Inhibition of RFX6 Suppresses the Invasive Ability of Tumor Cells Through the Notch Pathway and Affects Tumor Immunity in Hepatocellular Carcinoma

Mu, Song; Kuerban, Mulati; Zhao, Lu; Peng, Xiaolin; Xu, Youqin

doi:10.3389/fonc.2021.801222

Cited by 8 publications

(12 citation statements)

References 26 publications

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“…A previous study showed that RFX6 might contributes to the HCC progression through the Notch pathway 14 . Concurrently, this study also exhibited that RFX6 expression was inversely correlated with the dysfunction of progressive T cell, suggesting its functions in reshaping tumour microenvironment.…”

Section: Discussionsupporting

confidence: 70%

“…Previous studies have highlighted the linkage between the aberrant RFX6 expression and cancer development 12–16 . However, the precise role of RFX6 in HCC remained ambiguous.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, a genome‐wide association study identified GPRC6A/RFX6 as a susceptible locus for prostate cancer in a Japanese population, first revealing a link between RFX6 and tumourigenesis 12 . In subsequent studies, suppression of RFX6 profoundly diminished the development of prostate cancer and HCC, highlighting its pro‐tumoural functions 13,14 . However, some other researchers obtained opposite results in different malignancies, necessitating further detailed studies to elucidate its precise role in HCC 15,16 …”

Section: Introductionmentioning

confidence: 99%

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RFX6 facilitates aerobic glycolysis‐mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1

Qiu,

Wang,

Huang

et al. 2023

Clinical & Translational Med

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BackgroundHepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous.MethodsMicroarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non‐neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings.ResultsHCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC.ConclusionsRFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6–PGAM1 axis for therapeutic targeting.

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Section: Discussionsupporting

confidence: 70%

“…Previous studies have highlighted the linkage between the aberrant RFX6 expression and cancer development 12–16 . However, the precise role of RFX6 in HCC remained ambiguous.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

RFX6 facilitates aerobic glycolysis‐mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1

Qiu,

Wang,

Huang

et al. 2023

Clinical & Translational Med

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“…Through the activation of PI3K/Akt/mTOR, XPA suppressed the growth of cancer cells inside the liver by promoting autophagy and cell death ( 39 ). Additionally, a study has found that inhibiting RFX6 through the Notch pathway inhibits the invasive ability of tumor cells and affects tumor immunity in HCC ( 40 ). Our biological information analysis indicate that DLAT may be involved in the WNT and other pathways that contribute to the poor prognosis of HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Glycolysis-related gene dihydrolipoamide acetyltransferase promotes poor prognosis in hepatocellular carcinoma through the Wnt/β-catenin and PI3K/Akt signaling pathways

Zhou¹,

Gu²,

Shao³

et al. 2022

Ann Transl Med

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Background: Recent research suggests that dihydrolipoamide acetyltransferase (DLAT), which is a copperinduced cell death-related gene, is involved in multiple biological events in tumors. This study sought to investigate the relationship between DLAT and hepatocellular carcinoma (HCC).Methods: In the Cancer Genome Atlas (TCGA) database, we first identified the differentially expressed gene (i.e., DLAT), then confirmed DLAT expression, and found a link between it and the prognosis of HCC patients. An internal validation nomogram was built based on a multivariate Cox regression analysis.Data from the Tumor Immune Estimation Resource (TIMER) database was used to examine the association between DLT and immunological cells. A gene set enrichment analysis (GSEA) was conducted to investigate the probable mechanism of action. Finally, in vitro cytological research was conducted to further examin the involvement of DLAT in HCC-related unfavorable biological events. Results:The database screenings showed that DLAT was a differentially expressed molecule; that is, DLAT was more highly expressed in the cancer tissues than normal tissues. TCGA results and Kaplan-Meier-plotter data sets showed that HCC patients with reduced DLAT expression had greater diseasespecific survival (DSS), overall survival (OS), and progression-free interval (PFI). The prediction model had a concordance index of 0.659 (0.614-0.704), which indicates high accuracy. According to the TIMER database, tumor cells in the HCC microenvironment may be able to bypass the immune system due to the expression of DLAT. The in vitro cytological tests showed that DLAT knockdown significantly decreased the proliferation and invasion of the HCC cells. It also inhibited the activity of the phosphatidylinositol-4,5bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) and Wnt/β-catenin signaling pathways.Conclusions: Decreased DLAT expression significantly prolongs the OS, PFI, and DSS of HCC patients.DLAT may be employed as a new predictive biomarker for HCC, and may be linked to the immune system in HCC patients. The tumor microenvironment (TME) may have a significant effect on the ability of tumor cells to evade the immune system. The PI3K/Akt and Wnt/β-catenin signaling pathways may affect the prognosis of HCC by interfering with DLAT. Given these findings, HCC may be an ideal target for the development of anti-cancer therapies.

