Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor
Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor
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DOI：
10.1038/s41416-020-0965-9
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发表时间：
2020-06-29
影响因子：
8.8
通讯作者：
Eguchi, Hidetoshi
中科院分区：
文献类型：
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作者：
Iwamoto, Kazuya;Takahashi, Hidekazu;Eguchi, Hidetoshi
背景：Syntenin-1蛋白在多种细胞类型中表达，并在多种恶性肿瘤中表达上调，包括黑色素瘤、乳腺癌和胶质瘤。虽然Syntenin-1表达升高导致癌症的机制已经被描述，但确切的途径还没有被阐明。方法采用免疫组织化学方法检测139例结直肠癌手术标本中Syntenin-1的表达情况。我们还检测了结肠癌细胞系中Syntenin-1的基因敲除情况。结果Syntenin-1高表达与结直肠癌分化程度低、预后差有关，是判断结直肠癌预后的独立指标。在CRC细胞中敲除Syntenin-1可以减少肿瘤干细胞(CSCs)的存在，减少奥沙利铂的化疗耐药性和迁移。DNA芯片分析和实时定量聚合酶链式反应显示Syntenin-1基因敲除细胞中前列腺素E2受体2(PTGER2)的表达降低。在结直肠癌细胞中，PTGER2基因敲除产生与Syntenin-1基因敲除相同的表型。塞来昔布通过靶向环氧合酶-2而具有抗炎作用，可减少CSCs并降低化疗耐药性，而前列腺素E2(PGE2)则具有相反的作用。结论Syntenin-1通过调节PTGER2的表达增强了CSC的扩增、奥沙利铂耐药和迁移能力。Syntenin-1可能是一种很有前途的新的预后因子和抗癌治疗的靶点。
Background The protein syntenin-1 is expressed by a variety of cell types, and is upregulated in various malignancies, including melanoma, breast cancer and glioma. Although the mechanism by which elevated syntenin-1 expression contributes to cancer has been described, the exact pathway has not been elucidated. Methods To investigate the involvement of syntenin-1 in colorectal cancer (CRC), we performed immunohistochemical analysis of 139 CRC surgical specimens. We also examined syntenin-1 knockdown in CRC cell lines. Results High syntenin-1 expression was associated with less differentiated histologic grade and poor prognosis, and was an independent prognostic indicator in CRC. Syntenin-1 knockdown in CRC cells reduced the presence of cancer stem cells (CSCs), oxaliplatin chemoresistance and migration. DNA microarray analysis and quantitative real-time polymerase chain reaction showed decreased prostaglandin E2 receptor 2 (PTGER2) expression in syntenin-1-knockdown cells. PTGER2 knockdown in CRC cells yielded the same phenotype as syntenin-1 knockdown. Celecoxib, which has anti-inflammatory effects by targeting cyclooxygenase-2, reduced CSCs and decreased chemoresistance, while prostaglandin E2 (PGE2) had the opposite effect. Conclusions Our findings suggested that syntenin-1 enhanced CSC expansion, oxaliplatin chemoresistance and migration capability through regulation of PTGER2 expression. Syntenin-1 may be a promising new prognostic factor and target for anti-cancer therapies.