Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 predicts poor prognosis in hepatocellular carcinoma

Chen, Wanyuan; Fu, Qihan; Fang, Fengqin; Jin, Fang; Zhang, Qi; Hong, Yupeng

doi:10.1016/j.sjbs.2017.12.014

Cited by 8 publications

(9 citation statements)

References 22 publications

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“…(20,(42)(43)(44) In addition, recent studies have demonstrated that LGR5 increases OLFM4 expression through the Wnt signaling pathway and promotes stem cell property in the intestine. (27)(28)(29) LGR5 is reported to be expressed in HCC (45,46) ; however, no reports have focused on the interaction between LGR5 and OLFM4. Moreover, no previous studies have shown the effects of LGR5 or OLFM4 on cancer stem cell-like property in any malignancies.…”

Section: Discussionmentioning

confidence: 99%

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

et al. 2019

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Olfactomedin 4 (OLFM4) induces signal transducer and activator of transcription 3 (STAT3) activation by inhibiting gene associated with retinoid‐interferon‐induced mortality 19 (GRIM19), a strong STAT3 suppressor gene; however, the mechanisms of OLFM4 for regulating GRIM19‐STAT3 cascade in hepatocellular carcinoma (HCC) remain unclear. The functions and regulations of OLFM4, GRIM19, and STAT3 activation in HCC progression were evaluated using surgical specimens collected from 111 HCC patients or 2 HCC cell lines in vitro . Moreover, the cancer stem cell–like property of OLFM4 mediated by leucine‐rich repeat‐containing G protein‐coupled receptor 5 (LGR5), known as an intestinal stem cell marker, was investigated. OLFM4 was increased in HCC compared with adjacent liver tissue. The multivariate analysis revealed that high OLFM4 expression was an independent factor for poor prognosis. OLFM4 expression was negatively correlated with GRIM19 expression and positively correlated with STAT3 activation in HCC, thereby increasing cell cycle progression. OLFM4 knockdown in HCC cells increased GRIM19 expression and inhibited STAT3 activation; however, after double knockdown of GRIM19 and OLFM4, STAT3 activation decreased by OLFM4 knockdown was increased again. OLFM4 knockdown increased cell apoptosis, inhibited cell proliferation, and suppressed cancer stem cell–like property in HCC cells. The incidence of hematogenous recurrence was higher in HCC patients with high OLFM4 expression, suggesting that anoikis resistance of HCC was enhanced by OLFM4. In clinical cases, LGR5 expression and CD133 expression was correlated with OLFM4 expression in HCC, leading to poor patient prognosis. In vitro , LGR5 enhanced cancer stem cell–like property by up‐regulating OLFM4 through the Wnt signaling pathway. Conclusion : OLFM4 is induced by the LGR5‐Wnt signaling pathway and is strongly associated with aggressive tumor progression and poor prognosis in HCC by regulating STAT3‐induced tumor cell proliferation and cancer stem cell–like property. Therefore, OLFM4 is a novel prognostic predictor and a potential therapeutic target for patients with HCC.

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Section: Discussionmentioning

confidence: 99%

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

et al. 2019

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“…Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks as the second leading cause of cancer-associated mortality worldwide [ 1 – 3 ]. Furthermore, HCC patients have a poor prognosis, with a 5-year survival rate of 18% [ 4 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Low UGP2 Expression Is Associated with Tumour Progression and Predicts Poor Prognosis in Hepatocellular Carcinoma

Shen

et al. 2020

Disease Markers

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Hepatocellular carcinoma (HCC) is a malignant tumour associated with a high mortality rate and poor prognosis worldwide. Uridine diphosphate-glucose pyrophosphorylase 2 (UGP2), a key enzyme in glycogen biosynthesis, has been reported to be associated with the occurrence and development of various cancer types. However, its diagnostic value and prognostic value in HCC remain unclear. The present study observed that UGP2 expression was significantly downregulated at both the mRNA and protein levels in HCC tissues. Receiver operating characteristic (ROC) curve analysis revealed that UGP2 may be an indicator for the diagnosis of HCC. In addition, Kaplan-Meier and Cox regression multivariate analyses indicated that UGP2 is an independent prognostic factor of overall survival (OS) in patients with HCC. Furthermore, gene set enrichment analysis (GSEA) suggested that gene sets negatively correlated with the survival of HCC patients were enriched in the group with low UGP2 expression levels. More importantly, a significant correlation was identified between low UGP2 expression and fatty acid metabolism. In summary, the present study demonstrates that UGP2 may contribute to the progression of HCC, indicating a potential therapeutic target for HCC patients.

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“…EMT is associated with diverse tumor including breast cancer and pancreatic cancer 43,44. EMT in HCC caused by high expression of Lgr5 partly blame for a poor prognosis in HCC patient 27. So we play attention to the effect of Lgr5 on drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Lgr5-mediated p53 Repression through PDCD5 leads to doxorubicin resistance in Hepatocellular Carcinoma

Guo

Wang

et al. 2019

Theranostics

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The devastating prognosis of hepatocellular carcinoma (HCC) is partially attributed to chemotherapy resistance. Accumulating evidence suggests that the epithelial-mesenchymal transition (EMT) is a key driving force of carcinoma metastasis and chemoresistance in solid tumors. Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), as an EMT inducer, is involved in the potentiation of Wnt signaling in HCC. This study proposes uncovering the roles of Lgr5 in Doxorubicin (Dox) resistance of HCC to improve treatment efficacy for HCC. Methods: We investigated the expression and significance of Lgr5 in HCC tissue and different cell lines. The effect of Lgr5 in EMT and Dox resistance was analyzed in HCC cells and implanted HCC tumor models. A two-hybrid analysis, using the Lgr5 gene as the bait and a HCC cDNA library, was used to screen targeted proteins that interact with Lgr5. The positive clones were identified by coimmunoprecipitation (Co-IP) and Glutathione-S-transferase (GST) pull-down. The impact of the interaction on Dox resistance was investigated by a series of assays in vitro and in vivo . Result: We found that Lgr5 was upregulated and positively correlated with poor prognosis in HCC. Additionally, it functioned as a tumor promoter to increase cell migration and induce EMT in HCC cells and increase the resistance to Dox. We identified programmed cell death protein 5 (PDCD5) as a target gene of Lgr5 and we found that PDCD5 was responsible for Lgr5-mediated Dox resistance. Further analysis with Co-IP and GST pull-down assays showed that the N-terminal extracellular domain of Lgr5 could directly bind to PDCD5. Lgr5 induced p53 degradation by blocking the nuclear translocation of PDCD5 and leading to the loss of p53 stabilization. Lgr5 showed a protection against the inhibition of Dox on the growth of tumor subcutaneously injected. Moreover, Lgr5 suppressed Dox-induced apoptosis via the p53 pathway and attenuated the cytotoxicity of Dox to HCC. Conclusion: Lgr5 induces the EMT and inhibits apoptosis, thus promoting chemoresistance by regulating the PDCD5/p53 signaling axis. Furthermore, Lgr5 may be a potential target gene for overcoming Dox resistance.

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Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 predicts poor prognosis in hepatocellular carcinoma

Cited by 8 publications

References 22 publications

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

Low UGP2 Expression Is Associated with Tumour Progression and Predicts Poor Prognosis in Hepatocellular Carcinoma

Lgr5-mediated p53 Repression through PDCD5 leads to doxorubicin resistance in Hepatocellular Carcinoma

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