Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China.
Department of Laboratory Medicine, Guizhou Cancer Hospital, Guiyang, China.
J Transl Med. 2022 Jul 21;20(1):322. doi: 10.1186/s12967-022-03537-x.
Helicobacter pylori (H. pylori) can disrupt the tight junctions between gastric epithelial cells and penetrate the intercellular spaces acting on epithelial cells, normal fibroblasts (NFs), and cancer-associated fibroblasts (CAFs), but their interaction in gastric cancer tumorigenesis and progression remains unclear.
Primary CAFs and NFs were isolated from paired gastric cancer tissues and adjacent normal tissues and identified by immunofluorescence staining and western blot analysis for FSP-1, α-SMA, FAP, and vimentin expression. RNA-sequencing was used to compare the transcriptomes between CAFs and NFs. The expressions of FAP, lumican, and α-SMA, human cytokine array, and Transwell assay were used to assess the transformation of NFs to CAFs. CCK-8 assay, colony formation, flow cytometry, Transwell assay, and nude mouse xenograft model were used to determine the effects of Serpin E1 on cell proliferation and metastasis in vitro and in vivo. Finally, Serpin E1 and/or FAP expression was measured in H. pylori-infected gerbil gastric mucosa and human gastric cancer tissues.
Gastric CAFs are inflammatory CAFs with α-SMAFAPlumican. The interplay of H. pylori, fibroblasts, and cancer cells promotes the transition of NFs to CAFs by inducing cytokine release, especially Serpin E1. Long-term H. pylori infection and CAFs induce Serpin E1 expression in gerbil gastric tissues and human gastric cancer cells. Serpin E1 overexpression enhances the growth, migration, invasion of gastric cancer cells in vitro, and xenograft tumor growth in nude mice via inducing angiogenesis. Serpin E1 and FAP were highly expressed in cancer cells and CAFs of gastric cancer tissues, respectively, and a good correlation was observed between their expression. Higher Serpin E1 expression is negatively associated with the overall survival of patients with gastric cancer.
The interplay of H. pylori, fibroblasts, and cancer cells induced Serpin E1 expression to promote the activation of NFs to CAFs and gastric carcinogenesis. Targeting Serpin E1 will provide a promising therapeutic strategy for gastric cancer by disrupting the interaction between H. pylori, CAFs, and gastric cancer cells.
幽门螺杆菌（H. pylori）可以破坏胃上皮细胞之间的紧密连接，并通过作用于上皮细胞、正常成纤维细胞（NFs）和癌相关成纤维细胞（CAFs）来穿透细胞间隙，但它们在胃癌发生和进展中的相互作用尚不清楚。
从配对的胃癌组织和相邻正常组织中分离原代 CAFs 和 NFs，并通过免疫荧光染色和 Western blot 分析 FSP-1、α-SMA、FAP 和波形蛋白的表达进行鉴定。使用 RNA 测序比较 CAFs 和 NFs 之间的转录组。使用 FAP、亮氨酸丰富糖蛋白（lumican）和 α-SMA、人类细胞因子阵列和 Transwell 测定评估 NFs 向 CAFs 的转化。CCK-8 测定、集落形成、流式细胞术、Transwell 测定和裸鼠异种移植模型用于确定 Serpin E1 在体外和体内对细胞增殖和转移的影响。最后，在 H. pylori 感染的沙鼠胃黏膜和人类胃癌组织中测量 Serpin E1 和/或 FAP 的表达。
胃 CAFs 是具有 α-SMA/FAP/lumican 的炎症性 CAFs。H. pylori、成纤维细胞和癌细胞的相互作用通过诱导细胞因子释放，特别是 Serpin E1，促进 NFs 向 CAFs 的转化。长期 H. pylori 感染和 CAFs 诱导沙鼠胃组织和人类胃癌细胞中 Serpin E1 的表达。Serpin E1 过表达通过诱导血管生成增强胃癌细胞在体外的生长、迁移和侵袭，以及裸鼠异种移植肿瘤的生长。Serpin E1 和 FAP 在胃癌组织中的癌细胞和 CAFs 中均高表达，且两者表达之间存在良好的相关性。Serpin E1 表达较高与胃癌患者的总生存期呈负相关。
H. pylori、成纤维细胞和癌细胞的相互作用诱导 Serpin E1 的表达，促进 NFs 向 CAFs 的激活和胃癌的发生。靶向 Serpin E1 将通过破坏 H. pylori、CAFs 和胃癌细胞之间的相互作用，为胃癌提供一种有前途的治疗策略。
