PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin
Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is frequently inactivated in various types of cancers. Here, we explored the underlying mechanism of PTPRD-loss-induced cancer metastasis and investigated an efficient treatment option for PTPRD-inactivated gastric cancers (GCs)...
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doaj-c66418fe1be94560b30dfdc527492d812020-12-06T12:06:12ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-12-0138111110.1186/s13046-019-1469-4PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metforminWon Jung Bae0Ji Mi Ahn1Hye Eun Byeon2Seokwhi Kim3Dakeun Lee4Department of Pathology, Ajou University School of MedicineDepartment of Pathology, Ajou University School of MedicineInstitute of Medical Science, Ajou University School of MedicineDepartment of Pathology, Ajou University School of MedicineDepartment of Pathology, Ajou University School of MedicineAbstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is frequently inactivated in various types of cancers. Here, we explored the underlying mechanism of PTPRD-loss-induced cancer metastasis and investigated an efficient treatment option for PTPRD-inactivated gastric cancers (GCs). Methods PTPRD expression was evaluated by immunohistochemistry. Microarray analysis was used to identify differentially expressed genes in PTPRD-inactivated cancer cells. Quantitative reverse transcription (qRT-PCR), western blotting, and/or enzyme-linked immunosorbent assays were used to investigate the PTPRD-CXCL8 axis and the expression of other related genes. An in vitro tube formation assay was performed using HUVECs. The efficacy of metformin was assessed by MTS assay. Results PTPRD was frequently downregulated in GCs and the loss of PTPRD expression was associated with advanced stage, worse overall survival, and a higher risk of distant metastasis. Microarray analysis revealed a significant increase in CXCL8 expression upon loss of PTPRD. This was validated in various GC cell lines using transient and stable PTPRD knockdown. PTPRD-loss-induced angiogenesis was mediated by CXCL8, and the increase in CXCL8 expression was mediated by both ERK and STAT3 signaling. Thus, specific inhibitors targeting ERK or STAT3 abrogated the corresponding signaling nodes and inhibited PTPRD-loss-induced angiogenesis. Additionally, metformin was found to efficiently inhibit PTPRD-loss-induced angiogenesis, decrease cell viability in PTPRD-inactivated cancers, and reverse the decrease in PTPRD expression. Conclusions Thus, the PTPRD-CXCL8 axis may serve as a potential therapeutic target, particularly for the suppression of metastasis in PTPRD-inactivated GCs. Hence, we propose that the therapeutic efficacy of metformin in PTPRD-inactivated cancers should be further investigated.https://doi.org/10.1186/s13046-019-1469-4AngiogenesisCXCL8Gastric cancerMetastasisPTPRD |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Won Jung Bae Ji Mi Ahn Hye Eun Byeon Seokwhi Kim Dakeun Lee |
spellingShingle |
Won Jung Bae Ji Mi Ahn Hye Eun Byeon Seokwhi Kim Dakeun Lee PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin Journal of Experimental & Clinical Cancer Research Angiogenesis CXCL8 Gastric cancer Metastasis PTPRD |
author_facet |
Won Jung Bae Ji Mi Ahn Hye Eun Byeon Seokwhi Kim Dakeun Lee |
author_sort |
Won Jung Bae |
title |
PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin |
title_short |
PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin |
title_full |
PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin |
title_fullStr |
PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin |
title_full_unstemmed |
PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin |
title_sort |
ptprd-inactivation-induced cxcl8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2019-12-01 |
description |
Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is frequently inactivated in various types of cancers. Here, we explored the underlying mechanism of PTPRD-loss-induced cancer metastasis and investigated an efficient treatment option for PTPRD-inactivated gastric cancers (GCs). Methods PTPRD expression was evaluated by immunohistochemistry. Microarray analysis was used to identify differentially expressed genes in PTPRD-inactivated cancer cells. Quantitative reverse transcription (qRT-PCR), western blotting, and/or enzyme-linked immunosorbent assays were used to investigate the PTPRD-CXCL8 axis and the expression of other related genes. An in vitro tube formation assay was performed using HUVECs. The efficacy of metformin was assessed by MTS assay. Results PTPRD was frequently downregulated in GCs and the loss of PTPRD expression was associated with advanced stage, worse overall survival, and a higher risk of distant metastasis. Microarray analysis revealed a significant increase in CXCL8 expression upon loss of PTPRD. This was validated in various GC cell lines using transient and stable PTPRD knockdown. PTPRD-loss-induced angiogenesis was mediated by CXCL8, and the increase in CXCL8 expression was mediated by both ERK and STAT3 signaling. Thus, specific inhibitors targeting ERK or STAT3 abrogated the corresponding signaling nodes and inhibited PTPRD-loss-induced angiogenesis. Additionally, metformin was found to efficiently inhibit PTPRD-loss-induced angiogenesis, decrease cell viability in PTPRD-inactivated cancers, and reverse the decrease in PTPRD expression. Conclusions Thus, the PTPRD-CXCL8 axis may serve as a potential therapeutic target, particularly for the suppression of metastasis in PTPRD-inactivated GCs. Hence, we propose that the therapeutic efficacy of metformin in PTPRD-inactivated cancers should be further investigated. |
topic |
Angiogenesis CXCL8 Gastric cancer Metastasis PTPRD |
url |
https://doi.org/10.1186/s13046-019-1469-4 |
work_keys_str_mv |
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