladder cancer, liver cancer, prostate cancer, small cell lung cancer and so on. For example, Park et al. found that the tissues of human colorectal cancer showed greater CCT2 expression than did the normal colon tissues, which indicated that higher CCT2 expression in tumor tissues from colorectal cancer patients reduced their survival rate. Besides, on the basis of the research conducted by Zou et al., in gallbladder cancer, the positive expression of PDIA3 and CCT2 was significantly associated with clinicopathological features of both squamous carcinoma/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC) specimens, consisting of lymph node metastasis and high TNM stage. Though there were several valuable outcomes, much more work related to BLCA, ESCA, HNSC, STAD, UCEC and renal tumors remains to be done, which will inevitably leads to a much more comprehensive understanding of the function of CCT2 in numerous cancers.
With regard to breast cancer, there were only three previous work directed towards the CCT2 has been published. The first one was a study conducted by AH Charpentier et al. released in 2000, they illustrated that Pescadillo and chaperonin CCT2 were two presumptive autocrine/paracrine factors of potential function in the regulation of the growth of breast cancer cells, which were identified to be highly up-regulated by E2 (17beta estradiol). Besides, the research conducted by Stephen T. Guest et al. represented some unique new findings. They identified that CCT1 and CCT2 were necessary for growth/survival of breast cancer cells in vitro and were determinants of overall survival in breast cancer patients. Apart from that, another research conducted by Anne E. Showalter et al., published in this year also drew some conclusions. By depleting or overexpressing the subunit in breast cancer and breast epithelial cells, they found that increasing CCT2 in cells by 1.3-1.8-fold also increased other CCT subunits’ (CCT3, CCT4, and CCT5) levels, while silencing the expression of CCT2 by ~ 50% was able to cause other CCT subunits to reduce. Besides, their study also represented that cells expressing higher CCT2 were more invasive and showed a higher proliferative index, and depletion of CCT2 in a syngeneic murine model of triple negative breast cancer (TNBC) had a potential to prevent tumor growth.
Though all these previous studies laid emphasis on the significance of CCT2 in breast cancer, what they focused on was only the growth and survival of breast cancer cells. There was no comprehensive and detailed conclusion towards different biological, clinical and molecular characteristics of each distinct subtype. More importantly, transcriptome data we used in this study were derived from the top two biggest independent breast cancer databases, which enabled our outcomes much more overall and reliable.
As for other functions of CCT2, Park et al. found that reduction in CCT2 inhibited tumor induction by Gli-1, and ubiquitination-mediated Gli-1 degradation by β-TrCP occurred during incomplete folding of Gli-1 in hypoxia. CCT2 correlates with Gli-1 expression is an important determinant of survival in the colorectal cancer patients. Besides, based on the study conducted by Lu et al., they discovered that as an essential enzyme in de novo synthesis of purine, phosphoribosylformylglycinamidine synthase (PFAS) interacted with several proteins which played physiological roles in tumor development including CAD, CCT2, PRDX1, and PHGDH, and it was also able to deamidate PHGDH, and induce other posttranslational modification into CAD, CCT2 and PRDX1. When it comes to other subunits of CCT complex, previous studies has reported some valuable points. In various cancers, the expression levels of different CCT subunits were upregulated in varying degrees: CCT3 in hepatocellular carcinoma, and CCT8 in hepatocellular carcinoma and glioblastoma[39, 40]. Based on study conducted by Hallal et al., extracellular vesicles from neurosurgical aspirates identified CCT6A as a potential glioblastoma biomarker with prognostic significance. Another group found that overexpression of CCT1 in yeast did not exert any effect on levels of assembled complex, but the CCT1 subunits which were remained soluble in the cytosol had inherent activity of protein-folding. In terms of CCT subunits acting as monomers, scientiests found that CCT4 was able to produce a protusion phenotype by interacting with microtubules and p150glued[43, 44]. CCT5 and CCT8 could colocalize with actin fibers outside of the oligomer54, and CCT5 also played a key role in the transcriptional regulation of actin. Previous study also represented CCT5 had correspondence with breast cancer. Ooe A et al. discovered that CCT5, RGS3, and YKT6 mRNA expressions, which were up-regulated in p53-mutated breast cancers, might be involved in resistance to docetaxel and clinically feasible in distinguish the subset of breast cancer patients who may or may not be benefit from docetaxel therapy. Apart from that, CCT5 was identified to be closely related to lung cancer. Gao H et al. showed that CCT5 could induce an autoantibody response in non-small cell lung cancer (NSCLC) sera and showed higher expression in NSCLC tissues by Western blot and immunohistochemistry. Knockdown of CCT5, PIP4K2A, EXO1, CMBL, OPN3 and KMO, genes within 200 kb up/downstream of the 3 SNPs that were corresponded with small cell lung cancer (SCLC) overall survival. In addition, CCT5 also participated in replication of hepatitis C virus genome through interaction with the viral NS5B protein. However, the role of CCT in many diseases, including cancer, is far from fully characterized, needing much more researches and studies towards that.
Consistent to our results, some studies also reported the potential role of inhibiting cancer cell by targeting CCTs. For instance, Showalter Anne E et al., discovered one CCT inhibitor named CT20p, which had access to kill cancer cells in a CCT-dependent manner. In cancer cells where the CCT was inhibited, they were resistant to CT20p killing, while cells where the expression of CCT was increased were susceptible[15, 50]. However, given the fact that the complexity of CCT and its multiple subunits, as well as the lack of a complete understanding of CCT substrate selectivity in vivo, there are inevitably some challenges that impede the development of feasible and effective therapeutics like CT20p. In summary, we discussed the role of CCT2 in tumors together with current researches regarding CCTs gene family. Future research focus on investigating the underlying molecular mechanisms of CCT2 in promoting cancer might yield novel insights for possible treatments by targeting CCT2.