Ionizing Radiation-Induced GDF15 Promotes Angiogenesis in Human Glioblastoma Models by Promoting VEGFA Expression Through p-MAPK1/SP1 Signaling

Park, Hyejin; Nam, Ki-Seok; Lee, Hae June; Kim, Kwang Seok

doi:10.3389/fonc.2022.801230

Cited by 10 publications

(10 citation statements)

References 29 publications

(40 reference statements)

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“…Angiogenesis was not only required for tumor growth but also required for tumor dissemination [30,31]. Many studies have reported that traditional photon radiotherapy can activate tumor angiogenesis, besides its capability in killing the tumor cells [7,32]. However, patients who received carbon ion radiotherapy were reported to have decreased metastasis and recurrence rates [12,13].…”

Section: Resultsmentioning

confidence: 99%

Carbon ion irradiation suppresses angiogenic response in human lung adenocarcinoma cells mediated by LINC00167/miR-663a/TGF-β1 axis

Huang¹,

Xu²,

Guo³

et al. 2022

Preprint

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Background Radiotherapy plays an important role in numerous tumor clinical treatments and over 65% of cancer patients need to accept radiotherapy all over the world. However, tumor angiogenesis and metastasis induced by conventional photon radiotherapy adversely impact the survival of patients, and limit the clinical radiotherapy efficiency. Heavy-ion radiotherapy has attracted wide attention in recent years because of its excellent physical property and outstanding tumor control rate, however, the underlying gene expression regulation mechanism response to heavy-ion irradiation remains elusive. Methods RNA-sequencing (RNA-seq) and public database analysis were employed to identify the differential molecular changes in lung adenocarcinoma cells exposed to both X-ray and carbon ion (C-ion) irradiation. The expression of the identified LINC00167 was verified by real-time quantitative PCR in different lung cancer cell lines and pulmonary bronchial epithelial cell lines. The content of serum vascular endothelial growth factor (VEGF) and transforming growth factor beta 1 (TGF-β1) of 8 lung cancer patients who received X-ray or carbon ion radiotherapy were detected by ELISA experiment. Loss-of-function and gain-of-function experiments were performed to explore the biological roles of LINC00167 and miR-663a in lung cancer cell angiogenesis and metastasis. Comprehensive biochemical and biological techniques were utilized to explore the functions of LINC00167 in tumor angiogenesis and metastasis induced by different radiation types. Results In this study, we confirmed that LINC00167 was highly expressed and induced by X-ray irradiation in lung cancer cells. Moreover, increased LINC00167 expression was positively correlated with tumor angiogenesis and metastasis caused by conventional photon radiotherapy. LINC00167 worked as a sponge of miR-663a to positively regulate the expression of TGF-β1 and the downstream VEGF signaling and then promoted the tumor angiogenesis and metastasis of lung cancer cells. LINC00167 could strengthen the pro-angiogenesis and metastasis ability of lung cancer cells. Photon radiation-induced LINC00167 promoted angiogenesis both in vitro and in vivo. Conclusion Our data suggest that LINC00167/miR-663a/TGF-β1 axis is involved in the differential angiogenic response of lung adenocarcinoma cells exposed to X-ray or C-ion irradiation, providing the molecular mechanisms underlying the suppressed angiogenic response induced by carbon ion radiotherapy.

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Section: Resultsmentioning

confidence: 99%

Carbon ion irradiation suppresses angiogenic response in human lung adenocarcinoma cells mediated by LINC00167/miR-663a/TGF-β1 axis

Huang¹,

Xu²,

Guo³

et al. 2022

Preprint

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“…It is abundantly expressed in the placenta during physiological conditions and secreted by activated macrophages as a response to cellular stress signals, such as inflammation, tissue injury and hypoxia ( 23 ); its effect is to stimulate proliferation and migration of endothelial colony-forming cells ( 24 ). GDF15 exerts its pro-angiogenic effects at least partly by stimulation of VEGF-A synthesis ( 25 ). Increased levels of circulating GDF15 are seen in patients with various types of cancer including myeloproliferative neoplasms and in multiple myeloma increased GDF15 is associated with poor prognosis ( 26 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

