SAR1A regulates the RhoA/YAP and autophagy signaling pathways to influence osteosarcoma invasion and metastasis

作者全名："Zhan, Fangbiao; Deng, Qianrong; Chen, Zhiyu; Xie, Chaozheng; Xiang, Shuang; Qiu, Sheng; Tian, Lin; Wu, Chunrong; Ou, Yunsheng; Chen, Jian; Xu, Lixin"

作者地址："[Zhan, Fangbiao; Chen, Jian; Xu, Lixin] Chongqing Univ, Chongqing Univ Three Gorges Hosp, Chongqing Municipality Clin Res Ctr Geriatr, Sch Med,Dept Orthoped, Chongqing, Peoples R China; [Zhan, Fangbiao; Ou, Yunsheng] Chongqing Med Univ, Orthoped Lab, Chongqing, Peoples R China; [Zhan, Fangbiao; Chen, Zhiyu; Ou, Yunsheng] Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 1, Chongqing, Peoples R China; [Deng, Qianrong] Chongqing Univ, Chongqing Univ Three Gorges Hosp, Sch Med, Hlth Management Ctr, Chongqing, Peoples R China; [Xie, Chaozheng] Chongqing Med Univ, Dept Gastrointestinal Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Xiang, Shuang] Chongqing Univ, Chongqing Univ Three Gorges Hosp, Sch Med, Dept Pathol, Chongqing, Peoples R China; [Qiu, Sheng] Chongqing Med Univ, Affiliated Hosp 2, Dept Endocrinol, Chongqing, Peoples R China; [Tian, Lin] Chongqing Univ, Chongqing Univ Three Gorges Hosp, Sch Med, Dept Clin Lab, Chongqing, Peoples R China; [Wu, Chunrong] Chongqing Univ, Jiangjin Hosp, Sch Med, Dept Oncol, Chongqing, Peoples R China"

通信作者："Chen, J; Xu, LX (通讯作者)，Chongqing Univ, Chongqing Univ Three Gorges Hosp, Chongqing Municipality Clin Res Ctr Geriatr, Sch Med,Dept Orthoped, Chongqing, Peoples R China.; Ou, YS (通讯作者)，Chongqing Med Univ, Orthoped Lab, Chongqing, Peoples R China.; Ou, YS (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China."

来源：CANCER SCIENCE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000853742000001

JCR分区：Q1

影响因子：5.7

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：autophagy; ER stress; metastasis; RhoA; YAP; SAR1A

摘要："Osteosarcoma is the most prevalent form of primary bone malignancy affecting adolescents. Secretion-associated Ras-related GTPase 1A (SAR1A) is a key regulator of endoplasmic reticulum (ER) homeostasis, but its role as a regulator of osteosarcoma metastasis has yet to be clarified. Bioinformatics analyses revealed SAR1A and RHOA to be upregulated in osteosarcoma patients, with the upregulation of these genes being associated with poor 5-year metastasis-free survival rates. In addition, the upregulation of SAR1A and RHOA in osteosarcoma was highly positively correlated. Immunohistochemical analyses additionally revealed that SAR1A levels were increased in osteosarcoma pulmonary metastases. In vitro wound healing and Transwell assays indicated that knocking down SAR1A or RHOA impaired the invasive and migratory activity of osteosarcoma cells, whereas RHOA overexpression had the opposite effect. Western blotting and immunofluorescent staining revealed the inhibition of osteosarcoma cell epithelial-mesenchymal transition following SAR1A or RHOA knockdown; RHOA overexpression had the opposite effect. Following SAR1A knockdown, phalloidin staining indicated that osteosarcoma cells showed reduced lamellipodia formation. Endoplasmic reticulum stress levels and reactive oxygen species production were enhanced following the knockdown of SAR1A, as was autophagic activity, with lung metastases being reduced in vivo after such knockdown. Knocking down SAR1A suppresses osteosarcoma cell metastasis through the RhoA/YAP, ER stress, and autophagic pathways, offering new insights into the regulation of autophagic activity in the context of osteosarcoma cell metastasis and suggesting that these pathways could be amenable to therapeutic intervention."

基金机构："National Natural Science Foundation of China [81572634, 82172682]; General Project of Chongqing Natural Science Foundation [cstc2019jcyj-msxmX0358, cstc2020jcyj-msxmX0951, cstc cstc2021jcyj-msxmX0909]; Chongqing Medical Scientific Research Project (joint project of Chongqing Health Commission and Science and Technology Bureau) [2020FYYX087]; Graduate Education and Teaching Reform Research Project of Chongqing University [cquyjg21305]; Foundation of Chongqing University Three Gorges Hospital [2022YJKYXM-001, 2022YJKYXM-043]"

基金资助正文："This work was supported in part by The National Natural Science Foundation of China grants (81572634, 82172682), the General Project of Chongqing Natural Science Foundation (cstc2019jcyj-msxmX0358, cstc2020jcyj-msxmX0951, cstc cstc2021jcyj-msxmX0909), Chongqing Medical Scientific Research Project (joint project of Chongqing Health Commission and Science and Technology Bureau) (2020FYYX087), and Graduate Education and Teaching Reform Research Project of Chongqing University (cquyjg21305), sponsored by the Foundation of Chongqing University Three Gorges Hospital (2022YJKYXM-001, 2022YJKYXM-043)."