Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

Lee, Seon-Hyeong; Kang, Joo‐Hyon; Ha, Ji Sun; Lee, Jae‐Seon; Oh, Soo‐Jin; Choi, Hyun-Jung; Song, Jaewhan; Kim, Soo-Youl

doi:10.3390/ijms21145042

Cited by 16 publications

(12 citation statements)

References 37 publications

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“…In RCC, HIF-1α upregulation enhances proliferation, migration and survival by mediating metabolic reprogramming (de Carvalho et al, 2021). Transglutaminase 2 (TGase 2) promoted angiogenesis by inducing p53 degradation, thus activating HIF-1α/VEGF2R pathway (Lee et al, 2020). In addition, HIF-1α has a role in regulating RCC cell glycolysis.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Induces HECTD2 Up-Regulation and Aggravates the Malignant Progression of Renal Cell Cancer via Repressing miR-320a

Shen

Yao

et al. 2021

Front. Cell Dev. Biol.

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Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system. It has been found that hypoxia mediates the malignant evolvement of RCC. Here, we probe the impact and potential mechanism of HECT domain E3 ubiquitin-protein ligase 2 (HECTD2) and HIF-1α on regulating RCC evolvement. RCC tissues and adjacent normal tissues were collected, and the association between the expression profiles of HECTD2 and HIF-1α and the clinicopathological features was analyzed. Additionally, we constructed HECTD2/HIF-1α overexpression and knockdown models in RCC cell lines to ascertain the impacts of HECTD2 and HIF-1α on RCC cell proliferation, apoptosis, migration, and growth in vivo. We applied bioinformatics to predict the upstream miRNA targets of HECTD2. Meanwhile, RNA immunoprecipitation (RIP), and the dual-luciferase reporter assays were employed to clarify the targeting association between HECTD2 and miR-320a. The effect of miR-320a on HECTD2-mediated RCC progression was investigated. The results suggested that both HIF-1α and HECTD2 were up-regulated in RCC (compared with adjacent non-tumor tissues), and they had positive relationship. Moreover, higher level of HECTD2 and HIF-1α is associated with poorer overall survival of RCC patients. HECTD2 overexpression heightened RCC cell proliferation and migration, and weakened cell apoptosis. On the other hand, the malignant phenotypes of RCC cells were signally impeded by HECTD2 or HIF-1α knockdown. Moreover, miR-320a targeted the 3′-untranslated region of HECTD2 and suppressed HECTD2 expression. The rescue experiments showed that miR-320a restrained HECTD2-mediated malignant progression in RCC, while up-regulation of HIF-1α hampered miR-320a expression. Collectively, HIF-1α mediated HECTD2 up-regulation and aggravated RCC progression by attenuating miR-320a.

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Section: Discussionmentioning

confidence: 99%

HIF-1α Induces HECTD2 Up-Regulation and Aggravates the Malignant Progression of Renal Cell Cancer via Repressing miR-320a

Shen

Yao

et al. 2021

Front. Cell Dev. Biol.

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“…More recently Lei et al [ 42 ] demonstrated that inhibiting TG2 GTP-binding activity led to suppression of the downstream NF-κB/HIF1α pathways, ultimately leading to inhibition of angiogenesis. In renal cell carcinoma, TG2 has also been shown to promote angiogenesis through degradation of p53, which leads to HIF1α activation and increased production of VEGF [ 41 ]. The fundamental ability of TG2 to support or supress angiogenesis is most likely governed by its cellular context and structural conformation.…”

Section: Tg2 As a Key Functional Player In The Tmementioning

confidence: 99%

The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

Tempest

Guarnerio

Maani

et al. 2021

Cancers

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Transglutaminase-2 (TG2) is the most highly and ubiquitously expressed member of the transglutaminase enzyme family and is primarily involved in protein cross-linking. TG2 has been implicated in the development and progression of numerous cancers, with a direct role in multiple cellular processes and pathways linked to apoptosis, chemoresistance, epithelial-mesenchymal transition, and stem cell phenotype. The tumour microenvironment (TME) is critical in the formation, progression, and eventual metastasis of cancer, and increasing evidence points to a role for TG2 in matrix remodelling, modulation of biomechanical properties, cell adhesion, motility, and invasion. There is growing interest in targeting the TME therapeutically in response to advances in the understanding of its critical role in disease progression, and a number of approaches targeting biophysical properties and biomechanical signalling are beginning to show clinical promise. In this review we aim to highlight the wide array of processes in which TG2 influences the TME, focussing on its potential role in the dynamic tissue remodelling and biomechanical events increasingly linked to invasive and aggressive behaviour. Drug development efforts have yielded a range of TG2 inhibitors, and ongoing clinical trials may inform strategies for targeting the biomolecular and biomechanical function of TG2 in the TME.

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“…To improve the diagnosis rate, we further analyze the abnormally expressed genes in patients with aggressive pituitary adenomas from the perspective of genetics. It has been found that the expression of Ki67, P53, and VEGF is significantly increased in malignant tumors such as gastric cancer, bladder cancer renal cell carcinoma, and glioma ( 19 – 22 ). We speculate they are also abnormally expressed in aggressive pituitary adenomas.…”

Section: Discussionmentioning

confidence: 99%

Identification and Verification of SLC27A1, PTBP1 and EIF5A With Significantly Altered Expression in Aggressive Pituitary Adenomas

Cheng

Sun²,

Nie³

et al. 2022

Front. Surg.

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BackgroundAggressive pituitary adenoma encircling the internal carotid artery has a poor clinical prognosis because of a high surgical risk and a high recurrence rate. This seriously affects patients’ quality of life and yet there is no effective medical treatment. The European Diagnostic Guidelines have recommended the use of temozolomide (TMZ) for these aggressive pituitary adenomas, but the treatment remission rate has been less than 50%.MethodsIn this study, transcriptome sequencing of pituitary tumour tissues and TMZ-treated pituitary tumour cell lines were employed to explore the significance gene expressions affecting the efficacy of TMZ treatment for pituitary tumours. To clarify the roles of these gene expressions, six adult patients with pituitary adenomas treated in Tiantan Hospital from 2015 to 2020 and a pituitary adenoma cell line (Att20 sensitive to TMZ treatment) were analyzed by mRNA transcriptome sequencing. The differentially expressed genes were assayed by analyzing the sequencing results, and the expression level of these genes was further verified by immunohistochemistry. In addition, Ki67, VEGF, and p53 of the tumour tissues were also verified by immunohistochemistry.ResultsIn tumour tissues, mRNA sequencing showed that PTBP1 and EIF5A were significantly overexpressed in primary pituitary adenomas and SLC27A1 was significantly overexpressed in aggressive pituitary adenomas. Also in the pituitary adenoma cell line (AtT20), SLC27A1 expression levels were suppressed by TMZ treatment. Subsequent immunohistochemistry confirmed the sequencing results.ConclusionHigh expression of SLC27A1 and low expression of EIF5A and PTBP1 may be potential indicators to predict the progression of aggressive pituitary adenomas, and patients with high SLC27A1 subtype may be sensitive to TMZ in clinical treatments.

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Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

Cited by 16 publications

References 37 publications

HIF-1α Induces HECTD2 Up-Regulation and Aggravates the Malignant Progression of Renal Cell Cancer via Repressing miR-320a

HIF-1α Induces HECTD2 Up-Regulation and Aggravates the Malignant Progression of Renal Cell Cancer via Repressing miR-320a

The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

Identification and Verification of SLC27A1, PTBP1 and EIF5A With Significantly Altered Expression in Aggressive Pituitary Adenomas

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