LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway

Zhang, Xiao; Wu, Hua-Hui; Yan, Xin; Ma, Jiajun; Chen, Zhao

doi:10.3390/cells11223606

Cited by 5 publications

(5 citation statements)

References 34 publications

(36 reference statements)

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“…As expected, upregulated LTB4R is associated with poor prognoses in patients with TNBC. Previously, for another tumor type, e.g., clear cell renal cell carcinoma, Zhang et al [32] presented high LTB4R expression as an important cancer marker and possibly a highly specific target associated with a poor prognosis due to the promotion of cancer cell proliferation, migration, development, and progression via the Akt/mTOR pathway. Pan-cancer bioinformatic analysis revealed that higher LTB4R expression was associated with poor relapse-free survival (RFS), poor OS, and poor distant metastasis-free survival (DMFS) in breast cancer datasets without segregation into molecular subtypes [33].…”

Section: Discussionmentioning

confidence: 99%

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors

Kalinkin,

Sigin,

Kuznetsova

et al. 2023

IJMS

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Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the LTB4R/LTB4R2 genes’ CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high LTB4R/LTB4R2 expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the LTB4R and LTB4R2 genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = −0.4, p = 2.6 × 10−6; R = −0.21, p = 0.015) and cg21886367 (R = −0.45, p = 7.3 × 10−8; R = −0.24, p = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan–Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated LTB4R. To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated LTB4R/LTB4R2 genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating LTB4R/LTB4R2 hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents.

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Section: Discussionmentioning

confidence: 99%

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors

Kalinkin,

Sigin,

Kuznetsova

et al. 2023

IJMS

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“…Feng G et al found that miR-30e could inhibit the proliferation of liver cancer cells by targeting P4HA1 16 . Vitro and vivo studies con rm that P4HA2 can regulate PI3K/Akt/mTOR signaling pathway to promote the occurrence and development of liver cancer 17 .Similarly to P4HA2, P4HA3 can mediate clear cell renal cell carcinoma progression by regulating the PI3K/AKT/GSK3β pathway 18 . However, the expression and function of P4Hs in HNSC is not clear, and the clinical value of P4Hs in HNSC remain largely unknown.…”

Section: Introductionmentioning

confidence: 92%

Comprehensive Analysis Revealed P4Hs as New Biomarkers for Prognosis and Immunotherapy in Head and Neck Cancer

Zhou,

Lei,

Luo

et al. 2023

Preprint

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Prolyl 4-hydroxylases (P4Hs) are a family of key modifying enzymes in collagen synthesis. Notably, P4Hs have been confirmed to be closely associated with the occurrence and development of tumors. However, the P4Hs expression in Head and Neck Cancer (HNSC), as well as its relationship with prognosis and tumor immunity infiltration has not yet been analyzed. In this article, we investigated the transcriptional expression, survival data and immune infiltration of P4Hs in patients with HNSC from multiple databases. Intriguingly, we found that P4H1-3 expression was significantly higher in head and neck tumor tissues than in normal tissues. Moreover, P4HA1 and P4HA2 were associated with tumor stage, patient prognosis, and immune cell infiltration. P4HA3 was related to patient prognosis, and immune cell infiltration. Correlation experiments have also confirmed that P4HA1 can be a prognosis biomarker and promote the progression of nasopharyngeal carcinoma. These findings suggest that P4HA1-3 may be a novel biomarker for the prognosis and immunotherapy of head and neck cancer, which will be beneficial in providing new therapies for patients with head and neck tumors and thereby improving patient outcomes.

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Section: Eicosanoids In Renal Cancermentioning

confidence: 99%

“…A very recent study showed that LTB 4 R overexpression promoted proliferation and inhibited apoptosis of ccRCC cells by stimulating the AKT/mTOR signaling pathway [ 169 ]. Moreover, migration and invasion were inhibited when LTB 4 R was depleted [ 169 ]. According to the TCGA database, LTB 4 R was overexpressed in ccRCC samples compared to normal samples and patients with higher LTB 4 R expressions showed significantly poorer overall survival than patients with lower LTB 4 R [ 169 ].…”

Section: Eicosanoids In Renal Cancermentioning

confidence: 99%

“…Moreover, migration and invasion were inhibited when LTB 4 R was depleted [ 169 ]. According to the TCGA database, LTB 4 R was overexpressed in ccRCC samples compared to normal samples and patients with higher LTB 4 R expressions showed significantly poorer overall survival than patients with lower LTB 4 R [ 169 ]. Accordingly, LTB 4 R was identified as a prognostic biomarker for patients with ccRCC [ 170 ].…”

Section: Eicosanoids In Renal Cancermentioning

confidence: 99%

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Lipids as Targets for Renal Cell Carcinoma Therapy

Tanturovska

Manaila

Fabbro³

et al. 2023

IJMS

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Kidney cancer is among the top ten most common cancers to date. Within the kidney, renal cell carcinoma (RCC) is the most common solid lesion occurring. While various risk factors are suspected, including unhealthy lifestyle, age, and ethnicity, genetic mutations seem to be a key risk factor. In particular, mutations in the von Hippel–Lindau gene (Vhl) have attracted a lot of interest since this gene regulates the hypoxia inducible transcription factors HIF-1α and HIF-2α, which in turn drive the transcription of many genes that are important for renal cancer growth and progression, including genes involved in lipid metabolism and signaling. Recent data suggest that HIF-1/2 are themselves regulated by bioactive lipids which make the connection between lipids and renal cancer obvious. This review will summarize the effects and contributions of the different classes of bioactive lipids, including sphingolipids, glycosphingolipids, eicosanoids, free fatty acids, cannabinoids, and cholesterol to renal carcinoma progression. Novel pharmacological strategies interfering with lipid signaling to treat renal cancer will be highlighted.

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LTB4R Promotes the Occurrence and Progression of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating the AKT/mTOR Signaling Pathway

Cited by 5 publications

References 34 publications

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors

Comprehensive Analysis Revealed P4Hs as New Biomarkers for Prognosis and Immunotherapy in Head and Neck Cancer

Lipids as Targets for Renal Cell Carcinoma Therapy

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