Induction of filopodia formation by α-Actinin-2 via RelA with a feedforward activation loop promoting overt bone marrow metastasis of gastric cancer

作者：Caiqin Wang, Bo Xie, Shi Yin, Jianghua Cao, Junhao Huang, Longyang Jin, Ge Du, Xiaohui Zhai, Rongqin Zhang, Shanshan Li, Taiyuan Cao, Hongen Yu, Xinjuan Fan, Zuli Yang, Junsheng Peng, Jian Xiao, Lei Lian · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04156-w · 被引用次数：12 · 研究领域：Cellular Mechanics and Interactions、Genetics and Physical Performance、Chromatin Remodeling and Cancer

BACKGROUND: Bone marrow metastasis (BMM) is underestimated in gastric cancer (GC). GC with BMM frequently complicate critical hematological abnormalities like diffused intravascular coagulation and microangiopathic hemolytic anemia, which constitute a highly aggressive GC (HAGC) subtype. HAGC present a very poor prognosis with peculiar clinical and pathological features when compared with not otherwise specified advanced GC (NAGC). But the molecular mechanisms underlying BMM from GC remain rudimentary. METHODS: The transcriptomic difference between HAGC and NAGC were analyzed. Genes that were specifically upregulated in HAGC were identified, and their effect on cell migration and invasion was studied. The function of ACTN2 gene were confirmed by GC cell lines, bone-metastatic animal model and patients' tissues. Furthermore, the molecular mechanism of ACTN2 derived-BMM was explored by multiple immunofluorescence staining, western blot, chromatin immunoprecipitation, and luciferase reporter assays. RESULTS: We elucidated the key mechanisms of BMM depending on the transcriptomic difference between HAGC and NAGC. Five genes specifically upregulated in HAGC were assessed their effect on cell migration and invasion. The ACTN2 gene encoding protein α-Actinin-2 was detected enhanced the metastatic capability and induced BMM of GC cells in mouse models. Mechanically, α-Actinin-2 was involved in filopodia formation where it promoted the Actin filament cross-linking by replacing α-Actin...