PMID- 37378837 OWN - NLM STAT- MEDLINE DCOM- 20230714 LR - 20230718 IS - 1573-7276 (Electronic) IS - 0262-0898 (Linking) VI - 40 IP - 4 DP - 2023 Aug TI - EGFL6 promotes bone metastasis of lung adenocarcinoma by increasing cancer cell malignancy and bone resorption. PG - 357-371 LID - 10.1007/s10585-023-10219-5 [doi] AB - Lung adenocarcinoma is the most common and aggressive type of lung cancer with the highest incidence of bone metastasis. Epidermal growth factor-like domain multiple 6 (EGFL6) is an exocrine protein, and the expression of EGFL6 is correlated with survival of patient with lung adenocarcinoma. However, the association between EGFL6 expression in lung adenocarcinoma and bone metastasis has not been investigated. In this study, we found that EGFL6 levels in lung adenocarcinoma tissues correlate with bone metastasis and TNM stages in surgical patients. In vitro, overexpression of EGFL6 in lung adenocarcinoma cells promoted their proliferation, migration, and invasion ability compared with control by enhancing EMT process and activating Wnt/beta-catenin and PI3K/AKT/mTOR pathways. In the nude mouse model, overexpression of EGFL6 enhanced tumor growth and caused greater bone destruction. Moreover, the exocrine EGFL6 of human lung adenocarcinoma cells increased osteoclast differentiation of bone marrow mononuclear macrophages (BMMs) of mice via the NF-kappaB and c-Fos/NFATc1 signaling pathways. However, exocrine EGFL6 had no effect on osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs). In conclusion, high expression of EGFL6 in lung adenocarcinomas is associated with bone metastasis in surgical patients. The underlying mechanism may be the increased metastatic properties of lung adenocarcinoma cells with high EGFL6 level and the enhanced osteoclast differentiation and bone resorption by exocrine EGFL6 from tumors. Therefore, EGFL6 is a potential therapeutic target to reduce the ability of lung adenocarcinomas to grow and metastasize and to preserve bone mass in patients with bone metastases from lung adenocarcinomas. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature B.V. FAU - Song, Xiaoting AU - Song X AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. AD - Wenzhou Medical University, Wenzhou, China. FAU - Cheng, Xu AU - Cheng X AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. AD - Wenzhou Medical University, Wenzhou, China. FAU - Jin, Xiangang AU - Jin X AD - Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, China. FAU - Ruan, Shengyu AU - Ruan S AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. AD - Wenzhou Medical University, Wenzhou, China. FAU - Xu, Xianquan AU - Xu X AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. AD - Wenzhou Medical University, Wenzhou, China. FAU - Lu, Feng AU - Lu F AD - Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, China. FAU - Wu, Xinhui AU - Wu X AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. AD - Wenzhou Medical University, Wenzhou, China. FAU - Lu, Fangying AU - Lu F AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. AD - Wenzhou Medical University, Wenzhou, China. FAU - Feng, Mingxuan AU - Feng M AD - Department of Orthopedics, Taizhou Central Hospital affiliated to Taizhou College, Taizhou, China. FAU - Zhang, Liwei AU - Zhang L AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. FAU - Ge, Renshan AU - Ge R AD - Wenzhou Medical University, Wenzhou, China. FAU - Chen, Haixiao AU - Chen H AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. FAU - Hong, Zhenghua AU - Hong Z AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. 0001hzh@163.com. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. 0001hzh@163.com. FAU - Hong, Dun AU - Hong D AD - Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Road, Linhai, 317000, Zhejiang, China. hongdun@wmu.edu.cn. AD - Bone Metabolism and Development Research Center, Taizhou Hospital affiliated to Wenzhou Medical University, Linhai, China. hongdun@wmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230628 PL - Netherlands TA - Clin Exp Metastasis JT - Clinical & experimental metastasis JID - 8409970 RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (EGFL6 protein, human) RN - 0 (Calcium-Binding Proteins) RN - 0 (Cell Adhesion Molecules) SB - IM MH - Humans MH - Animals MH - Mice MH - Phosphatidylinositol 3-Kinases MH - *Adenocarcinoma of Lung MH - Signal Transduction MH - *Bone Neoplasms MH - *Bone Resorption MH - *Lung Neoplasms/genetics MH - Cell Line, Tumor MH - Calcium-Binding Proteins MH - Cell Adhesion Molecules OTO - NOTNLM OT - Bone metastasis OT - EGFL6 OT - EMT OT - Lung adenocarcinoma OT - Osteoclast differentiation EDAT- 2023/06/28 13:08 MHDA- 2023/07/14 13:08 CRDT- 2023/06/28 11:13 PHST- 2022/06/23 00:00 [received] PHST- 2023/06/08 00:00 [accepted] PHST- 2023/07/14 13:08 [medline] PHST- 2023/06/28 13:08 [pubmed] PHST- 2023/06/28 11:13 [entrez] AID - 10.1007/s10585-023-10219-5 [pii] AID - 10.1007/s10585-023-10219-5 [doi] PST - ppublish SO - Clin Exp Metastasis. 2023 Aug;40(4):357-371. doi: 10.1007/s10585-023-10219-5. Epub 2023 Jun 28.