Increased levels of a subset of angiogenesis-related plasma proteins in essential thrombocythemia

Vikman

Larsson

Thulin

et al. 2023

ujms

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Background: Increased local angiogenesis is important for the growth and dissemination of cancer. The myeloproliferative neoplasm essential thrombocythemia (ET) is known to involve increased bone marrow angiogenesis. Blood levels of several angiogenesis-related proteins are increased in different types of cancer. The aim of this study was to investigate whether a subset of such proteins was elevated in treatment-naïve ET patients. Methods: Blood plasma from 41 ET patients and 43 healthy aged-matched controls was analyzed for eight different angiogenesis-related proteins. Results: The ET cohort displayed a more homogenous expression pattern of these proteins compared with controls. Five of the eight proteins were significantly increased in ET patients. Conclusion: Increased plasma levels of matrix metallopeptidase 9 (MMP9) and endostatin have not previously been reported in ET. In our patients, MMP9 levels correlated positively with Janus kinase 2 (JAK2) V617F allele burden and leukocyte count.

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“…In accordance with our results, which showed a regulation of GDF15 expression by IR in the GSCs, it was previously published that IR could also induce the expression and secretion of this cytokine in oral carcinoma cells [ 34 , 35 ]. Similarly, it was shown that IR regulates GDF15 expression by cells in the tumor microenvironment, including macrophages, fibroblasts, or endothelial cells [ 11 , 36 , 37 ]. In particular, GDF15 secretion by irradiated endothelial cells has been shown to contribute to angiogenesis in GBM models [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, it was shown that IR regulates GDF15 expression by cells in the tumor microenvironment, including macrophages, fibroblasts, or endothelial cells [ 11 , 36 , 37 ]. In particular, GDF15 secretion by irradiated endothelial cells has been shown to contribute to angiogenesis in GBM models [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…GDF15 is overexpressed in many cancers (colorectal, gastric, pancreatic, hepatic, ovarian) and is often associated with tumor aggressiveness [ 5 , 6 , 7 , 8 , 9 , 10 ]. Its expression can be induced by cellular stress conditions or the tumor microenvironment [ 11 , 12 , 13 ]. Notably, GDF15 expression can also be induced following IR, hypoxia, or by tumor-associated macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance

Bentaberry-Rosa,

Nicaise,

Delmas

et al. 2023

Cancers

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GSCs play an important role in GBM recurrence. Understanding the resistance mechanisms in these cells is therefore crucial for radiation therapy optimization. In this study, using patient-derived GSCs, we demonstrate that GDF15, a cytokine belonging to the TGF-β superfamily, is regulated by irradiation (IR) and the transcription factor WWTR1/TAZ. Blocking WWTR1/TAZ using specific siRNAs significantly reduces GDF15 basal expression and reverses the upregulation of this cytokine induced by IR. Furthermore, we demonstrate that GDF15 plays an important role in GSC radioresistance. Targeting GDF15 expression by siRNA in GSCs expressing high levels of GDF15 sensitizes the cells to IR. In addition, we also found that GDF15 expression is critical for GSC spheroid formation, as GDF15 knockdown significantly reduces the number of GSC neurospheres. This study suggests that GDF15 targeting in combination with radiotherapy may be a feasible approach in patients with GBM.

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Ionizing Radiation-Induced GDF15 Promotes Angiogenesis in Human Glioblastoma Models by Promoting VEGFA Expression Through p-MAPK1/SP1 Signaling

Cited by 10 publications

References 29 publications

Carbon ion irradiation suppresses angiogenic response in human lung adenocarcinoma cells mediated by LINC00167/miR-663a/TGF-β1 axis

Carbon ion irradiation suppresses angiogenic response in human lung adenocarcinoma cells mediated by LINC00167/miR-663a/TGF-β1 axis

Increased levels of a subset of angiogenesis-related plasma proteins in essential thrombocythemia

Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance

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