Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system

Li, Koukou; Wu, Renfei; Zhou, Muya; Tong, Haibo; Luo, Kathy Qian

doi:10.1126/sciadv.abg7265

Cited by 32 publications

(45 citation statements)

References 73 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recently published study by Li et al accentuates that elevated DSC2 expression, in combination with the desmosomal protein Plakophilin-1 (PKP1), can activate PI3K/AKT or CDH1 to increase cluster formation to resist shear-stress-induced cell death. Furthermore, higher expression of DSC2 and PKP1 was correlated with lower overall survival and worse disease progression in patients with breast and lung cancer [31]. The aim of this study was to investigate the potential of DSC2 at mRNA and protein level as a predisposing factor for breast cancer progression and the development of breast cancer metastases, in particular to the lung and brain.…”

Section: Introductionmentioning

confidence: 99%

The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients

et al. 2023

View full text Add to dashboard Cite

Background The disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer. Methods We analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo. Results We found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free—also in multivariate analysis—and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions. Conclusion We conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation.

show abstract

Section: Introductionmentioning

confidence: 99%

The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients

et al. 2023

View full text Add to dashboard Cite

show abstract

“…For example, ACSL6 was down-regulated to possibly interfere in the metabolites of fatty acids, abnormality of which is one of the cancer hallmarks (63). Another gene of PKP1 was inhibited to prevent the survival and metastasis of cancer cells by decreasing cluster formation in circulatory system (64). Moreover, there are also other RNA editing events whose functions in cancers were bio-experimentally validated, including H241R editing (CAediting_604339) in PODXL (5), K242R/K242E (CAediting_1062027, CAediting_1062028) editing in NEIL1 (65), two editing events (CAediting_442015, CAediting_442019) in the 3’-UTR of GM2A (66), and so on.…”

Section: Discussionmentioning

confidence: 99%

The Integrative Studies on the Functional A-to-I RNA Editing Events in Human Cancers

Fan

Kim

et al. 2022

Preprint

View full text Add to dashboard Cite

A-to-I RNA editing, constituting nearly 90% of all RNA editing events in human, has been reported to contribute to the tumorigenesis in diverse cancers. However, there was not enough attention to the functional A-to-I RNA editing events in human cancers. To fill this gap, we systematically and intensively analyzed multiple tumorigenic mechanisms of A-to-I RNA editing events in samples across 33 cancer types from The Cancer Genome Atlas. For individual candidate among ~ 1.5M quantified RNA editing events, we performed diverse types of down-stream functional annotations. Finally, we identified 24,236 potentially functional A-to-I RNA editing events, including the cases in APOL1, IGFBP3, GluA2, BLCAP, and miR-589-3p. These events showed significant results and might play crucial roles in the scenarios of tumorigenesis, due to their tumor-related editing frequencies or probable effects on altered expression profiling, protein functions, splicing patterns, and miRNA regulations of tumor genes. Our functional A-to-I RNA editing events (https://ccsm.uth.edu/CAeditome/) will help better understanding of cancer pathology from the RNA editing aspect.

show abstract

“…We assume that these genes contribute to the formation of cell-cell junctions in the aggregate (Figure 3B). This observation is crucial because disrupting the formation of cell junctions by knocking down the desmosomal genes can lead to anoikis in breast cancer cell lines (18). We plan to observe the changes of these junctional structures by conducting a functional gene analysis in detached SAS cells.…”

Section: Discussionmentioning

confidence: 99%

“…Knockdown of these genes inhibits cancer cell aggregation and induces anoikis through inhibition of the Src and ERK1/2 pathways (10,16). Importantly, aggregated cancer cells have higher metastatic ability compared with single cancer cells in circulation of the lymphatic and blood systems (17)(18)(19). Therefore, disrupting aggregates is proposed as a therapeutic strategy for cancer metastasis.…”

mentioning

confidence: 99%

Cytomorphology and Gene Expression Signatures of Anchorage-independent Aggregations of Oral Cancer Cells

Sakurai

Nagai

Ando

et al. 2022

Cancer Genomics Proteomics

View full text Add to dashboard Cite

Background/Aim: Cancer cells with high anchorage independence can survive and proliferate in the absence of adhesion to the extracellular matrix. Under anchorage-independent conditions, cancer cells adhere to each other and form aggregates to overcome various stresses. In this study, we investigated the cytomorphology and gene expression signatures of oral cancer cell aggregates. Materials and Methods: Two oral cancerderived cell lines, SAS and HSC-3 cells, were cultured in a low-attachment plate and their cytomorphologies were observed. The transcriptome between attached and detached SAS cells was examined using gene expression microarrays. Subsequently, gene enrichment analysis and Ingenuity Pathway Analysis were performed. Gene expression changes under attached, detached, and re-attached conditions were measured via RT-qPCR. Results: While SAS cells formed multiple round-shaped aggregates, HSC-3 cells, which had lower anchorage independence, did not form aggregates efficiently. Each SAS cell in the aggregate was linked by desmosomes and tight junctions. Comparative transcriptomic analysis revealed 1,698 differentially expressed genes (DEGs) between attached and detached SAS cells. The DEGs were associated with various functions and processes, including cell adhesion. Moreover, under the detached condition, the expression of some epithelial genes (DSC3, DSP, CLDN1 and OCLN) were up-regulated. The changes in both cytomorphology and epithelial gene expression under the detached condition overall returned to their original ones when cells re-attached. Conclusion: The results suggest specific cytomorphological and gene expression changes in oral cancer cell aggregates. Our findings provide insights into the mechanisms underlying anchorage-independent oral cancer cell aggregation and reveal previously unknown potential diagnostic and therapeutic molecules.Oral cancer is the most common type of malignancy in the head and neck region and the most cases are histologically squamous cell carcinoma (1). The 5-year survival rate in the early stages of oral cancer is more than 80%. However, the survival rate is much lower in advanced cases (2). Oral 64

show abstract

Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system

Cited by 32 publications

References 73 publications

The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients

The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients

The Integrative Studies on the Functional A-to-I RNA Editing Events in Human Cancers

Cytomorphology and Gene Expression Signatures of Anchorage-independent Aggregations of Oral Cancer Cells

Contact Info

Product

Resources

About