The AKR1C3/AR‐V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression

Wang, Bin; Wu, Shiqi; Fang, Yong; Sun, Guangxi; He, Dalin; Hsieh, Jer Tsong; Wang, Xinyang; Zeng, Hao; Wu, Kaijie

doi:10.1111/jcmm.15831

Cited by 14 publications

(10 citation statements)

References 30 publications

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“…Most of the mRNAs in the ceRNA subnetwork associated with NKT cells may also play an important role in VaD. B4GALT1 is a member of the b-1 4-galactosyltransferase gene (B4GALT) family and plays an important role in many biological events, including morphogenesis, mammalian fertilization, brain development, and cell adhesion (30). This gene may also play an important role in thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

et al. 2021

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Background: To date, vascular dementia (VaD) lacks effective treatment in clinical practice. There is also growing evidence that VaD may be closely related to the immune response. The development of highthroughput technology, and the recently discovered group of new mediators called competitive endogenous RNAs (ceRNA), provides a unique opportunity to study the immunomodulation of VaD.Methods: In this study, we used gene expression profiles in the Gene Expression Omnibus (GEO) database to obtain immune-related gene coexpression modules through a weighted gene coexpression network analysis (WGCNA) and gene enrichment analysis. We extracted and merged long non-coding RNA (lncRNA) and microRNA (miRNA) expressions from the GEO database and mapped them with related databases.Subsequently, we used Cytoscape to construct a lncRNA-miRNA-mRNA network, and then we performed an enrichment analysis on the mRNAs in the network to determine their regulatory function. Subsequently, we used an ImmuCellAI immune infiltration analysis and constructed a ceRNA sub-network of related immune cells. Finally, we conducted a gene set enrichment analysis (GSEA) to determine the potential regulatory pathways of the key factors.Results: As a result, we identified the blue module as the key module of immunity and constructed the related CeRNA network. Immune infiltration analysis showed that natural killer T (NKT) cells may be the key immune cells of VaD. Using a Pearson correlation analysis, we identified that B4GALT1, PPP1R3B, MICB, HHAT, DSC2, DNA2, SCARA3, and lncRNA NEAT1 may be the key factors of VaD. Our subsequent GSEA analysis showed that lncRNA NEAT1 may be regulated by NK cells and toll-like receptors.Conclusions: Our research provides new therapeutic targets for vascular dementia from the immunological perspective for the first time, including B4GALT1, PPP1R3B, MICB, HHAT, DSC2, DNA2, SCARA3, and lncRNA NEAT1, and our research hopes to provide new treatment options for VaD.

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Section: Discussionmentioning

confidence: 99%

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

et al. 2021

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“…Although advances in combination chemotherapy and/or radiotherapy have prolonged the overall survival of EAC patients, the high rate of resistance to conventional chemotherapy is still the main obstacle to the effective therapy of EAC [ 37 , 38 ]. AKR1C3, as a key member of the AKR1Cs subfamily, has been identified as a potential novel therapeutic target in multiple types of cancer [ 13 , 39 , 40 ]. Recently, AKR1C3 has been reported to be upregulated in many human tumors and identified as a prognostic marker in various cancers, including breast cancer, prostate cancer and colon cancer [ 14 , 15 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

Zhou

Wang

et al. 2021

Cancers

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Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

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“…The AR variants arise owing to alternative splicing and/or structural rearrangements of the AR gene; the variants have variable structures, but each lacks all or a part of the ligand binding domain which produce constitutively active, ligand-independent, transcription factors or variants resistant to drugs that reduce androgen production and biosynthesis (9). Androgen receptor variant 7 (ARv7) is one of the most noticeable splice variants in prompting AR-mediated gene transcription even under conditions of androgen deprivation and in driving cancer progression in prostate cancer (10). Moreover, their role in BC has been recognized and is considered an area of active research (11).…”

Section: Introductionmentioning

confidence: 99%

Enzalutamide and EPI-001 in T47D: Blocking Androgen receptor/Androgen receptor variant7 modulates NF-ĸB/c-Myc axis, cyclins A, E, & C, epithelial to mesenchymal transition markers, angiogenesis, and metastasis

Ali

El-Abhar

Mohamed

et al. 2023

Preprint

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Androgen receptor (AR) and its splicing variant 7 (ARv7) play vital roles in the pathobiology of breast cancer (BC) but their role in the estrogen receptor-positive (ER+) type is controversial, hence, we studied the influence of the blockers of AR (Enzalutamide) and ARv7 (EPI-001) on tumorigenesis processes using T47D, an ER+ BC cell line. We showed that although both inhibitors failed to reduce cell growth and affect AR content, only Enzalutamide reduced the ARv7. Mechanistically, the drugs successfully arrested the cell cycle at S-phase and downregulated the protein expression of cyclins A, E, & C. Additionally, they inhibited the cell proliferation stimulator nuclear factor kappa B (NF-ĸB), whereas only EPI-001 reduced the cell regulatory marker c-Myc. They also opposed the endothelial-to-mesenchymal transition (EMT) process, by boosting the epithelial marker E-cadherin and reducing the protein expression of the mesenchymal marker fibronectin. Their anti-metastatic potential was evidenced by the hindrance of cell migration using the wound healing assay and further confirmed by the downregulation of metalloproteinase (MMP) 2 and 9 protein expression, and protein content of Rho kinase (ROCK)1 and 2. Besides, by downregulating the protein expression of vascular endothelial growth factor (VEGF) the drugs point to their anti-angiogenic aptitude. In conclusion, this in-vitro study is the first to prove the importance of blocking AR/ARv7 using Enzalutamide and EPI-001 in decreasing cancer cell survival, EMT, and metastasis in ER+ BC cells, findings that still need further studies to unveil the role of these inhibitors in BC.

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The AKR1C3/AR‐V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression

Cited by 14 publications

References 30 publications

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

Enzalutamide and EPI-001 in T47D: Blocking Androgen receptor/Androgen receptor variant7 modulates NF-ĸB/c-Myc axis, cyclins A, E, & C, epithelial to mesenchymal transition markers, angiogenesis, and metastasis

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The AKR1C3/AR‐V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression

Cited by 14 publications

References 30 publications

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

Enzalutamide and EPI-001 in T47D: Blocking Androgen receptor/Androgen receptor variant7 modulates NF-ĸB/c-Myc axis, cyclins A, E, &amp; C, epithelial to mesenchymal transition markers, angiogenesis, and metastasis

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Enzalutamide and EPI-001 in T47D: Blocking Androgen receptor/Androgen receptor variant7 modulates NF-ĸB/c-Myc axis, cyclins A, E, & C, epithelial to mesenchymal transition markers, angiogenesis, and metastasis