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“…According to global statistics, the number of newly diagnosed liver cancer patients and liver cancer-related deaths worldwide was 905,677 and 830,180, respectively, in 2020 [ 1 , 2 ]. Primary liver cancer mainly includes HCC, intrahepatic cholangiocarcinoma, and mixed hepatocellular carcinoma, of which HCC accounts for more than 75% to 85% [ 3 ]. HCC pathogenesis is correlated with certain pivotal risk factors, such as hepatitis virus infection, alcohol abuse, and metabolic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of NXPH4 Correlates with Immune Cell Infiltration and Unfavorable Prognosis in Hepatocellular Carcinoma

Tang

Chen

Shen

et al. 2022

Journal of Oncology

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Hepatocellular carcinoma (HCC) is one of the leading malignant carcinomas. Despite the advancement in the treatment for HCC, such as precise hepatectomy, radiotherapy, transarterial therapies, chemotherapy, targeted treatments, and immunotherapy, the 5-year overall survival rate of HCC is extremely low. Hence, novel biomarkers are urgently needed for advancing the therapy and prognosis of HCC. Neurexophilin 4 (NXPH4) is a neuropeptide-like glycoprotein. The study is designed to investigate the function of NXPH4 in HCC through a comprehensive bioinformatics analysis. NXPH4 expression status and prognostic values were analyzed via multiple datasets, such as TCGA, GEO, and ICGC. The association between NXPH4 and immune cell infiltration was estimated by TIMER, TISIDB, and CIBERSORT. In vitro, we explored the biological function of NXPH4 in JHH7 and SNU182 cells through knocking down the expression of NXPH4 via siRNA. In general, NXPH4 was predominantly upregulated in HCC tumors, and increased NXPH4 expression predicted unfavorable prognosis. The gene enrichment analysis displayed that NXPH4 was related with metabolic pathways. NXPH4 expression was correlated with immune cell infiltration. NXPH4 knockdown significantly suppressed proliferation, migration, and invasion of JHH7 and SNU182 cells. This study suggested that the upregulation of NXPH4 is associated with adverse prognosis and immune cell infiltration in HCC. NXPH4 could be a novel biomarker of unfavorable prognosis and an underlying target for immunotherapy in HCC.

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Inhibition of RFX6 Suppresses the Invasive Ability of Tumor Cells Through the Notch Pathway and Affects Tumor Immunity in Hepatocellular Carcinoma

Cited by 8 publications

References 26 publications

RFX6 facilitates aerobic glycolysis‐mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1

RFX6 facilitates aerobic glycolysis‐mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1

Glycolysis-related gene dihydrolipoamide acetyltransferase promotes poor prognosis in hepatocellular carcinoma through the Wnt/β-catenin and PI3K/Akt signaling pathways

Increased Expression of NXPH4 Correlates with Immune Cell Infiltration and Unfavorable Prognosis in Hepatocellular Carcinoma

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