TGIF2-mediated HMGB3 overexpression promotes esophageal squamous cell carcinoma proliferation and metastasis through TLR3/TGF-βsignalingOA
Proliferation and metastasis are the core malignant characteristics in esophageal squamous cell carcinoma(ESCC)that contribute to poor prognosis,However,the mechanisms underlying cell proliferation and metastasis remain elusive,We explored the function of high-mobility group box(HMGB3)in promoting ESCC progression,HMGB3 expression in ESCC tissues and cell lines was quantified using quantitative PCR,Western blotting,and immunohistochemistry,The proliferative and migratory characteristics of ESCC cells were assessed using in vitro and in vivo assays,respectively,An RNA sequencing analysis was conducted to identify the downstream signaling pathways of HMGB3,Co-immunoprecipitation was performed to identify HMGB3-interacting proteins,HMGB3 transcriptional regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays,Elevated levels of HMGB3 were observed in both patient-derived ESCC tissues and ESCC cell lines and were correlated with poor patient prognosis,HMGB3 up-regulation promoted ESCC proliferation and metastasis,whereas HMGB3 down-regulation inhibited these processes,Mechanistically,homeodomain protein transforming growth factor beta(TGF-β)-induced factor homeobox 2(TGIF2)transcriptionally up-regulates HMGB3,HMGB3 subsequently activates TGF-βsignaling through its regulation of and interaction with toll-like receptor 3(TLR3),ultimately promoting ESCC proliferation and metastasis,Clinically,HMGB3 expression was positively correlated with TGIF2 and TGF-β,and patients with ESCC who positively co-expressed TGIF2/HMGB3,HMGB3/TGF-β,or TGIF2/TGF-βexhibited poor prognosis,The functional role of HMGB3 in ESCC proliferation and metastasis was illustrated in our research,Targeting the TGIF2/HMGB3/TLR3/TGF-βaxis has the potential to serve as a promising therapeutic approach.
Liaoran Niu;Wanli Yang;Wei Zhou;Lili Duan;Qi Wang;Xiaoqian Wang;Yiding Li;Chengchao Xu;Yujie Zhang;Jinqiang Liu;Jian Zhang;Daiming Fan;Jianyong Zheng;Liu Hong
Department of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Dermatology,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,China94719 Military Hospital,Ji’an,Jiangxi 343000,ChinaDepartment of Histology and Embryology,School of Basic Medicine,Xi’an Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaThe State Key Laboratory of Cancer Biology,Department of Biochemistry and Molecular Biology,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,ChinaDepartment of Digestive Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases,Xijing Hospital of Digestive Diseases,Fourth Military Medical University,Xi’an,Shaanxi 710032,China
医药卫生
ESCCHMGB3MetastasisProliferationTGIF2
《Genes & Diseases》 2026 (3)
P.634-657,24
partially funded by grants from the National Natural Science Foundation of China(No.82073210,82372693,82303427)the National Clinical Research Center for Digestive Diseases(China)(No.2015BAl13B07)the Shaanxi Provincial Outstanding Youth Fund(China)(No.2024JC-JCQN-77)the Fund for Scientific and Technological Innovation Team of Shaanxi Innovation Capability Support Plan(China)(No.2023-CX-TD-67).
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