title: B7-H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting interleukin-6/signal transducer and activator of transcription 3 pathway activation.
abstract: B7-H4, one of the costimulatory molecules of the B7 family, has been found to be widely expressed in many kinds of tumor tissues and to play an important part in tumor progression and poor prognosis. However, the role of B7-H4 in esophageal squamous cell carcinoma (ESCC) cells has not been elucidated. In this study, we found that, compared with normal esophageal tissue, B7-H4 was highly expressed in three ESCC cell lines, Eca109, TE1, and TE13. B7-H4 silenced cells suppressed cellular proliferation and colony formation. Additionally, compared with control cells, B7-H4 silenced cells showed higher apoptosis rates, Bcl-2 and Survivin upregulation, and BAX downregulation. Further study revealed that B7-H4 silenced cells also showed reduction in interleukin-6 (IL-6) secretion, signal transducer and activator of transcription 3 (STAT3) activation, and p-STAT3 translocation from cytoplasm to nucleus. Moreover, B7-H4 depletion inhibited the IL-6 secretion of control cells but not JAK2/STAT3 inhibitor FLLL32-treated cells. Interleukin-6 receptor antagonist tocilizumab did not block the p-JAK2 or p-STAT3 downregulation induced by B7-H4 silence. It was suggested that B7-H4 silence suppressed IL-6 secretion through JAK2/STAT3 inactivation. Furthermore, cell proliferation and colony formation were downregulated by tocilizumab in control cells but not in B7-H4 silenced cells, indicating that IL-6 upregulation induced by B7-H4 was necessary for cell growth. On the other hand, B7-H4 expression was downregulated by tocilizumab. In all, our study provided the first evidence that B7-H4 facilitated ESCC cell proliferation through promoting IL-6/STAT3 positive loopback pathway activation.
authors.affiliation: Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Chen
authors.affiliation: Hebei Cancer Research Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.|Clinical Laboratory, Hebei General Hospital, Shijiazhuang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Lianmei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.|Hebei Cancer Research Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Baoen
authors.initials: B
authors.lastname: Shan
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D053614:Janus Kinase 2; C502936:tocilizumab
keywords: Apoptosis; B7-H4; IL-6/STAT3 signal pathway; cell proliferation; esophageal squamous cell carcinoma