Activation of VIPR1 suppresses hepatocellular carcinoma progression by regulating arginine and pyrimidine metabolism

Fu, Yukui; Liu, Shanshan; Rodrigues, Robim Marcelino; Han, Ying; Guo, Cao; Zhu, Zhanwei; He, Yong; Mackowiak, Bryan; Feng, Dechun; Gao, Bin; Zeng, Shan; Shen, Hong

doi:10.7150/ijbs.71134

Cited by 12 publications

(7 citation statements)

References 49 publications

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“…injection) for continuous 21 weeks, to induce HCC model as described previously 19. Mice were also subjected to single DEN injection or chronic CCl 4 alone 24…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

Mackowiak

Feng

et al. 2023

Gut

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ObjectiveThe current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimised therapeutic regimens are unmet needs, which require a thorough understanding of the underlying mechanisms by which tumour cells orchestrate an inflamed tumour microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumour microenvironment remains unknown.DesignWild-type and miR-223 knockout mice were subjected to two mouse models of inflammation-associated HCC induced by injection of diethylnitrosamine (DEN) or orthotopic HCC cell implantation in chronic carbon tetrachloride (CCl4)-treated mice.ResultsGenetic deletion of miR-223 markedly exacerbated tumourigenesis in inflammation-associated HCC. Compared with wild-type mice, miR-223 knockout mice had more infiltrated programmed cell death 1 (PD-1+) T cells and programmed cell death ligand 1 (PD-L1+) macrophages after DEN+CCl4administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumour hypoxia, a condition that is well-documented to regulate PD-1/PD-L1. In vivo and in vitro mechanistic studies demonstrated that miR-223 did not directly target PD-1 and PD-L1 in immune cells rather than indirectly downregulated them by modulating tumour microenvironment via the suppression of hypoxia-inducible factor 1α-driven CD39/CD73-adenosine pathway in HCC. Moreover, gene delivery of miR-223 via adenovirus inhibited angiogenesis and hypoxia-mediated PD-1/PD-L1 activation in both HCC models, thereby hindering HCC progression.ConclusionThe miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.

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“…injection) for continuous 21 weeks, to induce HCC model as described previously 19. Mice were also subjected to single DEN injection or chronic CCl 4 alone 24…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

Mackowiak

Feng

et al. 2023

Gut

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“…Regarding these genes, low expression of AC004538.3 , VIPR1 , and MASP2 was associated with a poor prognosis (Logrank p < 0.05; Figure 7 ). Furthermore, VIPR1 exhibited a strong association with the occurrence of HCC ( Table 4 ) ( 32 ).…”

Section: Resultsmentioning

confidence: 99%

“…The 12 characteristic genes are primarily enriched in pathway associated with metabolic process. Among the characteristic gene generated from the model, loss of VIPR1 expression in HCC facilitated CAD phosphorylation and tumor progression, suggesting that the restoration of VIPR1 and treatment with the VIPR1 agonist may represent a promising approach for HCC treatment ( 32 , 36 ). Our research suggested that VIPR1 may play a role in the classification of early stage HCC and advanced HCC, but further research is needed to determine its specific function.…”

Section: Discussionmentioning

confidence: 99%

Construction of diagnostic models for the progression of hepatocellular carcinoma using machine learning

Jiang,

Zhou,

Jiang

et al. 2024

Front. Oncol.

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Liver cancer is one of the most prevalent forms of cancer worldwide. A significant proportion of patients with hepatocellular carcinoma (HCC) are diagnosed at advanced stages, leading to unfavorable treatment outcomes. Generally, the development of HCC occurs in distinct stages. However, the diagnostic and intervention markers for each stage remain unclear. Therefore, there is an urgent need to explore precise grading methods for HCC. Machine learning has emerged as an effective technique for studying precise tumor diagnosis. In this research, we employed random forest and LightGBM machine learning algorithms for the first time to construct diagnostic models for HCC at various stages of progression. We categorized 118 samples from GSE114564 into three groups: normal liver, precancerous lesion (including chronic hepatitis, liver cirrhosis, dysplastic nodule), and HCC (including early stage HCC and advanced HCC). The LightGBM model exhibited outstanding performance (accuracy = 0.96, precision = 0.96, recall = 0.96, F1-score = 0.95). Similarly, the random forest model also demonstrated good performance (accuracy = 0.83, precision = 0.83, recall = 0.83, F1-score = 0.83). When the progression of HCC was categorized into the most refined six stages: normal liver, chronic hepatitis, liver cirrhosis, dysplastic nodule, early stage HCC, and advanced HCC, the diagnostic model still exhibited high efficacy. Among them, the LightGBM model exhibited good performance (accuracy = 0.71, precision = 0.71, recall = 0.71, F1-score = 0.72). Also, performance of the LightGBM model was superior to that of the random forest model. Overall, we have constructed a diagnostic model for the progression of HCC and identified potential diagnostic characteristic gene for the progression of HCC.

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“…Studies indicated that VIP/VIPR1 signaling stimulates the transactivation of HER-2 and EGFR in human breast cancer and that VIPR1 expression is maintained in breast tumors and might have a potential role in carcinogenesis 10 . Recent reports suggest that VIP/VIPR1 signaling protects cancer stem cells from drug-induced apoptosis by dephosphorylating pro-apoptotic Bcl2 family member BAD 11 . This dual role of VIPR1 in breast cancer is noteworthy since its association with tumor suppression and tumorigenic signalings' activation.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of GPCRs: A window into breast tumorigenesis and metastasis

Khan,

Hernández-González,

Murillo-González

et al. 2023

Preprint

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G-protein-coupled receptors (GPCRs) are known signal transducers and are increasingly implicated in tumorigenesis, but their precise roles in breast cancer progression remain underexplored. We scrutinized the mRNA expression profiles of fifty GPCRs in breast tumor tissue compared to normal tissue. Prominently, PTGFR, VIPR1, ADGRL2/3, LPAR1, and S1PR1 were found to be downregulated in breast cancer tissues, while ADGRL2 and CELSR1 exhibited upregulation. LPAR1, TSHR, and S1PR2/4 expression significantly influenced HPV and lncRNA entry in breast cancer compared to normal counterparts. We also explored correlations between GPCRs and various clinicopathological attributes, encompassing menopausal age, receptor status, nodal status, P53 status, triple-negative breast cancer (TNBC), Scarf–Bloom–Richardson grade (SBR), and nottingham prognostic index (NPI). Survival analysis unveiled thirty-three GPCRs that significantly influenced prognosis, with a high net alteration frequency of 84.41% across all 50 GPCRs. Our investigation unraveled complex co-expression associations between GPCRs and genes involved in pivotal signaling pathways, growth factor receptors, PKCs, GEFs, and markers indicative of metastasis and proliferation. Moreover, our study identified potential interactions between rutin, cucurbitacins, ellagic acid, and tilliroside with the targeted GPCRs. P2RY8, LPAR3, S1PR5, LPAR2, CELSR3, and GRM8 may function as oncogenes whereas, ADGRL2, LPAR1/4/6, and GRM6/7, PTGFR, TSHR, SMO, CCKBR, S1PR2/4 and CHRM1/3 may be tumor-suppressors for breast cancer.

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Activation of VIPR1 suppresses hepatocellular carcinoma progression by regulating arginine and pyrimidine metabolism

Cited by 12 publications

References 49 publications

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

Construction of diagnostic models for the progression of hepatocellular carcinoma using machine learning

Bioinformatics analysis of GPCRs: A window into breast tumorigenesis and metastasis

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