PHD3 affects gastric cancer progression by negatively regulating HIF1A

Xia, Yingjie; Jiang, Xiaoting; Jiang, Shi‐Bin; He, Xu; Luo, Jungang; Liu, Zhengchuang; Wang, Liang; Tao, Hou‐Quan; Chen, Jianzhong

doi:10.3892/mmr.2017.7455

Cited by 15 publications

(13 citation statements)

References 32 publications

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“…Taken together, our observations and those by others highlight the role of PHD3 as a tumor suppressor [27,41,42,43]. Moreover, we show for the first time that PHD3 inhibition in cancer cells has profound effects on the tumor vasculature by influencing vessel morphology and the emergence of mural cells in a PDGF-C-dependent manner.…”

Section: Discussionsupporting

confidence: 85%

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PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

Egners

Rezaei

Kuzmanov

et al. 2018

Cancers

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Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1α protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors.

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Section: Discussionsupporting

confidence: 85%

“…In colorectal and gastric cancer as well as in glioma and astrocytoma PHD3 was also reported to function as a tumor suppressor [27,41,42,43]. In contrast, strongly tumor type-dependent effects on progression were reported for the related PHD2 protein.…”

Section: Discussionmentioning

confidence: 99%

PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

Egners

Rezaei

Kuzmanov

et al. 2018

Cancers

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show abstract

“…PHD3 knockdown in other cell lines (A549 and H1299 cells) enhanced pulmonary metastasis in a HIF-dependent manner that involved upregulation of TGFα, an EGFR ligand [140]. In gastric cancer, cell migration and invasion were significantly higher in PHD3-silenced tumor cells than controls, and both HIF1 and VEGF showed greater expression [141]. In mouse LM8 osteosarcoma, we showed that PHD3 is a tumor suppressor as silencing of this oxygen sensor led to enhanced tumor growth and dramatically changed vessel morphology that was directly related to significantly activated platelet-derived growth factor (PDGF)-C signaling in the vasculature of PHD3 knockdown tumors [142].…”

Section: The Phd-hif Axis As a Central Regulator Of Tumor Developmentmentioning

confidence: 96%

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

Gaete¹,

Rodríguez²,

Watts³

et al. 2020

Preprint

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Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

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“…PHD3 knockdown in other cell lines (A549 and H1299 cells) enhanced pulmonary metastasis in a HIF-dependent manner that involved upregulation of TGFα, an EGFR ligand [37]. In gastric cancer, cell migration and invasion were significantly higher in PHD3-silenced tumor cells than controls, and both HIF-1 and VEGF showed greater expression [38]. In mouse LM8 osteosarcoma, we showed that PHD3 is a tumor suppressor as silencing of this oxygen sensor led to enhanced tumor growth and dramatically changed vessel morphology that was directly related to significantly activated platelet-derived growth factor (PDGF)-C signaling in the vasculature of PHD3 knockdown tumors [39].…”

Section: Phds As Central Regulators Of Tumor Developmentmentioning

confidence: 96%

HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

Gaete

Rodríguez

Watts

et al. 2021

Cancers

View full text Add to dashboard Cite

Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types, and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis, and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that were either recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

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PHD3 affects gastric cancer progression by negatively regulating HIF1A

Cited by 15 publications

References 32 publications

PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

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