PDF(Pubmed)
Abstract：
UNASSIGNED: B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC.
UNASSIGNED: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected.
UNASSIGNED: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well.
UNASSIGNED: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.
UNASSIGNED: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected.
UNASSIGNED: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well.
UNASSIGNED: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.
摘要：
■B7-H3（或CD276）代表在许多恶性实体瘤中表达的重要共刺激分子，包括结直肠癌（CRC）。B7-H3的受体未知，B7-H3的细胞内功能仍然不清楚。在这里，我们报道B7-H3上调表皮生长因子肝素结合表皮生长因子（HB-EGF），可能通过调节缺氧诱导因子1α（HIF-1α）从而促进CRC的进展。
在CRC细胞上进行慢病毒转染以建立稳定的低B7-H3表达细胞。使用Agilent人类基因表达谱芯片对它们进行了机理分析。收集临床数据和标本以检测CRC中B7-H3和HB-EGF之间的联系。定量实时聚合酶链反应(qRT-PCR)检测B7-H3、HB-EGF、和HIF-1α。进行染色质免疫沉淀(ChIP)定量实时PCR。Westernblot检测HIF-1α的蛋白水平和磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（AKT）通路。通过慢病毒转染回收HIF-1α,和HB-EGFmRNA水平，扩散,入侵,并检测到血管生成能力。
■B7-H3通过HB-EGF和PI3K-AKT途径促进肿瘤进展。由于B7-H3下调，HB-EGF水平同时显著降低,CRC细胞系和癌组织均显示出生长趋势。此外,在50例CRC患者中，B7-H3和HB-EGF与肿瘤淋巴结转移（TNM）分期和淋巴结转移显着相关。在shB7-H3RKO组中，HIF-1α与HB-EGF启动子区的结合能力显着降低。蛋白质印迹显示PI3K，AKT,和哺乳动物雷帕霉素靶蛋白（mTOR）的数量和p-AKT和p-mTOR磷酸化也下调shB7-H3RKO细胞，提示B7-H3可能通过PI3K-AKT信号通路调节HIF-1α。通过慢病毒转染恢复HIF-1α水平后，HB-EGFmRNA水平，扩散,入侵,CRC细胞中的血管生成也得到恢复。
■B7-H3可能通过PI3K-AKT-mTOR-HIF-1α信号传递细胞内信号，上调HB-EGF。作为该途径的最终转录因子，HIF-1α调节HB-EGF基因的转录,从而促进HB-EGF的表达，最终介导细胞增殖，入侵,和血管生成并促进CRC的进展。
在CRC细胞上进行慢病毒转染以建立稳定的低B7-H3表达细胞。使用Agilent人类基因表达谱芯片对它们进行了机理分析。收集临床数据和标本以检测CRC中B7-H3和HB-EGF之间的联系。定量实时聚合酶链反应(qRT-PCR)检测B7-H3、HB-EGF、和HIF-1α。进行染色质免疫沉淀(ChIP)定量实时PCR。Westernblot检测HIF-1α的蛋白水平和磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（AKT）通路。通过慢病毒转染回收HIF-1α,和HB-EGFmRNA水平，扩散,入侵,并检测到血管生成能力。
■B7-H3通过HB-EGF和PI3K-AKT途径促进肿瘤进展。由于B7-H3下调，HB-EGF水平同时显著降低,CRC细胞系和癌组织均显示出生长趋势。此外,在50例CRC患者中，B7-H3和HB-EGF与肿瘤淋巴结转移（TNM）分期和淋巴结转移显着相关。在shB7-H3RKO组中，HIF-1α与HB-EGF启动子区的结合能力显着降低。蛋白质印迹显示PI3K，AKT,和哺乳动物雷帕霉素靶蛋白（mTOR）的数量和p-AKT和p-mTOR磷酸化也下调shB7-H3RKO细胞，提示B7-H3可能通过PI3K-AKT信号通路调节HIF-1α。通过慢病毒转染恢复HIF-1α水平后，HB-EGFmRNA水平，扩散,入侵,CRC细胞中的血管生成也得到恢复。
■B7-H3可能通过PI3K-AKT-mTOR-HIF-1α信号传递细胞内信号，上调HB-EGF。作为该途径的最终转录因子，HIF-1α调节HB-EGF基因的转录,从而促进HB-EGF的表达，最终介导细胞增殖，入侵,和血管生成并促进CRC的进展。
