Overexpression of LGR-5 as a Predictor of Poor Outcome in Patients with Hepatocellular Carcinoma

Ko, Chih‐Jan; Li, Chia‐Jung; Wu, Meng‐Yu; Chu, Pei-Yi

doi:10.3390/ijerph16101836

Cited by 8 publications

(7 citation statements)

References 18 publications

(24 reference statements)

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“…20,21 LGR5 is overexpressed in a variety of tumors, and its high expression level is associated with poor prognosis of various cancers, including colorectal, gastric, hepatocellular, and ovarian cancer. [22][23][24][25] Studies have shown that the increased expression of LGR5 occurs in the initial stage of EC development. With proliferation and growth of tumor epithelial cells, the expression of LGR5 becomes undetectable, likely because of the inhibitory effect of estrogen and progesterone on LGR5, suggesting LGR5 may be a biomarker for the diagnosis of early EC.…”

Section: Discussionmentioning

confidence: 99%

<p>Decreased PTGDS Expression Predicting Poor Survival of Endometrial Cancer by Integrating Weighted Gene Co-Expression Network Analysis and Immunohistochemical Validation</p>

Zou¹,

Zheng²,

Tan³

et al. 2020

CMAR

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Purpose: To identify key pathogenic genes and reveal the potential molecular mechanisms of endometrial cancer (EC) using bioinformatics analysis and immunohistochemistry validation. Materials and Methods: Through weighted gene co-expression network analysis (WGCNA), a co-expression network was constructed based on the top 25% variant genes in the GSE50830 dataset downloaded from gene expression omnibus (GEO). GO and KEGG pathway enrichment analyses were performed using the DAVID online tool. Candidate genes were selected using the cytoHubba plug-in of Cytoscape, mRNA expression levels and prognostic values in EC were analyzed by Oncomine, GEPIA, and Kaplan-Meier Plotter database to determine hub genes. One hub gene was validated by immunohistochemical (IHC) staining of 116 paraffin-embedded endometrial tissues and TCGA-UCEC cohort. Genes co-expressed with this hub gene were identified by LinkedOmics. Finally, its correlation with immune infiltration was evaluated by TIMER. Results: Three co-expression modules and five candidate genes in each module were obtained by WGCNA; four hub genes were identified (LGR5, SST, ZNF558, and PTGDS). The mRNA levels of LGR5 and SST were significantly upregulated in EC, whereas those of ZNF558 and PTGDS were significantly downregulated; the expression of all four genes was associated with EC prognosis. Further validation demonstrated that PTGDS was significantly downregulated in the EC group compared with the atypical hyperplasia and normal endometrial groups, and its low expression was an independent risk factor for worse prognosis of EC. Biological function analysis indicated that PTGDS might be involved in the adaptive immune response, leukocyte migration, as well as in the regulation of cell adhesion molecules and chemokine signaling. Additionally, PTGDS expression was positively correlated with immune infiltration status of B cells, CD4 + T cells and macrophages. Conclusion:LGR5, SST, ZNF558, and PTGDS may participate in the development, progression, and prognosis of EC, in which PTGDS may be a novel biomarker and therapeutic target for EC.

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Section: Discussionmentioning

confidence: 99%

<p>Decreased PTGDS Expression Predicting Poor Survival of Endometrial Cancer by Integrating Weighted Gene Co-Expression Network Analysis and Immunohistochemical Validation</p>

Zou¹,

Zheng²,

Tan³

et al. 2020

CMAR

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“…The interactions between CSCs and Tregs further lead to tumor immunosuppression. Enriched LGR5 + LCSCs are associated with poor prognosis in HCC, whereas Tregs increased LGR5 of CSCs expression in gastric cancer through TGF-β1 [57][58][59] . Tregs and LGR5 + CSCs may also be associated in HCC.…”

Section: Regulatory T Cells (Tregs)mentioning

confidence: 98%

Targeting the interactions between lymphocytes and liver cancer stem cells in combination with immunotherapy is a promising therapeutic strategy

Chen¹,

Zhang²,

Yan³

et al. 2023

Hepatoma Res

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with a poor prognosis and high recurrence rate. Liver cancer stem cells (LCSCs), a small subset of HCC cells, have the capacity for self-renewal and the property of treatment resistance, suggesting that LCSCs are key factors in causing poor prognosis for HCC patients. In addition, LCSCs interact with immune cells to participate in the formation of an immunosuppressive microenvironment and escape the immune surveillance in HCC, especially lymphocytes. At present, immunotherapies for HCC are mainly based on reactivating the lymphocyte system, including immune checkpoint inhibitors, multifunctional antibodies, and adoptive cell therapy. Therefore, blocking the interactions between lymphocytes and LCSCs in combination with immunotherapy may be a promising therapeutic strategy. This review summarizes the interaction mechanisms of lymphocytes and LCSCs and the current exploration of combination therapy in HCC.

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“…However, one subset of those hepatocytes, which is marked by leucine-rich repeat-containing Gprotein-coupled receptor 5 (LGR-5), was found to be involved in the HCC development 51 . Indeed, LGR-5 expression was found to be upregulated in HBV-related HCC tissues, and patients with higher expression of LGR-5 might have a poor outcome 52 . A very recent study seems to find out a link between LGR-5 and HCC initiation:…”

Section: Hbv-induced Hepatoma Cell Transformationmentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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Overexpression of LGR-5 as a Predictor of Poor Outcome in Patients with Hepatocellular Carcinoma

Cited by 8 publications

References 18 publications

<p>Decreased PTGDS Expression Predicting Poor Survival of Endometrial Cancer by Integrating Weighted Gene Co-Expression Network Analysis and Immunohistochemical Validation</p>

<p>Decreased PTGDS Expression Predicting Poor Survival of Endometrial Cancer by Integrating Weighted Gene Co-Expression Network Analysis and Immunohistochemical Validation</p>

Targeting the interactions between lymphocytes and liver cancer stem cells in combination with immunotherapy is a promising therapeutic strategy

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

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