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.

中文翻译：

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PTPRD失活诱导的CXCL8促进胃癌的血管生成和转移，并被二甲双胍抑制。

背景技术蛋白酪氨酸磷酸酶受体δ（PTPRD）经常在各种类型的癌症中失活。在这里，我们探讨了PTPRD丢失诱导的癌症转移的潜在机制，并研究了PTPRD失活的胃癌（GC）的有效治疗选择。方法采用免疫组织化学方法检测PTPRD的表达。微阵列分析用于鉴定PTPRD灭活的癌细胞中差异表达的基因。定量逆转录（qRT-PCR），蛋白质印迹和/或酶联免疫吸附测定法用于研究PTPRD-CXCL8轴和其他相关基因的表达。使用HUVEC进行体外管形成试验。通过MTS分析评估二甲双胍的疗效。结果PTPRD在GC中经常被下调，并且PTPRD表达的丧失与晚期，总生存期较差和远处转移的风险较高有关。基因芯片分析显示PTPRD缺失后CXCL8表达显着增加。使用瞬态和稳定的PTPRD组合在各种GC细胞系中对此进行了验证。PTPRD损失诱导的血管生成是由CXCL8介导的，而CXCL8表达的增加是由ERK和STAT3信号转导介导的。因此，靶向ERK或STAT3的特异性抑制剂消除了相应的信号传导节点，并抑制了PTPRD-损失诱导的血管生成。此外，发现二甲双胍可有效抑制PTPRD缺失诱导的血管生成，降低PTPRD灭活的癌症中的细胞活力，并逆转PTPRD表达的降低。结论因此，PTPRD-CXCL8轴可作为潜在的治疗靶标，特别是对于抑制PTPRD灭活的GC中的转移。因此，我们建议应进一步研究二甲双胍在PTPRD灭活的癌症中的治疗效果。