The Role of CDK5 in Tumours and Tumour Microenvironments

Anh, Phuong; Lee, Chang Hoon

doi:10.3390/cancers13010101

Cited by 32 publications

(20 citation statements)

References 244 publications

(182 reference statements)

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“…low CDK3 expression and high CDK5 and CDK8 expression are associated with poor survival. CDK3 has been reported to promote myoblast cell proliferation; 31 Yue et al showed that CDK5 promotes the proliferation of medullary thyroid carcinoma cells; 32 in addition, Chen et al showed that the promotion of OSCC cell proliferation by direct binding of miR-567 leads to increased CDK8 expression. 33 These previous findings suggest that CDK3, CDK5 and CDK8 is an oncogene.…”

Section: Discussionmentioning

confidence: 99%

CDK3, CDK5 and CDK8 Proteins as Prognostic and Potential Biomarkers in Colorectal Cancer Patients

Wang¹,

Zhou²,

Liu³

et al. 2022

IJGM

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Introduction In the cell cycle, cyclin-dependent kinases (CDKs) play a positive regulatory role, which is essential for normal cell growth, but the expression pattern and prognostic significance of the CDK family in colorectal cancer (CRC) have not been systematically investigated. Methods In our study, we analyzed and visualized the expression of CDKs in CRC using TCGA, GEPIA, GSCALite, TIMER, HPA database, and R language CDKs risk model was constructed. Results Overall, CDKs (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7 and CDK8) were differentially expressed between normal controls and colorectal cancer. Three CDKs genes (CDK3, CDK5 and CDK8) associated with prognosis were obtained by univariate and multivariate Cox and LASSO regression analysis. In CRC, CDK3, CDK5 and CDK8 are significantly associated with expression levels of recognized immune infiltrates. Conclusion CDK3, CDK5 and CDK8 are potential diagnostic markers for CRC; meanwhile, CDK3, CDK5 and CDK8 are potential prognostic markers for CRC; studying the relationship between CDKs and tumor immunology may be helpful for immunotherapy of CRC, and more studies are needed to confirm these results.

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Section: Discussionmentioning

confidence: 99%

CDK3, CDK5 and CDK8 Proteins as Prognostic and Potential Biomarkers in Colorectal Cancer Patients

Wang¹,

Zhou²,

Liu³

et al. 2022

IJGM

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“…Cyclin-dependent kinase 5 (CDK5) is a member of the protein kinase family that has been shown to play a role in cancer development and the TME ( Do and Lee, 2020 ). Abnormal activation of CDK5 affects the development of triple negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Our study found that TMB score and MSI was positively correlated with the expression of EFNA3 and EFNA4 in gastric cancer. Cyclin-dependent kinase 5 (CDK5) is a member of the protein kinase family that has been shown to play a role in cancer development and the TME (Do and Lee, 2020). Abnormal activation of CDK5 affects the development of triple negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer

Xie

Yuan

Jiang

2022

Front. Cell Dev. Biol.

