Identification of Seven Cell Cycle-Related Genes with Unfavorable Prognosis and Construction of their TF-miRNA-mRNA regulatory network in Breast Cancer

Hong, Zhipeng; Wang, Qinglan; Hong, Chengye; Liu, Meimei; Qiu, Pengqin; Lin, Ronggui; Lin, Xiaolan; Chen, Fangfang; Li, Qiuhuang; Liu, Lingling; Chen, Debo

doi:10.7150/jca.48245

Cited by 16 publications

(11 citation statements)

References 62 publications

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“…Recent studies using breast cancer tissue-specific microarray databases (GSE42568, GSE45827, and GSE54002) have reported a strong enrichment in cell cycle pathway genes 23 , which we also illustrate in Figure 1 A and S1. Common up- and down-regulated genes from these three microarray datasets were highly enriched in cell cycle regulation pathways from KEGG and WikiPathways (Figure 1 B, Table S5 ).…”

Section: Resultssupporting

confidence: 66%

“…The relevance of alterations of cell cycle regulators in breast cancer is strengthened by several -omics analyses and bioinformatic processing. For example, a recent study revisited breast cancer microarray datasets uncovering that differentially expressed genes are mainly enriched in cell cycle regulators 23 . Specifically, CDK4/6 oncogenic activation has been reported in luminal breast cancer, constituting one of the main tumorigenic drivers.…”

Section: Discussionmentioning

confidence: 99%

“…(A,B) Human breast tumours are enriched in cell cycle regulators. (A) Analysis from three breast cancer databases (GSE42568, GSE45827, and GSE54002) delineated 97 common differential expressed genes, as reported in 23 . In the STRING network, proteins are represented by the nodes, and interaction between proteins by edges.…”

Section: Figurementioning

confidence: 99%

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BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

Castellanet¹,

Ahmad²,

Vinik³

et al. 2021

Theranostics

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Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. Methods: Bioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26 Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Orthotopic studies in nude mice were applied for preclinical evaluation of efficacy and toxicity. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug's mechanisms of action. Results: We report that high expression levels of the BCL2L1 gene encoding BCL-XL and of specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26 Met and human TNBC cell lines tested. Combined blockage of BCL-XL and CDK1/2/4 interfered with tumour growth in vivo . Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell viability by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. Conclusions: Our studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.

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Section: Resultssupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

Castellanet¹,

Ahmad²,

Vinik³

et al. 2021

Theranostics

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“…Notably, previous studies showed that cell cycle regulators affected the progression of multiple types of tumors. Seven cell cycle-related genes have been identified with unfavorable prognosis of their TF-miRNA-mRNA regulatory network in breast cancer [ 31 ]. For TNBC, the correlation and mechanism between cell cycle regulators and TNBC progression need further in-depth study [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Cyclin B2 (CCNB2) Stimulates the Proliferation of Triple-Negative Breast Cancer (TNBC) Cells In Vitro and In Vivo

Jia

2021

Disease Markers

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Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Currently, targeting therapy makes great advances for the treatment of TNBC, whereas more effective therapeutic targets are urgently needed. Cyclin B2 (CCNB2), which belongs to B-type cyclins, is known as a cell cycle regulator. CCNB2 is synthesized at G1 phase in cancer cells and downregulated at anaphase. The defects of CCNB2 led to the abnormal cell cycle and tumorigenesis. Though there are wide effects of CCNB2 on multiple types of tumors, the potential role of CCNB2 in TNBC progression is still unclear. Herein, we found that CCNB2 was highly expressed in human TNBC tissues and correlated with the prognosis and clinical pathological features including tumor size ( p = 0.022 ∗ ) and pTNM stage ( p = 0.021 ∗ ) of patients with TNBC. CCNB2 could promote the proliferation of TNBC cells in vitro and in mice. Our findings therefore confirmed the involvement of CCNB2 in TNBC progression and provided the evidence that CCNB2 could serve as a promising molecular target of TNBC.

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“…On the other hand, studies have illustrated that miRNAs functioned as cancer-promoting or a cancer-suppressive genes, which played essential roles in tumorigenesis [ 11 – 13 ], As for miRNAs, a number of studies showed the roles of miR-10a-5p on cancers [ 14 , 15 ]. Otherwise, evidence has demonstrated that TF-miRNA axis played an important role in the development of carcinomas [ 16 , 17 ]. In this present study, miR-10a-5p was significantly decreased in melanoma on the basis of bioinformatics methods.…”

Section: Introductionmentioning

confidence: 99%

TCF21 regulates miR-10a-5p/LIN28B signaling to block the proliferation and invasion of melanoma cells

2021

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Background and aim Some research has suggested that miRNA-10a (miR-10a-5p) had an inhibitory function in proliferation and invasion of cancers. Whereas the role of miR-10a-5p in melanoma has not been fully explored. This study aims to confirm LIN28B as the targeted gene of miR-10a-5p which was explored in melanoma cells. In addition, upstream regulatory molecule of miR-10a-5p was also investigated in melanoma cells. Methods Real-time Quantitative polymerase chain reaction (RT-qPCR) was adopted to analyze miR-10a-5p expression level in melanoma and the normal human epidermal melanocyte cells. Several biological assays were performed to evaluate miR-10a-5p influences on cell proliferation, migration and invasion ability in A375 and B16-F10 cells. Gene prediction of miRNA targeting and a dual luciferase assay were applied to assess miR-10a-5p-targeted LIN28B. Western blot assessed the impacts of miR-10a-5p on the protein expression of LIN28B. Western blot analyzed the TCF21 effects on the expression of LIN28B and RT-qPCR assessed the influence of TCF21 on the expression level of miRNA-10a. In addition, Chromatin Immunoprecipitation (ChIP) Assay and JASPAR databases were employed to explore the regulatory relationship between TCF21 and miR-10a-5p. Results We discovered that miR-10a-5p expression was lower in melanoma cells and high expression of miR-10a-5p suppressed the proliferation, migration and invasion abilities of melanoma cells. We also discovered that miR-10a-5p targeted the LIN28B mRNA 3′UTR area and diminished LIN28B protein expression. We found that LIN28B expression was strongly decreased by TCF21 upregulation in the two melanoma cells. The qRT-PCR assay showed that miR-10a-5p expression level was obviously boosted by increased TCF21 expression. The results also demonstrated that TCF21 directly regulated miR-10a-5p at transcript levels. Conclusion TCF21 induced miRNA-10a targeting LIN28B could affect the progression and growth of melanoma.

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Identification of Seven Cell Cycle-Related Genes with Unfavorable Prognosis and Construction of their TF-miRNA-mRNA regulatory network in Breast Cancer

Cited by 16 publications

References 62 publications

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

Cyclin B2 (CCNB2) Stimulates the Proliferation of Triple-Negative Breast Cancer (TNBC) Cells In Vitro and In Vivo

TCF21 regulates miR-10a-5p/LIN28B signaling to block the proliferation and invasion of melanoma cells

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