CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Zhang, Yinjiang; Wei, Haixia; Fan, Lu; Fang, Mingyan; Xu, He; Lu, Bingwei; Pang, Zhigang

doi:10.3389/fcell.2021.681372

Cited by 18 publications

(21 citation statements)

References 34 publications

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“…While there is little current research on the importance of Lman1l in BC, its high expression combined with its known molecular function may explain the lower tumor weight we observed in BSp-treated HER2/neu mice. Clec4e is an important regulator of the immune response, and higher levels of its expression are correlated with increased immune cell infiltration in hepatocellular carcinoma [60]. As infiltration of CD4+ and γδ T cells is associated with better overall and disease-free survival in BC patients, our overexpression findings may explain the increase in latency in HER2/neu mice, as well as the decrease in incidence we observed in both mouse strains [61].…”

Section: Discussionsupporting

confidence: 54%

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

Brane

Arora

Tollefsbol

2023

Cancers

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Breast cancer (BC) is a nearly ubiquitous malignancy that effects the lives of millions worldwide. Recently, nutritional prevention of BC has received increased attention due to its efficacy and ease of application. Chief among chemopreventive compounds are plant-based substances known as dietary phytochemicals. Sulforaphane (SFN), an epigenetically active phytochemical found in cruciferous vegetables, has shown promise in BC prevention. In addition, observational studies suggest that the life stage of phytochemical consumption may influence its anticancer properties. These life stages, called critical periods (CPs), are associated with rapid development and increased susceptibility to cellular damage. Puberty, a CP in which female breast tissue undergoes proliferation and differentiation, is of particular interest for later-life BC development. However, little is known about the importance of nutritional chemoprevention to CPs. We sought to address this by utilizing two estrogen receptor-negative [ER(-)] transgenic mouse models fed SFN-containing broccoli sprout extract during the critical period of puberty. We found that this treatment resulted in a significant decrease in tumor incidence and weight, as well as an increase in tumor latency. Further, we found significant alterations in the long-term expression of cancer-associated genes, including p21, p53, and BRCA2. Additionally, our transcriptomic analyses identified expressional changes in many cancer-associated genes, and bisulfite sequencing revealed that the antiproliferation-associated gene Erich4 was both hypomethylated and overexpressed in our experimental group. Our study indicates that dietary interventions during the CP of puberty may be important for later-life ER(-) BC prevention and highlights potential important genetic and epigenetic targets for treatment and study of the more deadly variants of BC.

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Section: Discussionsupporting

confidence: 54%

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

Brane

Arora

Tollefsbol

2023

Cancers

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“…In the previous study, the CLEC4 family played a critical role in immune response and the development of hepatocellular carcinoma. However, CLEC4D, as one of the CLEC4s, demonstrated a potential value in virus infection, including COVID-19 [ 34 ]. DUSP13 was associated with the regulation of the MAPK signaling pathway after stress stimulation in cardiomyocytes [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel 3-Gene Signature for Identifying COVID-19 Patients Based on Bioinformatics and Machine Learning

Lai

Liu

Deng

et al. 2022

Genes

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Although many biomarkers associated with coronavirus disease 2019 (COVID-19) were found, a novel signature relevant to immune cells has not been developed. In this work, the “CIBERSORT” algorithm was used to assess the fraction of immune infiltrating cells in GSE152641 and GSE171110. Key modules associated with important immune cells were selected by the “WGCNA” package. The “GO” enrichment analysis was used to reveal the biological function associated with COVID-19. The “Boruta” algorithm was used to screen candidate genes, and the “LASSO” algorithm was used for collinearity reduction. A novel gene signature was developed based on multivariate logistic regression analysis. Subsequently, M0 macrophages (PRAUC = 0.948 in GSE152641 and PRAUC = 0.981 in GSE171110) and neutrophils (PRAUC = 0.892 in GSE152641 and PRAUC = 0.960 in GSE171110) were considered as important immune cells. Forty-three intersected genes from two modules were selected, which mainly participated in some immune-related activities. Finally, a three-gene signature comprising CLEC4D, DUSP13, and UNC5A that can accurately distinguish COVID-19 patients and healthy controls in three datasets was constructed. The ROCAUC was 0.974 in the training set, 0.946 in the internal test set, and 0.709 in the external test set. In conclusion, we constructed a three-gene signature to identify COVID-19, and CLEC4D, DUSP13, and UNC5A may be potential biomarkers for COVID-19 patients.