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Background:EFNA1–5 have important physiological functions in regulating tumorigenesis and metastasis. However, correlating EFNA genes in the tumor immune microenvironment (TIME), and the prognosis of patients with gastric cancer remains to be determined.Methods: Using public databases, the expression of EFNA1-5 in pan-cancer and gastric cancer was comprehensively analyzed using UCSC Xena, the Oncomine dataset and UALCAN. We further completed survival analysis by Kaplan-Meier plotter to evaluate the prognosis of the high and low expression groups of the EFNAs gene in patients with gastric cancer. The TIMER tool was used to reveal the correlation between immune cell infiltration and genes of interest. Spearman correlation was used to find an association between the EFNA genes and tumor stem cells, TIME, microsatellite instability (MSI) or tumor mutational burden (TMB). We also used cBioportal, GeneMANIA and STRINGS to explore the types of changes in these genes and the protein interactions. Finally, we described the TIME based on QUANTISEQ algorithm, predicted the relationship between the EFNA genes and half-maximal inhibitory concentration (IC50), and analyzed the relationship between the EFNA family genes and immune checkpoints.Results: The expression of EFNA1, EFNA3, EFNA4, and EFNA5 was elevated in pan-cancer. Compared with normal adjacent tissues, EFNA1, EFNA3, and EFNA4 were up-regulated in gastric cancer. In terms of the influence on the survival of patients, the expression of EFNA3 and EFNA4 were related to overall survival (OS) and disease-free survival (DFS) for patients with gastric cancer. High expression of EFNA5 often predicted poor OS and DFS. In gastric cancer, the expression of EFNA3 and EFNA4 showed a significant negative correlation with B cells. The higher the expression of EFNA5, the higher the abundance of B cells, CD4+T cells and macrophages. CD8+T cells, dendritic cells infiltration and EFNA1-4 expression were negatively correlated. The infiltration of CD4+T cells, macrophages and neutrophils was negatively correlated with the expression of EFNA1, EFNA3, and EFNA4. TMB and MSI were positively correlated with EFNA3/EFNA4 expression. In the tumor microenvironment and drug sensitivity, EFNA3/4/5 also showed a significant correlation. In addition, we explored the relationship between the EFNA family genes and the immune microenvironment (B cells, M2 macrophages, monocytes, CD8+ T cells, regulatory T cells, myeloid dendritic cells, natural killer cells, non-regulatory CD4+ T cells), immune checkpoint (PDCD1, PDCD1LG2, CD274, CTLA4), and IC50 of common chemotherapeutic drugs for gastric cancer (5-fluorouracil, cisplatin, docetaxel and gemcitabine).Conclusions: Our study provides new ideas for tumor treatment and prognosis from the perspective of TIME, and nominates EFNA1–5 to become potential therapeutic targets for gastric cancer.

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“…However, there could be additional reasons for the failure of roscovitine to improve GC-induced impaired bone healing. For example, because Cdk5 is known to regulate inflammation [ 91 , 92 , 93 , 94 ], its inhibition could possibly exacerbate GC effects on the immune response upon fracture, which is essential for downstream regenerative processes [ 22 , 88 , 89 , 95 ]. Another possible reason could be that Cdk5 inhibition or high-dose GCs adversely affects angiogenesis [ 16 , 96 , 97 , 98 , 99 , 100 , 101 ], a process that is essential for uneventful fracture healing [ 89 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Cdk5 Ameliorates Skeletal Bone Loss in Glucocorticoid-Treated Mice

et al. 2022

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Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, their long-term use leads to glucocorticoid-induced osteoporosis, increasing morbidity and mortality. Both anabolic and anti-resorptive drugs are used to counteract GC-induced bone loss, however, they are expensive and/or have major side effects. Therefore, identifying new targets for cost-effective, small-molecule inhibitors is essential. We recently identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation and showed that its inhibition with roscovitine promoted osteoblastogenesis, thus improving the skeletal bone mass and fracture healing. Here, we assessed whether Cdk5 knockdown or inhibition could also reverse the GC-mediated suppression of osteoblast differentiation, bone loss, and fracture healing. We first demonstrated that Cdk5 silencing abolished the dexamethasone (Dex)-induced downregulation of alkaline phosphatase (Alp) activity, osteoblast-specific marker gene expression (Runx2, Sp7, Alpl, and Bglap), and mineralization. Similarly, Cdk5 inhibition rescued Dex-induced suppression of Alp activity. We further demonstrated that Cdk5 inhibition reversed prednisolone (Pred)-induced bone loss in mice, due to reduced osteoclastogenesis rather than improved osteoblastogenesis. Moreover, we revealed that Cdk5 inhibition failed to improve Pred-mediated impaired fracture healing. Taken together, we demonstrated that Cdk5 inhibition with roscovitine ameliorated GC-mediated bone loss but did not reverse GC-induced compromised fracture healing in mice.

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The Role of CDK5 in Tumours and Tumour Microenvironments

Cited by 32 publications

References 244 publications

CDK3, CDK5 and CDK8 Proteins as Prognostic and Potential Biomarkers in Colorectal Cancer Patients

CDK3, CDK5 and CDK8 Proteins as Prognostic and Potential Biomarkers in Colorectal Cancer Patients

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer

Inhibition of Cdk5 Ameliorates Skeletal Bone Loss in Glucocorticoid-Treated Mice

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