Inhibition of T-antigen expression promoting glycogen synthase kinase 3 impairs merkel cell carcinoma cell growth

Houben, Roland; Hesbacher, Sonja; Sarma, Bhavishya; Schulte, Carolin; Popp, Sabine; Adam, Christian; Kervarrec, Thibault; Schrama, David

doi:10.1016/j.canlet.2021.10.031

Cited by 12 publications

(14 citation statements)

References 61 publications

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“…The binding was less strong compared to the FLAG-HKDC1-OE cells likely due to the much lower level of endogenous HKDC1. When HKDC1-KO PLC/PRF/5 cells showed significantly reduced clonality compared to the control cells, treatment with a GSK3β inhibitor, laduviglusib (also known as CHIR99021) (37), restored the clonality of the KO cells to the levels similar to the KO/Res cells under both the normoxic and hypoxic culture conditions ( Figure 6F and 6G ). We also noticed that colony formation of the KO/Res cells were more robust under hypoxia than normoxia.…”

Section: Resultsmentioning

confidence: 99%

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Fan,

Tian,

Yang

et al. 2024

Preprint

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Background and AimsHexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell-type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis.Approach and ResultsWe found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models and, molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells.ConclusionsOverall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.

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Section: Resultsmentioning

confidence: 99%

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Fan,

Tian,

Yang

et al. 2024

Preprint

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“…Host factors involved in the regulation of NCCR activity, however, have rarely been reported. In this regard, we could demonstrate that GSK3 inhibition reduces T antigen expression on mRNA and protein levels, although the exact mechanisms are not yet clear [56].…”

Section: T Antigensmentioning

confidence: 88%

Merkel Cell Polyomavirus: Infection, Genome, Transcripts and Its Role in Development of Merkel Cell Carcinoma

Houben

Celikdemir

Kervarrec

et al. 2023

Cancers

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The best characterized polyomavirus family member, i.e., simian virus 40 (SV40), can cause different tumors in hamsters and can transform murine and human cells in vitro. Hence, the SV40 contamination of millions of polio vaccine doses administered from 1955–1963 raised fears that this may cause increased tumor incidence in the vaccinated population. This is, however, not the case. Indeed, up to now, the only polyomavirus family member known to be the most important cause of a specific human tumor entity is Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma (MCC). MCC is a highly deadly form of skin cancer for which the cellular origin is still uncertain, and which appears as two clinically very similar but molecularly highly different variants. While approximately 80% of cases are found to be associated with MCPyV the remaining MCCs carry a high mutational load. Here, we present an overview of the multitude of molecular functions described for the MCPyV encoded oncoproteins and non-coding RNAs, present the available MCC mouse models and discuss the increasing evidence that both, virus-negative and -positive MCC constitute epithelial tumors.

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“…It has been proven that CHIR-99021 and FFAR1 modulator one are beneficial for tumor treatments. For instance, CHIR-99021, as an inhibitor of glycogen synthase kinase 3 (GSK3), exhibited antitumor activity in Merkel cell carcinoma ( Houben et al, 2022 ); FFAR1 modulator 1 may activate the Hippo pathway to mediate apoptosis in androgen-independent prostate cancer cells ( Wang et al, 2018 ). Therefore, we believed that these two small-molecular compounds would facilitate efficacy in the clinical treatment of BRCA patients.…”

Section: Discussionmentioning

confidence: 99%

An Immune-Related Long Noncoding RNA Pair as a New Biomarker to Predict the Prognosis of Patients in Breast Cancer

et al. 2022

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Background: Immune-related long non-coding RNAs (irlncRNAs) might remodel the tumor immune microenvironment by changing the inherent properties of tumor cells and the expression of immune genes, which have been used to predict the efficacy of immunotherapy and the prognosis of various tumors. However, the value of irlncRNAs in breast cancer (BRCA) remains unclear.Materials and Methods: Initially, transcriptome data and immune-related gene sets were downloaded from The Cancer Genome Atlas (TCGA) database. The irlncRNAs were extracted from the Immunology Database and Analysis Portal (ImmPort) database. Differently expressed irlncRNAs (DEirlncRNAs) were further identified by utilizing the limma R package. Then, univariate and multivariate Cox regression analyses were conducted to select the DEirlncRNAs associated with the prognosis of BRCA patients. In addition, the univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were performed to determine the DEirlncRNA pairs with the independent prediction capability of prognosis in BRCA patients. Finally, the chosen DEirlncRNA pair would be evaluated in terms of survival time, clinicopathological characteristics, tumor-infiltrating immune cells, immune checkpoints (ICs), signaling pathways, and potential small-molecule drugs.Results: A total of 21 DEirlncRNA pairs were extracted, and among them, lncRNA MIR4435-2HG and lncRNA U62317.1 were chosen to establish a risk signature that served as an independent prognostic biomarker in BRCA patients. Patients in the high-risk group had a worse prognosis than those in the low-risk group, and they also had an abundance of infiltration of CD4+ T and CD8+ T cells to enhance the immune response to tumor cells. Furthermore, the risk signature showed a strong correlation with ICs, signaling pathways, and potential small-molecule drugs.Conclusion: Our research revealed that the risk signature independent of specific DEirlncRNA pair expression was closely associated with the prognosis and tumor immune microenvironment in BRCA patients and had the potential to function as an independent prognostic biomarker and a predictor of immunotherapy for BRCA patients, which would provide new insights for BRCA accurate treatment.

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Inhibition of T-antigen expression promoting glycogen synthase kinase 3 impairs merkel cell carcinoma cell growth

Cited by 12 publications

References 61 publications

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Merkel Cell Polyomavirus: Infection, Genome, Transcripts and Its Role in Development of Merkel Cell Carcinoma

An Immune-Related Long Noncoding RNA Pair as a New Biomarker to Predict the Prognosis of Patients in Breast Cancer

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