Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
Oncogene. 2019 Sep;38(37):6461-6477. doi: 10.1038/s41388-019-0886-3. Epub 2019 Jul 22.
Helicobacter pylori (Hp) infection and overexpression of hepatoma-derived growth factor (HDGF) are involved in gastric carcinogenesis. However, the relationship between Hp-induced gastric diseases and HDGF upregulation is not yet completely clear. This study aimed to elucidate the role of HDGF in Hp-induced gastric inflammation and carcinogenesis. HDGF expression in gastric biopsy and serum from patients was analyzed by immunohistochemical and ELISA analysis, respectively. Hp and gastric cells coculture system was employed to delineate the mechanism underlying HDGF overexpression during Hp infection. The gastric pathologies of wild type and HDGF knockout mice after Hp infection were investigated by immunohistochemical, immunoblot, and immunofluorescence analyses. HDGF level was significantly elevated in patients with Hp infection or intestinal metaplasia (IM, a precancerous lesion), and HDGF overexpression was positively correlated with Hp load, IM, and neutrophil infiltration in gastric biopsy. Consistently, patients with Hp infection or IM had significantly higher serum HDGF level. By using coculture assay, Hp infection led to HDGF upregulation and secretion in gastric cells. In mice model, HDGF ablation significantly suppressed the Hp-induced neutrophil infiltration and inflammatory TNF-α/COX-2 signaling, thereby relieving the tissue damage in stomach. This was further supported by that recombinant HDGF (rHDGF) stimulated the differentiation/chemotaxis of cultured neutrophils and oncogenic behaviors of gastric cells. Time series studies showed that Hp infection elicited an inflammatory TNF-α/HDGF/COX-2 cascade in stomach. HDGF secretion by Hp infection promotes the neutrophils infiltration and relays Hp-induced inflammatory signaling. Thus, HDGF may constitute a novel diagnostic marker and therapeutic target for Hp-induced gastritis and carcinogenesis.
幽门螺杆菌（Hp）感染和肝癌衍生生长因子（HDGF）的过表达与胃癌的发生有关。然而，Hp 引起的胃部疾病与 HDGF 上调之间的关系尚不完全清楚。本研究旨在阐明 HDGF 在 Hp 诱导的胃炎症和癌变中的作用。通过免疫组织化学和 ELISA 分析分别分析了患者胃活检和血清中 HDGF 的表达。采用 Hp 和胃细胞共培养系统，阐明了 Hp 感染过程中 HDGF 过表达的机制。通过免疫组织化学、免疫印迹和免疫荧光分析研究了 Hp 感染后野生型和 HDGF 敲除小鼠的胃病理变化。Hp 感染或肠上皮化生（IM，癌前病变）患者的 HDGF 水平显著升高，HDGF 过表达与胃活检中的 Hp 负荷、IM 和中性粒细胞浸润呈正相关。同样，Hp 感染或 IM 的患者血清 HDGF 水平显著升高。通过共培养试验，Hp 感染导致胃细胞中 HDGF 的上调和分泌。在小鼠模型中，HDGF 缺失显著抑制了 Hp 诱导的中性粒细胞浸润和炎症 TNF-α/COX-2 信号，从而减轻了胃组织损伤。重组 HDGF（rHDGF）刺激培养的中性粒细胞的分化/趋化作用以及胃细胞的致癌行为进一步支持了这一点。时间序列研究表明，Hp 感染在胃中引发了炎症 TNF-α/HDGF/COX-2 级联反应。Hp 感染分泌的 HDGF 促进中性粒细胞浸润并传递 Hp 诱导的炎症信号。因此，HDGF 可能成为诊断 Hp 诱导的胃炎和癌变的新型标志物和治疗靶标。