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“…In human tumorigenesis, a previous study explored the role of CLECs and their potential association with reshaping the immune system in the development of hepatocellular carcinoma. The result demonstrated that hepatocellular tissues had significantly higher mRNA levels of CLEC4A and CLEC4L compared to normal liver tissues 27 . CLEC4A is believed to be a biomarker involved in carcinogenesis with further research in NSCLC needed.…”

Section: Discussionmentioning

confidence: 94%

Differential expression of immune-regulatory proteins C5AR1, CLEC4A and NLRP3 on peripheral blood mononuclear cells in early-stage non-small cell lung cancer patients

Pakvisal

Kongkavitoon

Sathitruangsak

et al. 2022

Sci Rep

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Changes in gene expression profiling of peripheral blood mononuclear cells (PBMC) appear to represent the host’s response to the cancer cells via paracrine signaling. We speculated that protein expression on circulating T-lymphocytes represent T-lymphocyte trafficking before infiltration into the tumor microenvironment. The possibility of using protein expression on circulating T-lymphocytes as a biomarker to discriminate early-stage non-small cell lung cancer (NSCLC) was explored. Four independent PBMC gene expression microarray datasets (GSE12771, GSE13255, GSE20189 and GSE3934) were analyzed. We selected C5AR1, CLEC4A and NLRP3 based on their significant protein expression in tumor-infiltrating lymphocytes, but not in normal lymphoid tissue. A validation study using automated flow cytometry was conducted in 141 study participants including 76 treatment-naive early-stage non-small cell lung cancer patients (NSCLC), 12 individuals with non-malignant pulmonary diseases, and 53 healthy individuals. Median ratios of C5AR1, CLEC4A and NLRP3 specific antibody staining to CD3 positive cells in early-stage NSCLC patients compared to healthy controls were 0.014 [0–0.37] vs. 0.01 [0–0.07, p = 0.13], 0.03 [0–0.87] vs. 0.02 [0–0.13, p = 0.10] and 0.19 [0–0.60] vs. 0.09 [0.02–0.31, p < 0.0001], respectively. Median fluorescence intensity (MFI) of CD3+C5AR1+, CD3+CLEC4A+ and CD3+NLRP3+ expression in early-stage NSCLC patients compared to healthy volunteers was 185 [64.2–4801] vs. 107.5 [27–229, p < 0.0001], 91.2 [42.4–2355] vs. 71.25 [46.2–103, p = 0.0005], and 1585 [478–5224] vs. 758.5 [318–1976, p < 0.0001], respectively. NLRP3:CD3 ratio, CD3+C5AR1+, CD3+CLEC4A+ and CD3+NLRP3+ MFI were significantly higher in early-stage NSCLC than healthy volunteers with an area under the ROC curve of 0.69–0.76. The CD3+NLRP3+ MFI provided the most distinguishable expression at 71.5% sensitivity and 70% specificity. Furthermore, CD3+NLRP3+ MFI potentially discriminated between early-stage NSCLC from malignant-mimic inflammation and infection pulmonary disease. Further validation in various pulmonary inflammatory disease might be warranted. Our proof-of-principle findings strengthen the hypothesis that malignancies generate distinctive protein expression fingerprints on circulating T-lymphocytes.

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CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Cited by 18 publications

References 34 publications

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

A Novel 3-Gene Signature for Identifying COVID-19 Patients Based on Bioinformatics and Machine Learning

Differential expression of immune-regulatory proteins C5AR1, CLEC4A and NLRP3 on peripheral blood mononuclear cells in early-stage non-small cell lung cancer patients

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